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.

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

F1

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

F2

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

F3

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

F4

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

F5

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.

References

  • 1.

    Ferlay J, Soerjomataram I, Dikshit R. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359386.

    • Search Google Scholar
    • Export Citation
  • 2.

    Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006;15:17651777.

  • 3.

    Sanguineti G, Geara FB, Garden AS. Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 1997;37:985996.

    • Search Google Scholar
    • Export Citation
  • 4.

    Wang C. Radiation Therapy for Head and Neck Neoplasms, 3rd ed. New York, NY: Wiley-Liss; 1997.

  • 5.

    Dogan S, Hedberg ML, Ferris RL. Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a low-incidence population. Head Neck 2014;36:511516.

    • Search Google Scholar
    • Export Citation
  • 6.

    Robinson M, Suh YE, Paleri V. Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population. Infect Agent Cancer 2013;8:30.

    • Search Google Scholar
    • Export Citation
  • 7.

    Stenmark MH, McHugh JB, Schipper M. Nonendemic HPV-positive nasopharyngeal carcinoma: association with poor prognosis. Int J Radiat Oncol Biol Phys 2014;88:580588.

    • Search Google Scholar
    • Export Citation
  • 8.

    Chua ML, Wee JT, Hui EP, Chan AT. Nasopharyngeal carcinoma. Lancet 2016;387:10121024.

  • 9.

    Pathmanathan R, Prasad U, Sadler R. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 1995;333:693698.

    • Search Google Scholar
    • Export Citation
  • 10.

    Lewis JS Jr, Chernock RD. Human papillomavirus and Epstein Barr virus in head and neck carcinomas: suggestions for the new WHO classification. Head Neck Pathol 2014;8:5058.

    • Search Google Scholar
    • Export Citation
  • 11.

    Banko AV, Lazarevic IB, Folic MM. Characterization of the variability of Epstein-Barr virus genes in nasopharyngeal biopsies: potential predictors for carcinoma progression. PLoS One 2016;11:e0153498.

    • Search Google Scholar
    • Export Citation
  • 12.

    Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus-related disease. J Mol Diagn 2008;10:279292.

  • 13.

    Zeng Z, Fan S, Zhang X. Epstein-Barr virus-encoded small RNA 1 (EBER-1) could predict good prognosis in nasopharyngeal carcinoma. Clin Transl Oncol 2016;18:206211.

    • Search Google Scholar
    • Export Citation
  • 14.

    Jeon YK, Lee BY, Kim JE. Molecular characterization of Epstein-Barr virus and oncoprotein expression in nasopharyngeal carcinoma in Korea. Head Neck 2004;26:573583.

    • Search Google Scholar
    • Export Citation
  • 15.

    Gulley ML. Molecular diagnosis of Epstein-Barr virus-related diseases. J Mol Diagn 2001;3:110.

  • 16.

    Fung SY, Lam JW, Chan KC. Clinical utility of circulating Epstein-Barr virus DNA analysis for the management of nasopharyngeal carcinoma. Chin Clin Oncol 2016;5:18.

    • Search Google Scholar
    • Export Citation
  • 17.

    Lin JC, Wang WY, Chen KY. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004;350:24612470.

    • Search Google Scholar
    • Export Citation
  • 18.

    Lin JC, Wang WY, Liang WM. Long-term prognostic effects of plasma Epstein-Barr virus DNA by minor groove binder-probe real-time quantitative PCR on nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;68:13421348.

    • Search Google Scholar
    • Export Citation
  • 19.

    Prayongrat A, Chakkabat C, Kannarunimit D. Prevalence and significance of plasma Epstein-Barr virus DNA level in nasopharyngeal carcinoma. J Radiat Res 2017;58:509516.

    • Search Google Scholar
    • Export Citation
  • 20.

    Jin YN, Yao JJ, Zhang F. Is pretreatment Epstein-Barr virus DNA still associated with 6-year survival outcomes in locoregionally advanced nasopharyngeal carcinoma? J Cancer 2017;8:976982.

    • Search Google Scholar
    • Export Citation
  • 21.

    Leung SF, Chan AT, Zee B. Pretherapy quantitative measurement of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer 2003;98:288291.

    • Search Google Scholar
    • Export Citation
  • 22.

    Leung SF, Chan KC, Ma BB. Plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol 2014;25:12041208.

    • Search Google Scholar
    • Export Citation
  • 23.

    Zhang W, Chen Y, Chen L. The clinical utility of plasma Epstein-Barr virus DNA assays in nasopharyngeal carcinoma: the dawn of a new era?: a systematic review and meta-analysis of 7836 cases. Medicine (Baltimore) 2015;94:e845.

    • Search Google Scholar
    • Export Citation
  • 24.

    Liu LT, Tang LQ, Chen QY. The prognostic value of plasma Epstein-Barr viral DNA and tumor response to neoadjuvant chemotherapy in advanced-stage nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2015;93:862869.

    • Search Google Scholar
    • Export Citation
  • 25.

    Wang WY, Twu CW, Chen HH. Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res 2010;16:10161024.

    • Search Google Scholar
    • Export Citation
  • 26.

    Al-Sarraf M, LeBlanc M, Giri PG. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:13101317.

    • Search Google Scholar
    • Export Citation
  • 27.

    Chan AT, Leung SF, Ngan RK. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97:536539.

    • Search Google Scholar
    • Export Citation
  • 28.

    Lin JC, Jan JS, Hsu CY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 2003;21:631637.

    • Search Google Scholar
    • Export Citation
  • 29.

    Wee J, Tan EH, Tai BC. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005;23:67306738.

    • Search Google Scholar
    • Export Citation
  • 30.

    Chen L, Hu CS, Chen XZ. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol 2012;13:163171.

    • Search Google Scholar
    • Export Citation
  • 31.

    Blanchard P, Lee A, Marguet S. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 2015;16:645655.

    • Search Google Scholar
    • Export Citation
  • 32.

    Ribassin-Majed L, Marguet S, Lee AW. What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual patient data network meta-analysis. J Clin Oncol 2017:35;498505.

    • Search Google Scholar
    • Export Citation
  • 33.

    Sun Y, Li WF, Chen NY. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol 2016;17:15091520.

    • Search Google Scholar
    • Export Citation
  • 34.

    Cao SM, Yang Q, Guo L. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase II multicentre randomised controlled trial. Eur J Cancer 2017;75:1423.

    • Search Google Scholar
    • Export Citation
  • 35.

    Lee AW, Ngan RK, Tung SY. Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 2015;121:13281338.

    • Search Google Scholar
    • Export Citation
  • 36.

    Zhang Y, Li WF, Liu X. Nomogram to predict the benefit of additional induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: analysis of a multicenter, phase III randomized trial [published online December 16, 2017]. Radiother Oncol. doi: 10.1016/j.radonc.2017.12.002

    • Search Google Scholar
    • Export Citation
  • 37.

    Chen YP, Wang YQ, Li WF. Critical evaluation of the quality and recommendations of clinical practice guidelines for nasopharyngeal carcinoma. J Natl Compr Canc Netw 2017;15:336344.

    • Search Google Scholar
    • Export Citation
  • 38.

    Dechaphunkul T, Pruegsanusak K, Sangthawan D, Sunpaweravong P. Concurrent chemoradiotherapy with carboplatin followed by carboplatin and 5-fluorouracil in locally advanced nasopharyngeal carcinoma. Head Neck Oncol 2011;3:30.

    • Search Google Scholar
    • Export Citation
  • 39.

    Bae WK, Hwang JE, Shim HJ. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. Cancer Chemother Pharmacol 2010;65:589595.

    • Search Google Scholar
    • Export Citation
  • 40.

    Posner MR, Hershock DM, Blajman CR. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:17051715.

    • Search Google Scholar
    • Export Citation
  • 41.

    Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P. Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer 2007;43:13991406.

    • Search Google Scholar
    • Export Citation
  • 42.

    Rusthoven CG, Lanning RM, Jones BL. Metastatic nasopharyngeal carcinoma: patterns of care and survival for patients receiving chemotherapy with and without local radiotherapy. Radiother Oncol 2017;124:139146.

    • Search Google Scholar
    • Export Citation
  • 43.

    Hsieh JC, Hsu CL, Ng SH. Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective phase II trial. Jpn J Clin Oncol 2015;45:819827.

    • Search Google Scholar
    • Export Citation
  • 44.

    Zhang L, Huang Y, Hong S. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 2016;388:18831892.

    • Search Google Scholar
    • Export Citation
  • 45.

    Samlowski WE, Moon J, Kuebler JP. Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group phase II study. Cancer Invest 2007;25:182188.

    • Search Google Scholar
    • Export Citation
  • 46.

    Gibson MK, Li Y, Murphy B. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:35623567.

    • Search Google Scholar
    • Export Citation
  • 47.

    Forastiere AA, Metch B, Schuller DE. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992;10:12451251.

    • Search Google Scholar
    • Export Citation
  • 48.

    Chan AT, Hsu MM, Goh BC. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005;23:35683576.

    • Search Google Scholar
    • Export Citation
  • 49.

    Jin Y, Cai XY, Shi YX. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2012;138:17171725.

    • Search Google Scholar
    • Export Citation
  • 50.

    Jacobs C, Lyman G, Velez-Garcia E. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257263.

    • Search Google Scholar
    • Export Citation
  • 51.

    Burtness B, Goldwasser MA, Flood W. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:86468654.

    • Search Google Scholar
    • Export Citation
  • 52.

    Grau JJ, Caballero M, Verger E. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol 2009;129:12941299.

    • Search Google Scholar
    • Export Citation
  • 53.

    Guardiola E, Peyrade F, Chaigneau L. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 2004;40:20712076.

    • Search Google Scholar
    • Export Citation
  • 54.

    Catimel G, Verweij J, Mattijssen V. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:533537.

    • Search Google Scholar
    • Export Citation
  • 55.

    Stewart JS, Cohen EE, Licitra L. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:18641871.

    • Search Google Scholar
    • Export Citation
  • 56.

    Fury MG, Pfister DG. Current recommendations for systemic therapy of recurrent and/or metastatic head and neck squamous cell cancer. J Natl Compr Canc Netw 2011;9:681689.

    • Search Google Scholar
    • Export Citation
  • 57.

    Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol 2012;13:3546.

  • 58.

    Martinez-Trufero J, Isla D, Adansa JC. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer 2010;102:16871691.

    • Search Google Scholar
    • Export Citation
  • 59.

    Zhang L, Zhang Y, Huang PY. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol 2008;61:3338.

    • Search Google Scholar
    • Export Citation
  • 60.

    Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:26442652.

    • Search Google Scholar
    • Export Citation
  • 61.

    Forastiere AA, Shank D, Neuberg D. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer 1998;82:22702274.

    • Search Google Scholar
    • Export Citation
  • 62.

    Hsu C, Lee SH, Ejadi S. Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study. J Clin Oncol 2017;35:40504056.

    • Search Google Scholar
    • Export Citation
  • 63.

    Ang KK, Chen A, Curran WJ Jr. Head and neck carcinoma in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN). Cancer 2012;118:57835792.

    • Search Google Scholar
    • Export Citation
  • 64.

    Guadagnolo BA, Liu CC, Cormier JN, Du XL. Evaluation of trends in the use of intensity-modulated radiotherapy for head and neck cancer from 2000 through 2005: socioeconomic disparity and geographic variation in a large population-based cohort. Cancer 2010;116:35053512.

    • Search Google Scholar
    • Export Citation
  • 65.

    Chi A, Nguyen NP, Tse W. Intensity modulated radiotherapy for sinonasal malignancies with a focus on optic pathway preservation. J Hematol Oncol 2013;6:4.

    • Search Google Scholar
    • Export Citation
  • 66.

    Wolden SL, Chen WC, Pfister DG. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 2006;64:5762.

    • Search Google Scholar
    • Export Citation
  • 67.

    Kam MK, Leung SF, Zee B. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25:48734879.

    • Search Google Scholar
    • Export Citation
  • 68.

    Pow EH, Kwong DL, McMillan AS. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981991.

    • Search Google Scholar
    • Export Citation
  • 69.

    Madani I, Bonte K, Vakaet L. Intensity-modulated radiotherapy for sinonasal tumors: Ghent University Hospital update. Int J Radiat Oncol Biol Phys 2009;73:424432.

    • Search Google Scholar
    • Export Citation
  • 70.

    Moon SH, Cho KH, Lee CG. IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma: survival outcome in a Korean multi-institutional retrospective study (KROG 11-06). Strahlenther Onkol 2016;192:377385.

    • Search Google Scholar
    • Export Citation
  • 71.

    Zenda S, Kohno R, Kawashima M. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2011;81:14731478.

    • Search Google Scholar
    • Export Citation
  • 72.

    Fukumitsu N, Okumura T, Mizumoto M. Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys 2012;83:704711.

    • Search Google Scholar
    • Export Citation
  • 73.

    Allen AM, Pawlicki T, Dong L. An evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee. Radiother Oncol 2012;103:811.

    • Search Google Scholar
    • Export Citation
  • 74.

    Patel SH, Wang Z, Wong WW. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014;15:10271038.

    • Search Google Scholar
    • Export Citation
  • 75.

    Russo AL, Adams JA, Weyman EA. Long-term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2016;95:368376.

    • Search Google Scholar
    • Export Citation
  • 76.

    Dagan R, Bryant C, Li Z. Outcomes of sinonasal cancer treated with proton therapy. Int J Radiat Oncol Biol Phys 2016;95:377385.

  • 77.

    Lewis GD, Holliday EB, Kocak-Uzel E. Intensity-modulated proton therapy for nasopharyngeal carcinoma: decreased radiation dose to normal structures and encouraging clinical outcomes. Head Neck 2016;38(Suppl 1):E18861895.

    • Search Google Scholar
    • Export Citation
  • 78.

    Chen JZ, Le QT, Han F. Results of a phase 2 study examining the effects of omitting elective neck irradiation to nodal levels IV and Vb in patients with N(0-1) nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2013;85:929934.

    • Search Google Scholar
    • Export Citation
  • 79.

    Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 1981;7:447453.

    • Search Google Scholar
    • Export Citation
  • 80.

    Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 1976;37:26052612.

    • Search Google Scholar
    • Export Citation
  • 81.

    Lee NY, Zhang Q, Pfister DG. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol 2012;13:172180.

    • Search Google Scholar
    • Export Citation
  • 82.

    Lee AW, Ng WT, Pan JJ. International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma. Radiother Oncol 2018;126:2536.

    • Search Google Scholar
    • Export Citation
  • 83.

    Liauw SL, Mancuso AA, Amdur RJ. Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol 2006;24:14211427.

    • Search Google Scholar
    • Export Citation
  • 84.

    Yao M, Smith RB, Hoffman HT. Clinical significance of postradiotherapy [18F]-fluorodeoxyglucose positron emission tomography imaging in management of head-and-neck cancer-a long-term outcome report. Int J Radiat Oncol Biol Phys 2009;74:914.

    • Search Google Scholar
    • Export Citation
  • 85.

    Lango MN, Myers JN, Garden AS. Controversies in surgical management of the node-positive neck after chemoradiation. Semin Radiat Oncol 2009;19:2428.

    • Search Google Scholar
    • Export Citation
  • 86.

    Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemoradiation. Oncology (Williston Park) 2004;18:993998; discussion 999, 1003–1004, 1007.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Provided content development and/or authorship assistance.

Supplementary Materials

  • View in gallery

    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®.

  • View in gallery

    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®.

  • View in gallery

    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®.

  • View in gallery

    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®.

  • View in gallery

    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®.

All Time Past Year Past 30 Days
Abstract Views 5 0 0
Full Text Views 10392 7215 518
PDF Downloads 3094 2167 159
EPUB Downloads 0 0 0