NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

Abstract

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement NCCN

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-18-005-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/82996; and 3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: May 10, 2018; Expiration date: May 10, 2019

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Head and Neck Cancers

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Head and Neck Cancers

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NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5; 10.6004/jnccn.2018.0026

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

A. Dimitrios Colevas, MD, Panel Member, has disclosed that he has received grant/research support from AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Cellsite; Innate Pharma S.A.; IRX Therapeutics, Inc.; Merck & Co., Inc.; Regeneron Pharmaceuticals, Inc.; Tessa Therapeutics Pte Ltd.; and Threshold Pharmaceuticals. He has also received consulting fees/honoraria and other financial benefit from Pfizer Inc.

Sue S. Yom, MD, PhD, Panel Member, has disclosed that she has received grant/research support from Genentech, Inc., Merck & Co., Inc., and Bristol-Myers Squibb Company.

David G. Pfister, MD, Panel Chair, has disclosed that he has received grant/research support from AstraZeneca Pharmaceuticals LP; Bayer HealthCare; Eli Lilly and Company; Exelixis Inc.; Genentech, Inc.; GlaxoSmithKline; Incyte Corporation; MedImmune Inc.; Merck & Co., Inc.; and Novartis Pharmaceuticals Corporation. He has also received consulting fees/honoraria from Boehringer Ingelheim GmbH, Incyte Corporation, and Merck & Co., Inc.

Sharon Spencer, MD, Panel Vice-Chair, has disclosed that she has no relevant financial relationships.

Bharat B. Mittal, MD, Panel Member, has disclosed that he has no relevant financial relationships.

John A. Ridge, MD, PhD, Panel Member, has disclosed that he has no relevant financial relationships.

Jennifer L. Burns, Guidelines Coordinator, NCCN, has disclosed that she has no relevant financial relationships.

Susan D. Darlow, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.

This activity is supported by educational grants from AstraZeneca, Celldex Therapeutics, Celgene Corporation, Genentech, Jazz Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, and Seattle Genetics, Inc. This activity is supported by independent educational grants from AbbVie, Merck & Co., Inc. and NOVOCURE.

Overview

Nasopharyngeal carcinoma (NPC) is a rare cancer, accounting for 0.6% of all cancers diagnosed worldwide in 2012.1 However, there are areas of the world with endemic disease; global incidence rates are highest in Southeast Asia (especially southern China), Micronesia/Polynesia, Eastern Asia, and North Africa.1,2 Rates are 2 to 3 times higher in men than in women.1,2 Among head and neck (H&N) cancers, NPC has one of the highest propensities to metastasize to distant sites. Regional recurrences are uncommon, occurring in only 10% to 19% of patients.3,4 The NCCN Guidelines for the evaluation and management of NPC provide recommendations aimed at addressing the risks for local, regional, and distant disease.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Workup for NPC

The workup of NPC (see NASO-1, above) includes a complete H&N examination, nasopharyngeal endoscopic

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NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5; 10.6004/jnccn.2018.0026

examination, biopsy, and MRI encompassing the skull base, face, and entire neck with or without CT as needed for evaluation of bone invasion at the skull base. FDG-PET/CT and/or chest CT may be used to evaluate for distant metastases, especially for locoregionally advanced disease (when the incidence of metastasis at diagnosis is significant); if only a chest CT is ordered, a bone scan for distant bone metastasis is needed. These studies are important to determine the full extent of tumor in order to assign the stage, determine the appropriateness and choice of systemic therapy agents, and, if the disease remains limited to the H&N, to design radiation volumes that will encompass all the disease with appropriate doses. Epstein-Barr virus (EBV) DNA testing may also be considered (see “Epstein-Barr Virus,” following section). Multidisciplinary consultation is encouraged. Dental, nutritional, speech and swallowing, and audiology evaluations should be performed as clinically indicated. Ophthalmologic and endocrinologic assessments may also be considered.

Human papillomavirus (HPV) infection has been found to be associated with WHO type I NPC in case reports and very small case series, but the limited data regarding the impact on chemoradiation (CRT) outcomes are conflicting.57 Therefore, routine testing for HPV in NPC is not recommended by the NCCN H&N Panel.

Epstein-Barr Virus

Infection with EBV is an etiologic factor in the development of NPC.8,9 Workup for NPC may include EBV testing of both the tumor itself and the blood, particularly in the presence of nonkeratinizing and undifferentiated histology.1012 Testing methods for detection of EBV in the tumor include in situ hybridization for EBV-encoded RNA13 and immunohistochemical staining for LMP1.14 The former tends to be a more sensitive testing method for carcinomas, relative to LMP1 immunohistochemical staining.15 PCR may be used to evaluate EBV DNA load in plasma. Sensitivity and specificity values range

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NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5; 10.6004/jnccn.2018.0026

from 53% to 96% and 88% to 100%, respectively.16 Testing for plasma EBV DNA has been used in select centers as a means of residual disease monitoring. For patients with locoregional disease, studies have shown that high initial levels of plasma EBV DNA, or persistently elevated levels near or at the end of radiation therapy (RT), are associated with a significantly poorer outcome following RT or CRT.1722 A meta-analysis including 13 studies showed that plasma EBV DNA levels assessed pretreatment were associated with mortality (hazard ratio [HR], 2.81; 95% CI, 2.44–3.24; P<.001) and distant metastasis (HR, 3.89; 95% CI, 3.39–4.47; P<.001), although these studies were significantly heterogeneous (P=.03).23 Plasma EBV DNA has also been studied as an indicator of disease response to chemotherapy as induction therapy prior to CRT24 and in the setting of distant metastases.25

Treatment of NPC

Locoregionally Advanced Disease

The Intergroup 0099 trial, which randomly assigned patients to external-beam RT plus chemotherapy versus external-beam RT alone, closed early when an interim analysis disclosed a significant survival advantage favoring the combined chemotherapy and RT group.26 The addition of chemotherapy also decreased local, regional, and distant recurrence rates. Subsequent phase III randomized trials in Asia confirmed that concurrent CRT increased survival compared with RT alone.2729 In one of these trials, the 5-year overall survival (OS) rate was 70% for the CRT group versus 59% for the RT group.27 The randomized study conducted in Singapore, which was modeled after the Intergroup 0099 treatment regimen, continued to show the benefit of adding chemotherapy to RT. After combined cisplatin and RT, adjuvant cisplatin/5-FU was also given.29 This regimen appeared to reduce toxicity while still providing a beneficial antitumor effect. However, a phase III

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NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5; 10.6004/jnccn.2018.0026

randomized trial from China comparing concurrent cisplatin/RT with (or without) adjuvant cisplatin/5-FU showed that adjuvant chemotherapy did not significantly improve survival following CRT (HR, 0.74; 95% CI, 0.49–1.10; P=.13).30

An individual patient data meta-analysis by Blanchard et al,31 which included 19 trials and 4,806 patients with nonmetastatic NPC, showed that both adjuvant chemotherapy following CRT and CRT without adjuvant chemotherapy were associated with better OS (HR, 0.65; 95% CI, 0.56–0.76, and HR, 0.80; 95% CI, 0.70–0.93, respectively) and progression-free survival (PFS; HR, 0.62; 95% CI, 0.53–0.72, and HR, 0.81; 95% CI, 0.71–0.92, respectively). However, differences between the included studies assessing CRT with and without adjuvant chemotherapy (eg, different length of follow-up, fewer patients with stage II disease in trials assessing adjuvant chemotherapy) limited the ability to make a firm conclusion regarding the efficacy of one treatment modality over the other. A network meta-analysis based on this individual patient data meta-analysis31 (including 20 trials and 5,144 patients) showed that the addition of adjuvant chemotherapy to CRT was associated with better PFS (HR, 0.81; 95% CI, 0.66–0.98) compared with CRT only.32 The authors argued that more chemotherapy, in addition to concurrent CRT, could reduce recurrence rates. The NRG-HN001 trial (ClinicalTrials.gov identifier: NCT02135042) is currently in progress to further investigate the role of adjuvant chemotherapy following CRT in patients with locoregionally advanced NPC; in part, delivery of adjuvant chemotherapy is individualized based on EBV DNA plasma levels.

Induction chemotherapy (prior to concurrent CRT) is also a treatment option for patients with locoregionally advanced NPC. In a recent phase III randomized multi-institutional trial from China including 480 patients with stage III–IVb N-positive disease, those randomized to receive induction cisplatin/5-FU/docetaxel (TPF) with concurrent

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NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018

Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5; 10.6004/jnccn.2018.0026

CRT had a better 3-year failure-free survival rate (80%; 95% CI, 75–85) compared with patients who received solely CRT (72%; 95% CI, 66–78, and HR, 0.68; 95% CI, 0.48–0.97; P=.034).33 Grade 4 adverse events occurred in 18% of patients who received induction TPF with concurrent RT compared with 1% who received CRT only (P<.001), with neutropenia (15%) and leucopenia (5%) the most common grade 4 adverse events in the induction chemotherapy group. In another randomized trial from China, patients with stage III–IVb NPC who received induction cisplatin/5-FU followed by CRT (n=238) had a better 3-year disease-free survival rate (82%; 95% CI, 0.77–0.87) compared with patients (n=238) who received CRT only (74%; 95% CI, 0.68–0.80; P=.028).34 Multivariate analyses showed a significant difference between treatment arms for disease-free survival (HR, 0.67; 95% CI, 0.47–0.95; P=.023) and distant metastasis-free survival (HR, 0.63; 95% CI, 0.41–0.98; P=.038). However, OS was not significantly better in patients receiving the induction chemotherapy regimen. Finally, in a complex randomized trial (including one substudy comparing induction chemotherapy with adjuvant chemotherapy administration, given either before or after definitive CRT), unadjusted comparisons of induction versus adjuvant chemotherapy did not reach statistical significance, but select adjusted comparisons indicated some improvements in disease progression or death associated with assignment to induction.35

Taken together, results thus far suggest that induction chemotherapy prior to CRT in patients with locally advanced NPC may potentially impact tumor control, compared with CRT without additional chemotherapy.32,36 Expert groups (eg, ESMO, NCI) differ in their clinical practice guidelines regarding use of induction chemotherapy for these patients,37 and the NCCN Guidelines Panel could not reach uniform consensus in this regard. Clinical trials are currently ongoing to address the role of induction chemotherapy prior to CRT for patients with locoregionally advanced NPC (eg, ClinicalTrials.gov identifiers: NCT01872962, NCT02512315). Currently available evidence shows trends favoring the addition of chemotherapy to concurrent CRT in patients with locoregionally advanced NPC32; however, it is unclear whether to administer chemotherapy before or after CRT for these patients.

NCCN Recommendations: Patients with T1,N0,M0 nasopharyngeal tumors should be treated with definitive RT alone, including elective RT to the neck (see NASO-2, page 482). For patients with locoregionally advanced NPC (T1,N1–3; T2–T4,any N), enrollment in a clinical trial is preferred. The panel recommends concurrent CRT (cisplatin) with adjuvant chemotherapy (cisplatin/5-FU) for locoregionally advanced NPC. Concurrent CRT (cisplatin) without adjuvant systemic therapy is a category 2B recommendation based on a single randomized trial from China, which did not demonstrate a clear superiority over delivery of adjuvant chemotherapy.30 Cisplatin for CRT is recommended for patients with no contraindication to the drug, because most randomized trials support the use of cisplatin in this setting (see CHEM-A 1 of 5, page 484).26,27 If using adjuvant chemotherapy, adjuvant carboplatin/5-FU is a widely accepted option; however, this recommendation is a category 2B option due to the uncertainty about the benefits of adjuvant chemotherapy for all patients with NPC.38

Induction chemotherapy (followed by CRT) is also recommended for patients with NPC with either T1,N1–3 or T2–T4,any N lesions (see NASO-2, page 482). Based on the results from randomized trials3335 and a meta-analysis,32 the panel voted to change the category recommendation for induction chemotherapy followed by CRT from category 3 to category 2A for the 2018 update. Besides TPF, several other induction/sequential chemotherapy regimens are recommended in the algorithm for NPC27,3941 (see CHEM-A 1 of 5, page 484).

Metastatic Disease

For patients with NPC who present with metastatic (M1) disease, enrollment in a clinical trial is preferred. Other recommended initial therapy options include either a platinum-based combination systemic therapy regimen or CRT; treatment depends on whether disease is mostly localized or widespread and if it is symptomatic or posing a clinical risk to the patient.26,27,38 Patients who receive chemotherapy alone may receive subsequent RT to the primary and neck or concurrent CRT as clinically indicated. Population-based data appear to support the role of earlier RT in the management of metastatic disease.42

Active combination regimens for these patients include gemcitabine/cisplatin (category 1)43,44; cisplatin or carboplatin, plus a taxane45,46; cisplatin/5-FU46,47; or carboplatin/cetuximab.48 Results from a trial that compared 5 different cisplatin-based regimens for NPC showed that a gemcitabine/cisplatin regimen was effective, although not better than either cisplatin/5-FU or cisplatin/paclitaxel.49 However, results from a recent randomized phase III trial showed that patients with recurrent or metastatic NPC (N=362) who received gemcitabine/cisplatin had a greater median PFS compared with those who received cisplatin/5-FU (7.0 vs 5.6 months, respectively; HR, 0.55; 95% CI, 0.44–0.68; P<.001).44 Gemcitabine/vinorelbine was removed from the list of recommendations for the 2018 update because there are more data to support use of other regimens. Active and more commonly used single agents include cisplatin, carboplatin, paclitaxel, docetaxel, 5-FU, methotrexate, capecitabine, and gemcitabine.47,5061

In 2016, the anti–PD-1 antibody pembrolizumab received FDA approval for use in patients with recurrent or metastatic squamous cell H&N cancer who have progressed on or following platinum-based chemotherapy. The panel subsequently added pembrolizumab to the NCCN Guidelines for this indication, excluding NPC. Pembrolizumab in patients with PD-L1–positive recurrent or metastatic NPC was assessed in the nonrandomized, multi-institutional, phase IB KEYNOTE-028 trial (N=27).62 All but 2 of the patients had previously received systemic therapy for recurrent or metastatic disease. The objective response rate (partial response only; none had a complete response) was 26%, with a median duration of response of 17.1 months. The OS rate at 6- and 12-months was 85% and 63%, respectively, with PFS rates of 39% and 34%, respectively. Approximately 30% of patients experienced a grade 3–5 drug-related adverse event. The panel voted to include pembrolizumab for patients with previously treated, PD-L1–positive recurrent or metastatic NPC for the 2018 update, but this is a category 2B option based on panel consensus.

Combination and single-agent systemic therapy regimens recommended by the panel for patients with recurrent, unresectable, or metastatic NPC can be found on CHEM-A 2 of 5, page 485.

Radiation Therapy

Intensity-modulated RT (IMRT) is now widely used in H&N cancers and is the predominant technique used at NCCN Member Institutions.63,64 It is useful in reducing long-term toxicity in H&N cancers and particularly NPC by reducing the dose to ≥1 major salivary glands, temporal lobes, mandible, auditory structures (including the cochlea), and optic structures.6569 IMRT may help to preserve the optic pathway in patients with sinonasal malignancies.65 A prospective Korean study showed that 3-dimensional and IMRT techniques were superior to 2-dimensional radiation for both PFS and OS, and IMRT was associated with improved survival in multivariate analysis, particularly in T3–T4 tumors.70

Proton therapy has also been used to treat sinonasal malignancies.7173 A systematic review and meta-analysis of 41 noncomparative observation studies suggested that patients with malignant diseases of the nasal cavity and paranasal sinuses who received proton therapy had statistically superior disease-free survival at 5 years and locoregional control at longest follow-up than those receiving IMRT. Compared with all photon-treated patients, patients with sinonasal malignancies who received charged particle therapy had significantly more neurologic toxic effects, although the authors noted a strong possibility of reporting bias, with significantly more particle therapy articles reporting toxic effects.74 More recent reports show that proton-beam therapy for treatment of sinonasal cancer is associated with good locoregional control, freedom from distant metastasis, and acceptable toxicity.75,76 Specifically for NPC, proton therapy has established dosimetric superiority, although trials are ongoing to determine the level of clinical benefit.77 However, without high-quality prospective comparative data, it is premature to conclude that proton therapy has been established as superior to other modern radiation techniques, such as IMRT. For the 2018 NCCN Guidelines update, the panel added a statement that proton therapy may be considered for treatment of NPC when normal tissue constraints cannot be met by photon-based therapy (see NASO-A, page 483).

For early-stage high-risk NPC, radiation doses of 66 to 70.2 Gy given with standard fractions are necessary for control of the primary tumor and involved lymph nodes (see NASO-A, page 483). Limited prospective evidence supports elective radiation volume reductions for very early-stage patients.78 The local control rate for these tumors ranges from 80% to 90%, whereas T3–T4 tumors have a control rate of 30% to 65% with RT alone.79,80 Radiation dose-fractionation schedules may vary slightly depending on institutional preference. Usually, these deliver between 2.0 and 2.12 Gy/fraction daily (Monday–Friday) for 33 to 35 fractions to all areas of gross disease to a total dose of approximately 70 Gy.81 Low-risk subclinical disease in the low neck is often treated with 44 to 54.1 Gy at 1.64 to 2.0 Gy per fraction, and for intermediate-risk disease 59.4 to 63 Gy in 1.8 to 2.0 Gy per fraction is often given with dose-painting to different regions of the skull base and neck. International guidelines have been recently published describing the design of radiation clinical target volumes.82

Follow-Up/Surveillance for NPC

Recommendations for surveillance following treatment of NPC include a complete H&N examination, endoscopic examination, and supportive care and rehabilitation. Because the deep areas of the skull base may be inaccessible to clinical examination, periodic cross-sectional imaging may be necessary. The clinical benefit of blood EBV DNA monitoring is currently uncertain (see “Epstein-Barr Virus,” page 482), but it may be considered (category 2B). Within the immediate several months after treatment with either RT or CRT, evaluation with imaging (eg, CT and/or MRI with contrast, FDG-PET/CT) guides the use of neck dissection.8386 The rare patient who completes all therapy with residual disease in the neck and experiences a complete response at the primary should undergo a neck dissection.

Conclusions

Although NPC is a relatively rare cancer, there are areas of endemic incidence in some areas of the world. Infection with EBV is implicated in the development of endemic-type NPC. Patients with early-stage NPC should be treated with RT. For those with locoregionally advanced NPC, the panel recommends concurrent CRT with additional chemotherapy (either before or after CRT). For patients with M1 disease, recommended initial therapy options include either a platinum-based combination systemic therapy regimen or CRT for patients with limited metastatic burden and advanced locoregional disease. For the 2018 update, the panel voted to include pembrolizumab for patients with previously treated, PD-L1–positive recurrent or metastatic NPC (category 2B). When RT is used to treat patients with NPC, proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy, although IMRT is preferred.

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