# GUIDELINE OBJECTIVES
The objectives of the guideline are to make recommendations regarding the addition of neoadjuvant/concurrent/adjuvant chemotherapy to chemoradiotherapy in the management of locally advanced squamous cell or undifferentiated nasopharyngeal cancer (NPC) and to identify the optimal chemotherapeutic regimen that improves overall survival. Our recommendations are based on the 2021 Guideline on Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline.

# TARGET POPULATION
Newly diagnosed patients, eligible for chemotherapy, with locally advanced squamous cell or undifferentiated NPC (stage III or IV).

# INTENDED USERS
Healthcare providers involved in the management of NPC patients.
The Chemotherapy and Radiotherapy for Nasopharyngeal Cancer Development Group (GDG) of Ontario Health (Cancer Care Ontario) endorses the Chinese Society of Clinical Oncology (CSCO)/American Society of Clinical Oncology (ASCO) recommendations of Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline modified by the endorsement process described in this document. They were reprinted with the permission of Wolters Kluwer Health, Inc. and Copyright Clearance Center.
Sixteen of the 21 CSCO/ASCO recommendations were endorsed without changes. Four (R 1.1, R 3.3, R 4.1, R 5.1) recommendations were endorsed with modifications and/or clarifications and one recommendation (R 3.4) was not endorsed (see Table 1-1). 
In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC.

# Endorsed (with clarification)
R 4.2. For patients with NPC receiving induction chemotherapy, the regimens should be administered every three weeks for a total of three cycles, or at the minimum two cycles.

# Endorsed R 4.3.
For patients with NPC receiving induction chemotherapy, chemoradiotherapy should be commenced within 21-28 days from the first day of the last cycle of induction chemotherapy.
Adjuvant chemotherapy R 5.1. For all patients with NPC receiving adjuvant chemotherapy, PF (cisplatin 80 mg/m 2 d1 or 20 mg/m 2 per day, d1-5; 5-fluorouracil 1000 mg/m 2 per day, continuous intravenous infusion d1-4, or 800 mg/m 2 per day, continuous intravenous infusion d1-5) administered every four weeks for a total of three cycles should be offered.
Use of GP for a total of three cycles as adjuvant therapy is a reasonable alternative to PF.

# Endorsed (with modification)
R 5.2. For all patients with NPC receiving adjuvant chemotherapy and with a contraindication to cisplatin, carboplatin (AUC 5) may be combined with 5fluorouracil. 

# BACKGROUND FOR GUIDELINE
During the annual document assessment and review, this guideline was identified as needing an update because the recommendations no longer reflect current practice. Current practice standards include using radiotherapy with concurrent cisplatin-based chemoradiation to treat locally advanced squamous cell or undifferentiated NPC. The question now is whether the use of neoadjuvant chemotherapy and/or adjuvant chemotherapy after chemoradiotherapy is worthwhile.

# GUIDELINE ENDORSEMENT DEVELOPERS
This endorsement project was developed by the Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG, which was convened at the request of the Head and Neck Cancer Advisory Committee (CAC). The project was led by a small Working Group of the GDG, which was responsible for reviewing the evidence base and recommendations in "Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA" in detail and making an initial determination as to any necessary changes, drafting the first version of the endorsement document, and responding to comments received during the document review process. The Working Group members had expertise in medical oncology, radiation oncology, and pathology. Other members of the Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG served as the Expert Panel and were responsible for the review and approval of the draft document produced by the Working Group. Conflict of interest declarations for all GDG members are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy.

# ENDORSEMENT METHODS
The Program in Evidence-based care endorses guidelines using the process outlined in Ontario Health (Cancer Care Ontario)'s Guideline Endorsement Protocol. This process includes selection of a guideline, assessment of the recommendations (if applicable), drafting of the endorsement document by the Working Group, internal review by content and methodology experts, and external review by Ontario clinicians and other stakeholders.
The Program in Evidence-based care assesses the quality of guidelines using the AGREE II tool. AGREE II is a 23-item validated tool that is designed to assess the methodological rigour and transparency of guideline development and to improve the completeness and transparency of reporting in practice guidelines.
Implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations may be provided along with the recommendations for information purposes.

# Selection of Guidelines
The following sources were initially searched for existing guidelines in September 2020 with the search term(s) nasopharyngeal cancer, chemotherapy 

# Assessment of Guideline(s)
The Working Group selected the CSCO/ASCO guideline because the rigour of development domain, which assesses the methodological quality of the guideline, had the highest score.
Details of the AGREE II assessment can be found in Appendix 2. The overall quality of the guideline was rated as "6" by one appraiser and "7" by the other (on a scale of 1 to 7). Both appraisers stated that they would recommend this guideline for use. The AGREE II quality ratings for the individual domains were varied; they were assessed at 97% for scope and purpose, 86% for stakeholder involvement, 89% for rigour of development, 89% for clarity of presentation, 92% for applicability, and 92% for editorial independence.

# DESCRIPTION OF ENDORSED GUIDELINE(S)
The CSCO/ASCO guideline (published on-line January 2021) assessed treatment options with chemotherapy in combination with radiotherapy for patients with stage I-IVA NPC. As pointed out by the authors "the nonkeratinizing pathological subtype accounts for more than 95% of NPC cases in endemic areas, which is highly associated with Epstein-Barr virus (EBV) infection, whereas the keratinizing subtype constitutes, <20% of cases worldwide. Despite the relatively lower radiotherapy sensitivity of the keratinizing compared with nonkeratinizing subtypes, NPC almost exclusively relies on (chemo-)radiotherapy to achieve disease control in most presentations, particularly in the definitive treatment of stage II to IVA disease".
The guideline recommendations were based five clinical questions and assessed on the basis of a systematic literature review and expert consensus. Forty-two systematic reviews and 66 randomized controlled trials published between 1990 and August 2020 were included, focusing on radiotherapy techniques and fractionation regimens, chemotherapy sequence in addition to radiotherapy, chemotherapy options for patients receiving concurrent chemoradiotherapy, options for patients receiving induction chemotherapy, and options for patients receiving adjuvant chemotherapy. A complete list of recommendations from the CSCO and ASCO guideline are presented in Table 1-1.

# ENDORSEMENT PROCESS
The Working Group assessed the 2021 CSCO/ASCO Guideline in detail and reviewed each recommendation of the guideline to determine whether it could be endorsed, endorsed with modifications, or rejected. There are 21 recommendations based on five research questions. The Working Group considered the following issues for each of the recommendations: 1) Does the Working Group agree with the interpretation of the evidence and the justification of the original recommendation? 2) Are modifications required to align with the Ontario context? 3) Is it likely there is new, unidentified evidence that would call into question the recommendation? 4) Are statements of qualification/clarification to the recommendation required?

# ENDORSEMENT REVIEW AND APPROVAL

# Internal Review
For the endorsement document to be approved, 75% of the content experts who comprise the GDG Expert Panel must cast a vote indicating whether or not they approve the document, or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. The Expert Panel may specify that approval is conditional, and that changes to the document are required.

# External Review
Feedback on the approved draft endorsement document is obtained from content experts through Professional Consultation. Relevant care providers and other potential users of the endorsement document are contacted and asked to provide feedback on the recommendations through a brief online survey. This consultation is intended to facilitate the dissemination of the final guidance report to Ontario practitioners.

# DISSEMINATION AND IMPLEMENTATION
The endorsement document will be published on the Ontario Health (Cancer Care Ontario) website. Ontario Health (Cancer Care Ontario) -Program in Evidence-based Care guidelines are routinely included in several international guideline databases including the CPAC Cancer Guidelines Database, the CMA/Joule CPG Infobase database, NICE Evidence Search (UK), and the Guidelines International Network (GIN) Library.

# UPDATING THE ENDORSEMENT
Ontario Health (Cancer Care Ontario)/Program in Evidence-based Care will review the endorsement on an annual basis to ensure that it remains relevant and appropriate for use in Ontario.

# ENDORSEMENT and MODIFICATIONS
Sixteen of the 21 CSCO/ASCO recommendations were endorsed without changes. Four (R 1.1, R 3.3, R 4.1, R 5.1) recommendations were endorsed with modifications and/or clarifications and one recommendation (R 3.4) was not endorsed (Table 2-1). See Section 1, Table 1-1 for a list of all 21 recommendations. VMAT is a reasonable alternative to IMRT and may be preferred in this setting.

# Endorsed (with modification)
R 3.3. For patients with NPC with a contraindication to cisplatin, nedaplatin (100 mg/m 2 triweekly) may be offered for concurrent chemoradiotherapy. Other options that may be offered are carboplatin (area under curve 5-6 triweekly) or oxaliplatin (70 mg/m 2 weekly).

# Clarification and Modification:
The recommendation is endorsed for carboplatin only. Carboplatin plus infusional fluorouracil is considered an acceptable alternative based on its activity in NPC generalized from the meta-analysis of chemotherapy in head and neck cancer (MACH-NC). 
In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC.

# Endorsed (with clarification)
R 5.1. For all patients with NPC receiving adjuvant chemotherapy, PF (cisplatin 80 mg/m 2 d1 or 20 mg/m 2 per day, d1-5; 5-fluorouracil 1000 mg/m 2 per day, continuous intravenous infusion d1-4, or 800 mg/m 2 per day, continuous intravenous infusion d1-5) administered every four weeks for a total of three cycles should be offered. Modification: Use of GP for a total of three cycles as adjuvant therapy is a reasonable alternative to PF.

# Endorsed (with modification)
Abbreviations: AJCC = American Joint Committee on Cancer; ASCO = American Society of Clinical Oncology; AUC = area under curve; CSCO = Chinese Society of Clinical Oncology; EBV = Epstein Barr virus; IMRT = intensity-modulated radiotherapy; MRI = magnetic resonance imaging; NPC = nasopharyngeal carcinoma; VMAT = volumetric modulated therapy 

# INTERNAL REVIEW
The endorsement was evaluated by the GDG Expert Panel (Appendix 1). The results of these evaluations and the Working Group's responses are described below.

# EXPERT PANEL REVIEW AND APPROVAL
Following the formulation of the first draft, the recommendation endorsement was reviewed by the Director and Assistant Director of the Program in Evidence-based and the Working Group was responsible for ensuring the necessary changes were made. An Expert Panel of clinical content experts (members of the head and neck community) reviewed the draft endorsement document, provided feedback, and approved the final version (See Appendix 1 for a list of Expert Panel members and conflict of interest declarations).
All nine members of the GDG Expert Panel voted, for a total of 100% response in September 2021. All nine GDG members approved the document (100%). The main comments from the Expert Panel and the Working Group's responses are summarized in Table 3-1. - DPYD testing prior to fluoropyrimidine-based chemotherapy should be addressed for all patients receiving these drugs with guideline recommendations; however, it is out of scope for this specific guideline. - Agreed. Statement modified to "In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC."
- I approve these guidelines with one general comment. - R 4.1 indicates many different allowable "induction" chemotherapy regimens but the clarification states that only gemcitabine (G) and cisplatin (C) is endorsed and the others are not. There seems to be a disconnect with those two statements. Either you should say GC is preferred and others are allowable or do not indicate the others as allowable at all. The clarification says other regimens are not endorsed indicating that they are not allowable. Please try to reconcile this gap.
Agreed. See modification above.

# EXTERNAL REVIEW Professional Consultation
Feedback was obtained through a brief online survey of healthcare professionals and other stakeholders who are the intended users of the endorsement document. All head and neck oncologists in the Program in Evidence-based database were contacted by email to inform them of the survey (n=67). Five of the 67 approached (7.5%) indicated that they were interested in participating. Four of the non-responders stated that they did not have interest in this area or were unavailable to review this endorsement document at the time; the remaining nonresponders did not give a reason. The results of the feedback survey from five clinicians are summarized in Table 3-2. The main comments from the consultation and the Working Group's responses are summarized in Table 3-   We agree and have endorsed the recommendation as originally written in the EAU guideline ("For patients with NPC receiving induction chemotherapy, chemoradiotherapy should be commenced within 21-28 days from the first day of the last cycle of induction chemotherapy") (see Table 3.1 above for previous changes made during internal review).
The final endorsed recommendations contained in Section 1 reflect the integration of feedback obtained through the external review processes with the document as drafted by the GDG Working Group and approved by the GDG Expert Panel.
- The overall objective(s) of the guideline is (are) specifically described. 7
- The health question(s) covered by the guideline is (are) specifically described. 7
- The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.
The Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG would like to thank the following individuals for their assistance in developing this report:
- Jonathan Sussman and Sheila McNair for providing feedback on draft versions.
- Sara Miller for copy editing.