systematic reviews involving human subjects (19+ years) and published in English. Although phase II studies may be referenced in the discussion section, only phase III randomized studies and metaanalyses were considered for the literature search and review. The ECRI Guidelines Trust and SAGE Directory of Cancer Guidelines were also searched from 2008 to May 2020 for guidelines on nasopharyngeal cancer.The recommendations outlined in this guideline are intended for adults over the age of 18 years with NPC. Different principles may apply to pediatric patients.The Alberta Provincial Head and Neck Tumour Team reviewed the recommendations of several different guidelines, including those from the European Society for Medical Oncology, 3 the Spanish Society of Medical Oncology 4 and the National Comprehensive Cancer Network. 5 The Alberta Provincial Head and Neck Tumour Team have adopted the recommendations of the ESMO and NCCN, with modifications to fit the Alberta context.# Background
The most recent Canadian cancer statistics suggest approximately 250 new cases of nasopharyngeal cancer (NPC) are identified in Canada each year, resulting in 90 deaths. 1 NPC arises from the lining of the nasopharynx, the narrow tubular passage behind the nasal cavity and although rare in North America, is common in Southern China, Southeast Asia, North Africa and the Arctic. Risk factors for NPC include, race (Asian, African or Inuit ancestry), sex (male), diet (salt-cured foods) and exposure to the Epstein-Barr virus. Some studies have reported that tobacco use may contribute to the development of NPC, however, this link is much weaker than the link between tobacco use and most other types of head and neck cancers.
Three types of NPC have been classified by the World Health Organization including, keratinizing squamous cell carcinoma, non-keratinizing differentiated carcinoma and undifferentiated carcinoma. In North America, as in endemic region, the undifferentiated subtype type is the most common 2. Although the different types of NPC exist, the treatment is usually the same and the stage of cancer is more important in predicting a person's prognosis than the type. NPC is staged according to the tumour node metastasis (TNM) system. For more information on the TNM classifications, along with anatomic stage/prognostic groups, please refer to Appendix A.
NPC is commonly treated with radiotherapy (RT) and chemotherapy. Surgery at the primary site is not often used as first-line treatment because of the anatomical location of the nasopharynx and its proximity to critical neurovascular structures. This guideline was developed to outline treatment recommendations for patients with NPC. These guidelines should be applied in the context of the recommendations outlined in Alberta Health Services, CancerControl Alberta guideline, The Organization and Delivery of Healthcare Services for Head and Neck Cancer Patients.
The 8 th edition of the AJCC staging system has been used for this guideline.

# Initial Work-Up and Supportive Care Evaluation
NPC is most often diagnosed when an individual goes to their physician with a lump in the neck. A complete head and neck examination is required to begin to diagnose NPC. Attention should be paid to the most common presenting symptoms including a neck mass, cervical lymphadenopathy and bilateral involvement. Epistaxis (nasal bleeding), nasal congestion, hearing loss, otitis media (middle ear infection) and headaches are also common symptoms. For individuals with suspected NPC, a more thorough examination of the nasopharynx by a specialist is needed. The diagnosis of NPC can only be confirmed with a tissue biopsy. Imaging studies using MRI with gadolinium and/or CT with contrast of the head and neck areas should be considered to evaluate the local and regional extent of disease. Consideration should be given to assess for metastatic disease (i.e. CT, bone scan, PET/CT etc.) based on extent of presenting disease and clinical/biochemical concerns. Dental evaluation is required in all patients who require radiation treatment, prior to the commencement of treatment to assess, restore or extract decayed teeth. Finally, nutritional counselling, speech and swallowing assessment/therapy and audiogram are critical to optimize quality of life during and after treatment. Patients should have access to Speech-Language Pathology during and after treatment, as clinically indicated.

# Treatment for Patients with Early-Stage NPC (T1, N0, M0)
For patients with early stage NPC, optimal outcomes can be expected employing RT alone. Guidelines published by the European Society for Clinical Oncology (ESMO), 3 National Comprehensive Cancer Network (NCCN) 5 and the Spanish Society of Medical Oncology (SEOM) 4 support this recommendation. Evidence suggests that the overall survival (OS) rate for patients with early stage NPC is approximately 80 percent to 90 percent with RT alone. 12 Although a survival benefit for chemoRT over RT alone was suggested in a subgroup analysis of two phase III trials, 13 patients with early stage NPC have largely been excluded from clinical trials using combined modality treatment, likely given the good treatment outcome after RT alone.
The consensus from the Alberta Provincial Head and Neck Tumour Team is that radiation doses of 66-70 Gy with 2.0-2.2 Gy/fraction over 6 to 7 weeks (daily, Monday to Friday) is needed for primary tumour treatment. For uninvolved nodal stations, a total dose of 54-60 Gy with 1.6-2.0 Gy/fraction is needed. Two randomized studies have shown that IMRT is superior to conventional RT techniques in preserving parotid function and resulted in less severe late xerostomia (dry mouth) without affecting local control in patients with early stage NPC.

# Treatment for Patients with Advanced-Stage NPC (T1, N1-3; T2-4 Any N)
Although patients with Stage I (so called early-stage NPC) have good outcomes with RT alone, more intensive treatment strategies are recommended to manage advanced-stage disease; RT alone for advanced-stage disease should be limited to individuals who would not be candidates for systemic therapy.

# Stage II (intermediate risk):
While SEOM 3 recommends RT alone for stage II (so called intermediate-stage NPC), both ESMO 3 and NCCN 5 recommend concurrent chemotherapy. In a randomized phase III trial, 230 patients with stage II NPC were randomly assigned to RT or concurrent chemoRT without adjuvant chemotherapy. Results showed that the addition of weekly cisplatin to RT significantly improved the 5-year OS rate (from 85.8 percent to 94.5 percent), progression-free survival (PFS) (from 77.8 percent to 87.9 percent) and distant metastasis-free survival (from 83.9 percent to 94.8 percent) 12. However the concurrent chemoRT arm experienced significantly more acute toxic effects, including leukopenia/neutropenia, nausea/vomiting and mucositis. Late toxic effects were similar between the two groups. Although this trial suggests a benefit from a concurrent chemoRT approach for stage II NPC patient, further randomized trials are warranted.

# Stage III/IV (high risk)
. ESMO, NCCN and SEOM all recommend concurrent chemoRT in patients with stage III and IV A-B NPC. The updated MAC-NPC meta-analysis by Blanchard et al. of chemotherapy as an adjunct to RT in locally advanced NPC (n=4806) found that the addition of chemotherapy to standard RT provides a small but significant survival benefit in patients with NPC 6. The pooled hazard ratio (HR) of death was 0.79 (95 percent confidence interval  0.73-0.86, p=0.006) corresponding to an absolute benefit of 6.3 percent at five years from chemotherapy compared to radiotherapy alone. A significant interaction was observed between chemotherapy timing and OS, with the highest benefit derived from concomitant chemotherapy with adjuvant chemotherapy (12.4% absolute difference (CI 6.8-18%).
Adjuvant chemotherapy following concurrent chemoRT. Several randomized phase III trials have investigated the efficacy of concurrent chemoRT with  or without 20 adjuvant chemotherapy. ChemoRT followed by adjuvant chemotherapy has been shown to increase overall survival and decrease local, regional and distant recurrence rates without a substantial increase in local toxicity.
In the landmark phase III randomized Intergroup study 099, 147 patients with stage III and IV NPC were treated with either chemoRT followed by adjuvant chemotherapy or RT alone. The study was closed and reported on early because the hazard ratio (HR) between the RT and combined arm was 3.28. The 3-year OS estimate for the combination arm was 76 percent versus 46 percent for the RT arm (p<0.001). The 3-year PFS estimate for the combination arm was 66 percent versus 26 percent for the RT arm (p<0.001). The chemotherapy regimen used in the Intergroup study is generally considered the standard. In the study, the investigational arm received chemotherapy with cisplatin (100 mg/m 2 on days 1, 22 and 43 during RT. Following RT, chemotherapy with cisplatin (80 mg/m 2 on day 1) and fluorouracil (5-FU) (1,000 mg/m 2 /d on days 1 to 4) was administered every 4 weeks for three cycles. 16 Alternative regimens that are easier to administer than cisplatin have also been investigated. In a prospective, randomized, non-inferiority, open trial comparing concurrent chemoRT with carboplatin to concurrent chemoRT with cisplatin in patients with locally advanced NPC (n=206), the toxicity and tolerability of the cisplatin containing regimen limited the number of patients who managed to complete the full course of treatment. In addition, there was no difference in terms of disease-free survival (DFS) and OS between the two regimens. 21 In a more recent phase III trial, patients with non-metastatic stage III or IV NPC were randomly assigned to concurrent chemoRT plus adjuvant chemotherapy or concurrent chemoRT alone (n=508). 22 Patients in both arms received cisplatin weekly (40 mg/m 2 up to 7 weeks with radiotherapy. The concurrent chemoRT plus adjuvant chemotherapy arm subsequently received adjuvant cisplatin (80 mg/m2) and 5-FU (800 mg/m2 per day) every 4 weeks for 3 cycles. After a median follow-up of 37.8 months, the estimated 2-year failure-free survival rate was 86 percent in the concurrent chemoRT plus adjuvant chemotherapy arm versus 84 percent in the concurrent chemoRT only group (HR=0.74, 95% CI 0.49-1.10, p=0.13). However, several limitations are noteworthy including a short follow-up period, the exclusion of T3-4N0 patients and the variability of RT techniques used.
Two meta-analyses involving over ten randomized trials of more than 2,500 patients with advanced NPC reported an absolute benefit on OS of 4-6 percent at 5 years with the use of chemotherapy. However, the survival benefit of the addition of chemotherapy was noted when chemotherapy was given concomitantly with radiotherapy. 6 In summary, the evidence suggests that concurrent chemoRT should be considered for all advancedstage patients; the addition of adjuvant chemotherapy should be based on the clinician's judgment, the patient's performance status and goals of therapy.

# Neoadjuvant (induction) chemotherapy.
Neoadjuvant chemotherapy alone prior to RT (i.e., without concurrent chemotherapy) is not routinely indicated for definitive treatment of locally advanced NPC when followed by RT. While the NCCN shows induction chemotherapy followed by chemoRT as a treatment option, there is major disagreement. 5 Trials of neoadjuvant chemotherapy in patients with locoregionally advanced NPC followed by RT alone have failed to show significant survival benefits compared to RT alone.  To evaluate the long-term outcome in patients with NPC treated with induction chemotherapy and RT versus RT alone, Chua et al. conducted a pooled data analysis of two phase III trials (n=784). 26 Although the addition of cisplatin-based induction chemotherapy to RT was associated with a decrease in relapse by 14.3 percent and cancer-related deaths by 12.9 percent at 5 years, there was no improvement in OS (61.9 percent vs. 58.1 percent, p=0.092) because of more frequent late intercurrent deaths in the induction chemotherapy and radiotherapy arm.
Another treatment option under study is sequential therapy with the administration of induction chemotherapy followed by concurrent chemoRT. Preliminary results from several recent phase III studies  have revealed promising improvements over chemoRT alone although no study to date has compared this strategy to chemoRT followed by adjuvant chemotherapy. There remains concern regarding toxicity from induction chemotherapy precluding pursuit of chemoRT (which remains the main contribution of benefit) in a significant proportion of individuals. Although there remains insufficient evidence to adopt as standard of care, this sequencing could be considered in select situations (i.e. for very advanced cancers for which radical RT not feasible due to dosing constraints).
Alternative RT schedules. Recent advances in radiobiology have allowed changes to conventional treatment modalities with the intention of achieving better locoregional control without increasing longterm toxicity. Increasing evidence exists that outcomes in head and neck squamous cell cancer may benefit from alternative fractionation schedules, including hyperfractionation and accelerated fractionation regimens. 27,28 A phase III trial randomized 189 patients with T3-4, N0-1, M0 NPC to one of four arms, accelerated versus conventional RT, with or without adjuvant chemotherapy. 29 All groups were given 2 Gy per fraction; the number of fractions per week was 5 in the conventional arms versus 6 in the accelerated arms. Patients assigned to chemoRT arms received concurrent cisplatin (100 mg/m 2 every 3 weeks for 3 cycles followed by adjuvant cisplatin (80 mg/m 2 plus 5-FU (1000 mg/m 2 /day) every 4 weeks for 3 cycles. The accelerated-fractionation RT plus concurrent-adjuvant chemotherapy arm achieved a significantly higher failure-free rate (88 percent at 5 years) than accelerated fractionation without chemotherapy (56 percent, p=0.001), or conventional fractionation with (65 percent, p=0.027) or without chemotherapy (63 percent, p=0.013). As compared with the conventional-fractionation RT alone arm, the increase in late toxicity was statistically insignificant (36 percent vs. 20 percent, p=0.25). Despite the favourable results, the authors note patients should be duly informed that the use of accelerated fractionation with chemotherapy currently remains experimental and vigilant follow-up is required if this therapy is selected.

# Treatment for Patients with Distant Metastatic Disease (Any T, Any N, M1)
Treatment failures in patients with locally advanced NPC are mainly distant metastasis, which develop in approximately 20 percent of patients. 30 For patients with distant metastasis, treatment is palliative in nature. RT can be administered to palliate symptoms. Participation in a clinical trial, if available, is the preferred treatment option. In metastatic NPC patients with good performance status, cisplatin-containing regimens are accepted as the standard with cis/gem preferred given advantages seen when compared to Cis/FU. 11  Other active agents include taxanes, gemcitabine, oxaliplatin, vinorelbine, irinotecan, capecitabine, methotrexate and anthracyclines. Targeted therapies (cetuximab, sorafenib, erotinib, gefitinib) and immunotherapies have been studied, but their role is currently investigational. 34 Referral to palliative care programs should be considered early on in the patient's care to help relieve suffering and improve quality of life. Speech-Language Pathologists should participate in the palliation of dysphagia. Clinical and instrumental assessment can be provided as necessary. Management of aspiration should take into account patient's wishes and informed choice, as well as their tolerance of aspiration.

# Treatment for Patients with Recurrent or Persistent Disease
Patients with recurrent or persistent NPC should be restaged after primary treatment to assess local, regional and distant disease. PET can detect head and neck tumour recurrence when it may be undetectable by other clinical methods. 35 As clinically indicated a confirmatory needle biopsy of the area in question is recommended. Treatment should be individualized based on patient performance status and extent of disease. According to Lee et al. 36 treatment options include salvage nasopharyngectomy, or re-irradiation with brachytherapy, and/or stereotactic guided treatments.

# Follow-up and Surveillance
Similar to NCCN recommendations 5 in Alberta the follow-up of patients with NPC is recommended every 1 to 3 months in the first year after treatment, every 2 to 6 months in the second year, every 4 to 8 months in years 3 to 5 and then only yearly, as clinically indicated, in the period five years after treatment. Surveillance of TSH is recommended annually for up to 5 years. Additionally, speech/hearing and swallowing evaluation and rehabilitation are suggested, as clinically indicated. Follow-up with a registered dietitian to evaluate nutritional status and until the patient achieves a nutritionally stable baseline is recommended due to common weight loss in NPC patients. Finally, routine hospital-based dental follow-up and evaluation is recommended annually up to 3 years.

# Recurrent or Persistent Disease
Restage to assess recurrent or persistent diseaseconsider PET scan - Biopsy of recurrent lesion(s), as clinically indicated
The Head and Neck Tumour Team encourages patient participation in clinical trials. In addition, all patient cases should be presented and discussed at a multidisciplinary Tumour Board.

# Distant disease
Treatment should be individualized based on patient performance status and extent of disease

# Local disease Regional disease
Options include:  This guideline was originally developed in 2013 and updated in 2021.
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.