Guideline sources The following summarized guidelines for the evaluation and management of nasopharyngeal cancer (NPC) are prepared by our editorial team based on guidelines from the Spanish Group for the Treatment of Head and Neck Tumors (TTCC/SEOM 2022), the American Society of Clinical Oncology (ASCO 2022; 2018), the European Reference Network on Rare Adult Solid Cancers (EURACAN/ESMO 2022; 2021), the Chinese Society of Clinical Oncology (CSCO/ASCO 2021), the American College of Radiology (ACR 2019; 2016), the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF 2017), the United Kingdom National Multidisciplinary Guidelines (UKNMG 2016), and the American Cancer Society (ACS 2016). 1 2 3 4 5 6 7 8 9 10 11 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s TNM class Guidelines https://web.pathway.md/diseases/recubEPRTwTSdycBk 1/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway 1. Screening and diagnosis Indications for screening: As per SEOM 2022 guidelines, consider obtaining plasma EBV deoxyRNA with a primer/probe assay targeting the BamHI-W region of the EBV genome (carried out in duplicate, at least 4 weeks apart), coupled with endoscopic examination and MRI, for detecting early asymptomatic NPC in individuals at higher risk (males aged 40-62 years) in endemic areas. B As per ESMO 2021 guidelines, consider obtaining plasma EBV deoxyRNA, coupled with endoscopic examination and MRI, for early detection of asymptomatic NPC in endemic regions. B 2. Diagnostic investigations History and physical examination: As per ESMO 2021 guidelines, elicit medical history and perform a physical examination with cranial nerve examination in the initial evaluation and staging of patients with NPC. E Show 2 more As per AAO-HNSF 2017 guidelines, elicit an initial history and perform a physical examination in adult patients with a neck mass to identify suspicious findings representing an increased risk for malignancy. B Show 4 more Audiometry: obtain baseline audiometric testing as appropriate. E Baseline laboratory tests: Obtain a CBC, and serum biochemistry (including liver and renal function tests and LDH) for the routine staging of patients with NPC. E Obtain baseline endocrine evaluation as appropriate. E Epstein-Barr virus deoxyribonucleic acid: As per SEOM 2022 guidelines, consider measuring pretreatment levels of plasma EBV deoxyRNA for prognostic purposes. C As per ESMO 2022 guidelines, measure pre- and post-treatment plasma/serum load of EBV deoxyRNA for prognosis. B Diagnostic imaging: As per ACR 2019 guidelines: Obtain contrast-enhanced neck CT or MRI for the initial imaging of nonpulsatile neck masses (not in the parotid region or thyroid). B Obtain contrast-enhanced neck CT or MRI or neck ultrasound for the initial imaging of neck masses (not in the parotid region or thyroid) in pediatric patients. B As per AAO-HNSF 2017 guidelines, obtain contrast-enhanced neck CT (or MRI) in patients with a neck mass deemed at increased risk for malignancy. B https://web.pathway.md/diseases/recubEPRTwTSdycBk 2/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway Imaging for staging: As per SEOM 2022 guidelines: Obtain MRI of the nasopharynx, skull base, and neck to assess locoregional disease extent. B Obtain additional imaging with positron emission tomography or CT-positron emission tomography imaging if available in patients with an advanced nodal stage (N3) or clinical or biochemical evidence of distant metastases; otherwise, consider obtaining CT of the chest and abdomen and a bone scan. B As per ESMO 2021 guidelines: Obtain MRI to define local and nodal tumor staging. B Obtain FDG-positron emission tomography to add further accuracy in nodal staging, as well as in locally advanced disease and for detecting distant metastases. B As per UKNMG 2016 guidelines, obtain multislice CT of the head, neck, and chest in all patients and MRI where appropriate to optimize staging. B 3. Diagnostic procedures Nasopharyngoscopy: As per ESMO 2021 guidelines, obtain nasopharyngoscopy for the routine staging of patients with NPC. E As per UKNMG 2016 guidelines, obtain rigid or fiberoptic nasendoscopy for the assessment of patients with NPC. B Fine-needle aspiration: Perform FNA instead of open biopsy in patients with a neck mass of uncertain diagnosis deemed at increased risk for malignancy. B Continue evaluating patients with a cystic neck mass, as determined by FNA or imaging, until a diagnosis is obtained instead of assuming that the mass is benign. B Tumor biopsy: As per ESMO 2021 guidelines: Perform an endoscopy-guided biopsy of the primary tumor for a definitive diagnosis of NPC. B Avoid performing diagnostic neck biopsy and/or neck nodal dissection. As per AAO-HNSF 2017 guidelines, evaluate the upper aerodigestive tract under anesthesia before performing an open biopsy in patients with a neck mass deemed at increased risk for malignancy and without a diagnosis or primary site identified with FNA, imaging, and/or ancillary tests. B As per UKNMG 2016 guidelines, perform nasopharyngeal biopsies preferably with endoscopic guidance. B Ancillary testing: https://web.pathway.md/diseases/recubEPRTwTSdycBk 3/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway As per ASCO 2022 guidelines: Obtain PD-L1 immunohistochemistry testing in patients with recurrent or metastatic head and neck SCC. Interpret PD-L1 CPS 1 as positive, recognizing that it correlates with a clinical benefit to PD-L1 inhibitors. A Consider obtaining tumor mutational burden testing in patients with recurrent or metastatic head and neck SCC when CPS is unavailable or in patients with rare tumors. Interpret tumor mutational burden 10 as high, recognizing that it correlates with a clinical benefit to PD-L1 inhibitors. B As per ESMO 2021 guidelines, obtain in situ hybridization to detect EBV on the histological specimen. B As per ASCO 2018 guidelines, do not obtain routine high-risk HPV testing in patients with non- oropharyngeal primary tumors of the head and neck. D 4. Medical management Management of local/locoregional disease, radiotherapy, indications: As per ASCO/CSCO 2021 guidelines: Offer intensity-modulated radiotherapy with daily image guidance in all patients with NPC. A Consider offering both sequential boost and simultaneous integrated boost radiotherapy in all patients with NPC. C As per EURACAN/ESMO 2021 guidelines: Offer radiotherapy alone in patients with stage I-II disease. Offer this approach in patients with stage II disease only if intensity-modulated radiotherapy is adopted. B Offer radiotherapy targeted according to the primary tumor, pathological nodes, and adjacent regions considered at risk of microscopic spread from the tumor, and generally to both sides of the neck (levels II-V and retropharyngeal nodes). As per UKNMG 2016 guidelines: Offer radiotherapy as the mainstay for radical treatment of NPC. B Offer intensity-modulated radiotherapy as the treatment of choice in patients with stage I-II disease. B Management of local/locoregional disease (radiotherapy, target delineation): obtain careful delineation of the gross tumor volume in all patients with NPC. Obtain MRI image fusion with CT for target delineation, especially to appreciate the potential tumor extension at the skull base and rule out or confirm the presence of cranial nerve involvement and/or intracranial extension. B Show 2 more Management of local/locoregional disease, radiotherapy, dosing: As per TTCC/SEOM 2022 guidelines, administer 70 Gy in 33-35 fractions (2.0-2.12 Gy per fraction) over 7 weeks (once daily, 5 fractions per week) in the primary tumor and affected lymph node areas and 50-60 Gy for the treatment of potential at-risk sites. A https://web.pathway.md/diseases/recubEPRTwTSdycBk 4/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway As per ASCO/CSCO 2021 guidelines, administer 70 Gy in 33-35 fractions (2.0-2.12 Gy per fraction) over 7 weeks (once daily, 5 fractions per week) in all patients with NPC. Consider adjusting radiation dose according to tumor volume and its response to chemoradiotherapy. A As per EURACAN/ESMO 2021 guidelines, administer a total dose of 70 Gy for the eradication of macroscopic disease and 50-60 Gy for the treatment of potential at-risk sites. E Management of local/locoregional disease, induction chemotherapy: As per TTCC/SEOM 2022 guidelines, offer induction chemotherapy for improved distant relapse-free survival and consequently overall survival in patients with locally advanced nasopharyngeal carcinoma at high risk of developing metastases (non-keratinizing histology, significant lymph node involvement, very fast-growing tumors). Offer induction chemotherapy with cisplatin and gemcitabine followed by chemoradiotherapy for improved recurrence-free survival, distant recurrence-free survival, and overall survival. A As per ASCO/CSCO 2021 guidelines, offer induction chemotherapy in addition to concurrent chemoradiotherapy in patients with stage III-IVA (except T3N0) disease. A Show 3 more As per EURACAN/ESMO 2021 guidelines, offer induction chemotherapy with cisplatin and gemcitabine followed by chemoradiotherapy for improved recurrence-free survival, overall survival, and distant recurrence-free survival in patients with locally advanced NPC. A Management of local/locoregional disease, concurrent chemoradiotherapy: As per ESMO/EURACAN 2022 guidelines, consider adding metronomic or standard dose adjuvant capecitabine to chemoradiotherapy in patients with high-risk locoregionally advanced nasopharyngeal carcinoma. C As per TTCC/SEOM 2022 guidelines, offer chemoradiotherapy with cisplatin 30 mg/m /week and conventional radiotherapy for improved overall survival, progression-free survival, and distant metastases-free survival. B Show 3 more As per ASCO/CSCO 2021 guidelines, consider offering chemotherapy in patients with stage T2N0 disease if there are adverse features, such as bulky tumor volumes or high EBV deoxyRNA load. C Show 7 more As per EURACAN/ESMO 2021 guidelines: Offer chemoradiotherapy in patients with stage III-IVA disease. Offer cisplatin 100 mg/m every 3 weeks, A or 40 mg/m every week, B concomitantly to radiotherapy, with the optimal cumulative total dose of > 200 mg/m . B Consider offering concurrent nedaplatin as an alternative to cisplatin. B Intensify the systemic treatment in patients with stage III-IVA non-keratinizing NPC. E As per UKNMG 2016 guidelines, offer concurrent chemotherapy with radiotherapy as the treatment of choice in patients with stage III-IV disease. B Management of local/locoregional disease, adjuvant chemotherapy: https://web.pathway.md/diseases/recubEPRTwTSdycBk 5/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway As per ASCO/CSCO 2021 guidelines, consider offering adjuvant chemotherapy in patients with T3N0 disease. C Show 3 more As per ACR 2016 guidelines, consider offering adjuvant chemotherapy in patients with locally advanced NPC with poor tolerance to initial concurrent therapy, provided it can be administered in a timely manner and they have a good recovery from their toxicity. E Management of local/locoregional disease (surgery): offer surgery only for obtaining tissue for diagnosis and for the management of otitis media with effusion. B Management of metastatic disease: As per ASCO 2022 guidelines, offer toripalimab, camrelizumab, or tislelizumab, with gemcitabine and cisplatin, as first-line therapy in patients with metastatic NPC. A Consider offering pembrolizumab or nivolumab, with gemcitabine and cisplatin, if the previous agents are unavailable. Show 4 more As per ESMO 2022 guidelines, consider adding immunotherapy (camrelizumab or toripalimab) to cisplatin and gemcitabine and as maintenance as first-line therapy in patients with advanced and metastatic disease. B As per ESMO 2021 guidelines, consider offering palliative chemotherapy with a combination of cisplatin and gemcitabine in patients with metastatic NPC with adequate performance status. B Show 3 more As per ACR 2016 guidelines: Consider offering definitive concurrent chemoradiation to the primary site and definitive radiation (or stereotactic radiotherapy) to the metastatic bone disease for lengthy progression- free survival in patients with NPC presenting with an isolated bone focus of metastatic disease. E Offer a platinum doublet as the standard systemic regimen in patients with metastatic NPC. E Management of persistent/recurrent disease: As per ASCO 2022 guidelines, offer toripalimab, camrelizumab, or tislelizumab, with gemcitabine and cisplatin, as first-line therapy in patients with recurrent NPC. A Consider offering pembrolizumab or nivolumab, with gemcitabine and cisplatin, if the previous agents are unavailable. Show 3 more As per SEOM 2022 guidelines, offer local treatment in patients with locoregional recurrences. B Show 2 more As per ESMO 2021 guidelines, consider offering a personalized approach with non-cross- resistant drugs or participation in clinical trials in patients with persistently high EBV deoxyRNA levels after definitive treatment. C Show 3 more https://web.pathway.md/diseases/recubEPRTwTSdycBk 6/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway As per ACR 2016 guidelines, offer nasopharyngectomy, stereotactic radiotherapy, and intensity- modulated radiotherapy (with or without concurrent chemotherapy with a platinum doublet) for the management of locally recurrent NPC in the absence of distant disease. E As per UKNMG 2016 guidelines, consider offering nasopharyngectomy as a first-line treatment of residual or recurrent disease at the primary site. C Show 2 more 5. Follow-up and surveillance Serial clinical assessment: As per SEOM 2022 guidelines, perform periodic examinations (every 3 months in the first year, every 6 months in the second and third year, and annually thereafter for the first 5 years) of the nasopharynx (with fiberoptic endoscopy), neck, and cranial nerve function, and assess systemic complaints to identify distant metastasis. B As per ESMO 2021 guidelines, perform periodic examinations of the nasopharynx, neck, and cranial nerve function, and assessment of systemic complaints to identify distant metastasis. B As per ACS 2016 guidelines, educate and counsel all head and neck cancer survivors about the signs and symptoms of local recurrence. B Show 4 more As per UKNMG 2016 guidelines, obtain follow-up nasendoscopy in patients with NPC. E Serial imaging assessment: As per SEOM 2022 guidelines, obtain an FDG-positron emission tomography/CT and/or MRI 2- 3 months after treatment. B Show 2 more As per ESMO 2021 guidelines: Consider obtaining the first radiological imaging 3 months after the completion of curative treatment. Recognize that the sensitivities of MRI and positron emission tomography are similar, whereas the specificity of positron emission tomography is higher and so helps to differentiate between post-irradiation changes and recurrent tumors. C Consider obtaining MRI on a 6-monthly basis for at least the first 3 years after treatment in patients with T2-T4 tumors. C As per UKNMG 2016 guidelines: Obtain positron emission tomography-CT or MRI for the assessment of treatment respince after 3 months of treatment completion. B Obtain multislice CT of the head, neck, and chest and MRI whenever possible in patients with suspected recurrence. B Serial laboratory assessment: As per SEOM 2022 guidelines: Obtain annual evaluation of thyroid function in patients received radiotherapy to the neck. B https://web.pathway.md/diseases/recubEPRTwTSdycBk 7/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway Consider assessing plasma EBV deoxyRNA levels at least annually C for the diagnosis of recurrence. C As per ESMO 2021 guidelines, obtain annual evaluation of thyroid function in patients treated with radiotherapy to the neck region. Obtain pituitary function evaluation according to signs/symptoms. B Surveillance for other cancers: do not focus long-term follow-up on the detection of second neoplasms as patients with NPC have a lower risk of second neoplasms than other tobacco- related head and neck sites. D Survivorship and rehabilitation (lifestyle modifications): advise achieving and maintaining a healthy weight in head and neck cancer survivors, B including offering nutrition strategies to maintain a healthy weight if at risk for cachexia. B Advise limiting consumption of high-calorie foods and beverages and increase physical activity to promote and maintain weight loss if overweight or obese. A Show 4 more Survivorship and rehabilitation (neuromuscular complications): refer patients with spinal accessory nerve palsy occurring after radical neck dissection to a rehabilitation specialist to improve their ROM and ability to perform daily tasks. A Show 3 more Survivorship and rehabilitation (neurosensory complications): Refer patients with altered or loss of taste to a registered dietitian for dietary counseling and assistance in additional seasoning of food, avoiding unpleasant food, and expanding dietary options. B Refer patients to appropriate specialists (audiologists) for loss of hearing, vertigo, or vestibular neuropathy related to treatment. B Survivorship and rehabilitation (speech disturbance): assess patients for speech disturbance B and refer to an experienced speech-language pathologist if a communication disorder is present. B Survivorship and rehabilitation (oral and dental care): advise maintaining regular dental care, including frequent visits to dental professionals, early interventions for dental complications, and meticulous oral hygiene. Test fitting dentures to ensure proper fit and advise removing them at night to avoid irritation. B Show 9 more Survivorship and rehabilitation (gastroesophageal complications): refer patients with complaints of dysphagia, postprandial cough, unexplained weight loss, or pneumonia to an experienced speech-language pathologist for instrumental evaluation of swallowing function to assess and manage dysphagia and possible aspiration. Recognize the potential for psychosocial barriers to swallowing recovery and refer to an appropriate clinician if barriers are present. Refer patients to a speech-language pathologist for videofluoroscopy as the first-line test in patients with suspected stricture due to the high degree of coexisting physiologic dysphagia. B Show 2 more https://web.pathway.md/diseases/recubEPRTwTSdycBk 8/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway Survivorship and rehabilitation (thyroid dysfunction): measure TSH every 6-12 months to monitor thyroid function in head and neck cancer survivors. B Survivorship and rehabilitation (lymphedema): use the National Cancer Institute Common Toxicity Criteria for Adverse Events v.4.03 or refer for endoscopic evaluation of mucosal edema of the oropharynx and larynx, tape measurements, ultrasound, or external photographs for the assessment of lymphedema. Refer patients to a rehabilitation specialist for treatment consisting of manual lymphatic drainage and, if tolerated, compressive bandaging. B Survivorship and rehabilitation (fatigue): Assess for fatigue and treat any causative factors, including anemia, thyroid dysfunction, and cardiac dysfunction. B Offer treatment for factors that may impact fatigue, such as mood disorders, sleep disturbance, and pain, in patients without an otherwise identifiable cause of fatigue. A Advise regular physical activity and offer CBT as appropriate. A Survivorship and rehabilitation (sleep disorders): ask patients and their partners about snoring and symptoms of sleep apnea to screen for sleep disturbance. Refer patients with suspected sleep apnea to a sleep specialist for a sleep study (polysomnography). B Show 2 more Survivorship and rehabilitation (psychosocial distress): assess head and neck cancer survivors for body and self-image concerns. Refer for psychosocial care as indicated. A Show 3 more Clinical findings Patient demographics Symptoms Native Eskimo Diplopia Southern Chinese Dysphagia Facial numbness Past medical history Facial pain Headache Bone metastasis Hearing loss Chronic rhinosinusitis Nasal congestion EBV infection Nasal discharge Lung metastasis Nasal obstruction Otitis media with effusion Nosebleed Social history Tinnitus Exposure to dust Medication history Preserved food consumption Herbal supplements Tobacco use Neurological exam Head and neck exam https://web.pathway.md/diseases/recubEPRTwTSdycBk 9/10 6/30/23, 1:14 AM Nasopharyngeal cancer Pathway Conductive hearing loss Cranial nerve palsy Neck mass Speech disturbance Lab findings Lymphatic exam EBV deoxyRNA Cervical lymphadenopathy References 1. Antonio Rueda Dom nguez, Beatriz Cirauqui, Almudena Garc a Casta o et al. SEOM TTCC clinical guideline in nasopharynx cancer 2021 . Clin Transl Oncol. 2022 Apr;24 4 670 680. Open 2. R Simo, M Robinson, M Lei et al. Nasopharyngeal carcinoma: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016 May;130 S2 S97 S103. Open 3. Yu-Pei Chen, Nofisat Ismaila, Melvin L K Chua et al. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. J Clin Oncol. 2021 Mar 1;39 7 840 859. Open 4. P Bossi, A T Chan, L Licitra et al. Nasopharyngeal carcinoma: ESMO EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Apr;32 4 452 465. Open 5. Nabil F Saba, Joseph K Salama, Jonathan J Beitler et al. ACR Appropriateness criteria for nasopharyngeal carcinoma. Head Neck. 2016 Jul;38 7 979 86. Open 6. Melissa A Pynnonen, M Boyd Gillespie, Benjamin Roman et al. Clinical Practice Guideline: Evaluation of the Neck Mass in Adults. Otolaryngol Head Neck Surg. 2017 Sep;157 2_suppl):S1 S30. Open 7. Ezra E W Cohen, Samuel J LaMonte, Nicole L Erb et al. American Cancer Society Head and Neck Cancer Survivorship Care Guideline. CA Cancer J Clin. 2016 May;66 3 203 39. Open 8. Expert Panel on Neurologic Imaging:, Joseph M Aulino, Claudia F E Kirsch et al. ACR Appropriateness Criteria Neck Mass-Adenopathy. J Am Coll Radiol. 2019 May;16 5S S150 S160. Open 9. Emrullah Yilmaz, Nofisat Ismaila, Julie E Bauman et al. Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline. J Clin Oncol. 2023 Feb 10;41 5 1132 1146. Open 10. Carole Fakhry, Christina Lacchetti, Lisa M Rooper 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 Nov 1;36 31 3152 3161. Open 11. P Bossi, A T Chan, C Even et al. ESMO EURACAN Clinical Practice Guideline update for nasopharyngeal carcinoma: adjuvant therapy and first-line treatment of recurrent/metastatic disease. Ann Oncol. 2022 Dec 15;S0923 7534 22 04759 7. Open 12. Ellie Maghami, Nofisat Ismaila, Adriana Alvarez et al. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline. J Clin Oncol. 2020 Aug 1;38 22 2570 2596. Open 13. Maria K. Gule-Monroe, MDa, Susana Calle et al. ACR Appropriateness Criteria Staging and Post- Therapy Assessment of Head and Neck Cancer. ACR. 2023. Open https://web.pathway.md/diseases/recubEPRTwTSdycBk 10/10