SEOM clinical guideline in nasopharynx cancer (2017)

Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. Radiation therapy is an essential component of curative-intent of non-disseminated disease and the association of chemotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum/gemcitabine-based chemotherapy and patients may achieve a long survival time.

# Introduction
Nasopharyngeal carcinoma (NPC) is distinct from other cancers of the head and neck in biology, epidemiology, histology, natural history, and response to treatment. These differences justify a different approach.
NPC is an unusual tumor in our country. In Europe, in 2012 the rate of incidence was 0.4 cases/100,000/year (in Spain, 0.5 cases/100,000/year). The incidence of NPC is two to threefold higher in males compared with females. NPC displays a distinct racial and geographic distribution, which is reflective of its multifactorial etiology. In endemic populations, risk appears to be due to an interaction of

## Diagnosis pathological diagnosis
A definitive diagnosis is made by endoscope-guided biopsy of the primary tumor. Incisional neck biopsy or nodal dissection should be avoided as this procedure will negatively impact in the subsequent treatment.
The pathological diagnosis of NPC should be made according to the World Health Organization (WHO) classification. Basaloid squamous cell carcinoma was added to the WHO classification in 2005; there are few reported cases but these have an aggressive clinical course and poor survival.
For nonkeratinizing or undifferentiated histology, consider testing for EBV in tumor and blood. Common means for detecting EBV in pathologic specimens include in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemically staining for latent membrane protein (LMP) . The EBV DNA load within the serum or plasma may be quantified using polymerase chain reaction (PCR) targeting genomic sequences of the EBV DNA such as BamHI-W, EBNA, or LMP; these tests vary in their sensitivity[IIA].

## Diagnosis and staging
The study should include: In pathologic specimens include EBER or LMP [IA].
(g) Nutritional and dental status assessment [bib_ref] Nutrition impact symptoms: Key determinants of reduced dietary intake, weight loss, and..., Kubrak [/bib_ref] [bib_ref] Impact of radiotherapy dose on dentition breakdown in head and neck cancer..., Walker [/bib_ref].
Staging TNM classification has been modified in the 8th edition, 2017. There are two changes in nasopharynx T classifications relating to anatomic markers rather than depth of invasion. The previous T4 criteria ''masticator space'' and ''infratemporal fossa'' were used as synonyms, but their anatomic descriptions differ, sowing confusion among clinicians. These terms will now be replaced by a specific description of soft-tissue involvement to avoid ambiguity. In addition, adjacent muscle involvement (including medial pterygoid, lateral pterygoid, and prevertebral muscles) will now be ''down-staged'' to T2 based on a recent analysis showing them to have a more favorable outcome using current treatment.
In the N classification of nasopharynx, the iconic, traditional description of the supraclavicular fossa that was unique to this site will be replaced by contemporary definitions used for other head and neck sites and more suited to axial cross-sectional imaging. In addition, low neck involvement and [ 6 cm size will be merged into a single N3 designation (formerly N3a and N3b), and T4 and N3 will both designate stage IVA (formerly IVA and IVB) in stage grouping [fig_ref] Table 3: TNM staging classification [/fig_ref].

## Treatment
Radiation therapy (RT) is the mainstay of treatment and is an essential component of curative-intent treatment of nondisseminated NPC. Surgery has no role in the initial : tumor confined to the nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal extension T2: tumor with extension to parapharyngeal space and/or infiltration of the medial pterygoid, lateral pterygoid, and/or prevertebral muscles T3: tumor invades bony structures of skull base cervical vertebra, pterygoid structures, and/or paranasal sinuses T4: tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, parotid gland and/or infiltration beyond the lateral surface of the lateral pterygoid muscle Regional lymph nodes (N) NX: regional lymph nodes cannot be assessed N0: no regional lymph nodes metastasis N1: unilateral metastasis, in cervical lymph node(s), and/or unilateral, or bilateral metastasis in retropharyngeal lymph nodes, 6 cm or less, above the caudal border of cricoid cartilage The techniques of 3D planning and intensity-modulated radiation therapy (IMRT) can improve outcomes without worsening toxicity and can offer a better protection of the different organs in the area that usually limit the dose of radiation that can be given (the use of IMRT can reduce the xerostomy frequently seen with the irradiation of the salivary glands) [IIA].

## Treatment of early stages (i and ii)
The treatment for early stage tumors is RT, including both sides of the neck and retropharyngeal nodes. The dose should be 66-70 Gy to the primary tumor and affected lymph nodes areas, and 50 Gy to the uninvolved neck. In patients treated with IMRT alone, 5-year distant-metastases-free survival rate is 92-94% [bib_ref] Evolution of treatment for nasopharyngeal cancer-success and setback in the intensitymodulated radiotherapy..., Lee [/bib_ref] [IA].
Given the significant toxicities of concurrent chemoradiotherapy (CT/RT) and the generally excellent prognosis of stage II nasopharyngeal cancer with IMRT, the role of administering chemotherapy (CT) concurrently with radiation in all stage II patients remains to be clearly defined, although consideration on individual bases should be made based on risk factors such as significant nodal disease, parapharyngeal tumor extension, and plasma EBV level [bib_ref] Improvement of survival after addition of induction chemotherapy to radiotherapy in patients..., Chua [/bib_ref] [IIB].

## Treatment of locally advanced stage (iii and iv a/b)
Concurrent CT/RT is the standard treatment for locoregionally advanced nasopharyngeal carcinoma (with CDDP at 100 mg/m2 every 21 days) substantially improved locoregional control compared with exclusive RT, but distant metastasis is the main source of treatment failure [bib_ref] What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual..., Ribassin-Majed [/bib_ref] [IA].
Additional cycles of CT (with induction or adjuvant chemotherapy) could improve results and increases failurefree survival, overall survival, and distant failure-free survival with acceptable toxicity profile but its role is uncertain .
A high rate of toxicity that usually leads to a low percentage of patients that are able to complete the adjuvant treatment and compliance is a significant problem with only about 50-75% of patients who were initially planned for adjuvant chemotherapy receiving the three planned cycles. Induction CT could avoid this problem [bib_ref] Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized..., Al-Sarraf [/bib_ref] [bib_ref] Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally..., Lee [/bib_ref] [IIA].
The use of one or another should be tailored according to the patient's clinical condition (ex, CT induction in highly symptomatic patients, adjuvant therapy to the rest). In patients with good general condition, TPF induction CT should be an option to be considered problem [bib_ref] Improvement of survival after addition of induction chemotherapy to radiotherapy in patients..., Chua [/bib_ref] [bib_ref] Neoadjuvant chemotherapy followed by concurrent chemoradiation for locally advanced nasopharyngeal carcinoma, Kong [/bib_ref] [bib_ref] Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced..., Sun [/bib_ref] [IIB].
When there is persistent cervical disease after standard CT/RT treatment, cervical rescue surgery should be performed. In cases with large cervical disease (N3), irrespective of the response to CT/RT, its systematic use could be considered. This could be especially relevant in cases with WHO type 1 histology WHO. However, the morbidity of this approach can be substantial and it has not been generally accepted. There are no studies to clarify this point definitively .

## Recurrent and metastatic disease treatment (rm-npscc) (iv c)
In the setting of local and/or regional relapse, the multidisciplinary team should assess the possibility of salvage local therapy, whether by surgery or re-irradiation, with or without CT. These approaches can rescue a small percentage of cases, albeit at the cost of high toxicity. The election of one or another approach has not been well established [bib_ref] Salvage treatment for locally recurrent nasopharyngeal carcinoma (NPC), Chen [/bib_ref]. The best results have been achieved when the previous interval free of disease is longer. If loco-regional relapse of NPSCC occurs, local treatment with surgery and/or chemo-radiotherapy is recommended .
When salvage treatment is not feasible or the patient develops a metastatic disease, the treatment of choice is palliative CT. A wide range of chemotherapy drugs has been tested mainly in retrospective and small phase II trials such as: platinum compounds (cisplatin, carboplatin), fluoropirimidines (5-fluorouracil, capecitabine), taxanes (paclitaxel, docetaxel), gemcitabine, anthracyclines, irinotecan and vinorelbine. Traditionally, the most used schedules included platinum-based combinations, mainly with 5-FU, with responses rates between 50 and 70% in retrospective uncontrolled studies [bib_ref] Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx. A review of..., Choo [/bib_ref] [bib_ref] Combined chemotherapy for recurrent and metastatic nasopharyngeal carcinoma, Airoldi [/bib_ref] [bib_ref] Excellent response to cis-platinum-based chemotherapy in patients with recurrent or previously untreated..., Al-Kourainy [/bib_ref].
A recent phase III randomized trial comparing cisplatin-5-FU with cisplatin-gemcitabine in 362 patients, showed a significant advantage in terms of progression-free survival in the gemcitabine-based cohort. Owing to no other phase III trials in this setting, this schedule has become the new standard first line approach in RM-NPC [bib_ref] Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal..., Zhang [/bib_ref]. Cisplatingemcitabine is the first choice as first line palliative CT treatment in RM-NPSCC [IA].
To date, there is not an established standard treatment after the failure of the first line. If the patient has a good performance status, any of the previously reported active drugs could be considered but the inclusion in clinical trials should be encouraged.
Follow-up [fig_ref] Table 5: Follow-up of nasopharyngeal carcinoma [/fig_ref] Evaluation of response in the nasopharynx and neck should be performed through clinical, endoscopic examination and imaging studies (18FDG-PET/CT scan or MR). A final assessment of the disease is recommended to be undertaken at 3 months after the end of the treatment to confirm the complete remission. MR is often preferred to evaluate the response to RT or chemo-radiotherapy, especially for T3 and T4 tumors, though distinction between post-irradiation changes and recurrent tumors may be difficult.
Sometimes early detection of possible relapses could be managed with salvage treatment. Follow-up of the patients include periodic examination of the nasopharynx, neck, cranial nerve function and evaluation of systemic complaints to identify distant metastasis. Clinical exam and fibroscopy every three to 4 months during the first 2 years, then every 6 months until 5 years, then yearly should be followed. For T3 and T4 tumors, MR might be used on a 6-to 12-month basis to evaluate the nasopharynx and the base of the skull at least for the first few years after treatment. Thyroid function tests (if neck irradiated) and thoracic imaging test should be carried out at least once a year [bib_ref] Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Chan [/bib_ref].

## 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 performed by any of the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Final assessment (2-3 months after the end of treatment) Local and regional exam plus nasopharyngeal fibroscopy FDG-PET/CT and/or RMI First two years Local and regional exam plus nasopharyngeal fibroscopy (every 3 to 4 months) Chest X-ray, thyroid function test, CT/MRI (yearly)
Two to five years Local and regional exam plus nasopharyngeal fibroscopy (every 6 months)
Chest X-ray, thyroid function test, CT/MRI (yearly)
[fig] -: Cranialcervical computed tomography (CT) scan or magnetic resonance (MR) scan. Chestabdomenpelvis CT scan. Bone scan. Positron emission tomographyCT (PETCT). CT and MR can be complementary in this regard: CT is superior for the study of bony structures and for the presence of cervical lymph nodes, while the MR provides a better assessment of the primary tumor location and of intracranial structures and retropharyngeal spaces. PET scan may assist in the accurate planning of radiotherapy treatment (RT). PETCT scan can replace the traditional workup for detection of distant metastatic disease [4] [IIIA]. (f) Special pathologic studies: Consider EBV/DNA testing [IIIB]. [/fig]
[table] Table 1: Strength of recommendation and quality of evidence score [/table]
[table] Table 3: TNM staging classification (AJCC Cancer Staging Manual, 8th; 2017) TX primary tumor cannot be assessed T0 no tumor identified, but EBV-positive cervical node(s) involvement [/table]
[table] Table 5: Follow-up of nasopharyngeal carcinoma [/table]