NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022

Featured Updates to the NCCN Guidelines

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  • 1 Moffitt Cancer Center;
  • | 2 The University of Texas MD Anderson Cancer Center;
  • | 3 City of Hope National Medical Center;
  • | 4 O'Neal Comprehensive Cancer Center at UAB;
  • | 5 Memorial Sloan Kettering Cancer Center;
  • | 6 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 7 UC Davis Comprehensive Cancer Center;
  • | 8 Duke Cancer Institute;
  • | 9 Massachusetts General Hospital Cancer Center;
  • | 10 Vanderbilt-Ingram Cancer Center;
  • | 11 Stanford Cancer Institute;
  • | 12 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 13 Fox Chase Cancer Center;
  • | 14 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 15 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 16 Roswell Park Comprehensive Cancer Center;
  • | 17 Huntsman Cancer Institute at the University of Utah;
  • | 18 University of Colorado Cancer Center;
  • | 19 UC San Diego Moores Cancer Center;
  • | 20 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 21 The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute;
  • | 22 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 23 Mayo Clinic Cancer Center;
  • | 24 St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;
  • | 25 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 26 UCLA Jonsson Comprehensive Cancer Center;
  • | 27 Abramson Cancer Center at the University of Pennsylvania;
  • | 28 University of Michigan Rogel Cancer Center;
  • | 29 University of Wisconsin Carbone Cancer Center;
  • | 30 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 31 Fred & Pamela Buffett Cancer Center; and
  • | 32 National Comprehensive Cancer Network.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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

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

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-003-H01-P

Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until March 10, 2023. PAs should only claim credit commensurate with the extent of their participation.

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 https://education.nccn.org/node/91074; 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: March 10, 2022; Expiration date: March 10, 2023

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

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Sharon Spencer, MD, Panel Vice Chair

Ellie Maghami, MD, Panel Member

Jennifer L. Burns, BS, Manager, Guidelines Support, NCCN

Susan D. Darlow, PhD, Oncology Scientist/Senior Medical Writer, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

David Pfister, MD, Panel Chair, grant/research support from Bristol-Myers Squibb Company, Genentech, Inc., Cue Biopharma, Hookipa Pharma Inc., Kura Oncology, Inc., Merck & Co., Inc., and Novartis Pharmaceuticals Corporation; and data safety monitoring committee member for Boehringer-Ingelheim, GmbH.

Douglas Adkins, MD, Panel Member, grant/research support from AstraZeneca Pharmaceuticals LP, BeiGene, Blueprint Medicines, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Eisai Inc., Eli Lilly and Company, Exelixis Inc., Gilead Sciences, Inc., Hookipa Pharma Inc., Kura Oncology, Inc., Merck & Co., Inc., Adlai-Nortye, CUE Biosciences, Debio, Epizme, Isa Therapeutics, Oncolys, Rubius, Vaccinex, Pfizer Inc., and Roche Laboratories, Inc.; and consulting fees from Blueprint Medicines, Boehringer Ingelheim GmbH, Eisai Inc., Exelixis Inc., Kura Oncology, Inc., Merck & Co., Inc., Coherus Biosciences, CUE Biosciences, Immunitas, Targimmune, Vaccinex, and Xilio.

David M. Brizel, MD, Panel Member, royalty income from UpToDate.

Jimmy J. Caudell, MD, PhD, Panel Member, grant/research support from Varian Medical Systems, Inc.; and scientific advisor for Galera.

A. Dimitrios Colevas, MD, Panel Member, grant/research support from AbbVie, Inc., Atara Biotherapeutics, BioNTech, Cue, Cullinan Oncology, Exelixis, Inc., Gilead Sciences, Inc., Innate Pharma, Replimune Group, and Tessa Therapeutics; consulting fees from Grand Rounds and PDS Biotech; and scientific advisor for Gilead Sciences, Inc.

Maura L. Gillison, MD, PhD, Panel Member, grant/research support from Bristol-Myers Squibb Company, Gilead Sciences, Inc., and Kura Oncology, Inc.; and consulting fees from Bayer HealthCare, Bristol-Myers Squibb Company, Eisai Inc., EMD Serono, Ipsen, Merck & Co., Inc., Nektar Therapeutics, and Roche Laboratories, Inc.

Cristina P. Rodriguez, MD, Panel Member, grant/research support from AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Kura Oncology, Inc., Merck & Co., Inc., Ayala, and Cue; and scientific advisor for Coherus and Cue.

David Sher, MD, MPH, Panel Member, grant/research support from Varian Medical Systems, Inc.

Gregory Weinstein, MD, Panel Member, royalty income from Olympus Corporation.

Francis Worden, MD, Panel Member, honoraria from Bayer HealthCare; and scientific advisor for Eisai Inc., Exelixis Inc., Merck & Co., Inc.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.

This activity is supported by educational grants from AstraZeneca; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.

Overview

The overall incidence of HPV-positive oropharynx cancers is increasing in the United States, whereas the incidence of HPV-negative (primarily tobacco- and alcohol-related) cancer is decreasing.1 The attributable fraction for HPV in newly diagnosed oropharyngeal cancer is estimated to be 60% to 70% in the United States and parts of the European Union.15 Patients with HPV-positive cancer have tended to be younger6,7; however, HPV-positive oropharynx cancer rates are increasing among older adults as the exposed cohorts age.8,9 Oral HPV16 infection increases the risk of oropharynx cancer,1013 and a strong causal relationship has been established.10,11 HPV16 accounts for approximately 90% of cases, and HPV18, 33, and 35 are responsible for the vast majority of the small remaining fraction.6 The prevalence of HPV16 is higher in oropharyngeal cancer than in cervical cancer (∼50%), in which HPV18 is also highly prevalent.2,1416 Expression of the HPV E6 and E7 oncogenes inactivates the tumor suppressor proteins p53 and pRb, respectively, which are frequently mutated in tobacco-related mucosal squamous cell carcinomas. Inactivation of p53 and pRb promotes genomic instability and the development of cancer, and is responsible for the upregulation of p16 protein expression, a reliable surrogate marker of the presence of HPV DNA in these tumors. Genetic profiling of HPV-positive cancer has demonstrated it to be genetically distinct from HPV-negative squamous cell carcinoma of the head and neck (SCCHN).17

Analyses from the National Health and Nutrition Examination Survey (2011–2014), including 2,627 adults aged 18 to 33 years, showed that HPV vaccination was associated with reduced vaccine-type oral HPV infection (0.1% in vaccinated individuals vs 1.6% in unvaccinated individuals; P=.008).18 Moreover, HPV vaccination in the United States has led to herd protection against oral HPV16, 18, 6, and 11 infections in unvaccinated men.19 Results of an ongoing randomized clinical trial to investigate the efficacy of HPV vaccines for the prevention of oral HPV infections have not yet been reported. Although data are not yet available, the HPV types that cause the overwhelming majority of SCCHN are included in the HPV nonavalent vaccine (provides protection against 9 high-risk HPV types). Since there is evidence that vaccination prevents HPV-related cervical and anal cancers,2022 the FDA expanded the indication for HPV vaccination to include prevention of oral HPV infections and related oropharyngeal cancers in 2020.

Patients with locally advanced HPV-positive SCCHN have improved response to treatment and survival (overall survival [OS] and progression-free survival [PFS]) when compared with HPV-negative tumors.2329 Treatment response is improved in patients receiving radiation therapy (RT) or chemoradiation.23,30,31 A meta-analysis including 18 studies with 4,424 patients with SCCHN showed that patients with tumors that were both HPV-positive and p16-positive had better 5-year OS and 5-year disease-free survival (DFS) than patients with tumors that were HPV-negative/p16-negative, HPV-positive/p16-negative, and HPV-negative/p16-positive.32 However, patients with tumors that were HPV-negative/p16-positive had greater 5-year OS than patients with tumors that were p16-negative (regardless of HPV status). Discrepancies between HPV status and p16 status are usually attributable to use of assays for HPV detection that do not cover all high-risk HPV types.33

The impact of smoking and cancer stage on survival of patients with HPV-positive SCCHN has been investigated in numerous studies.3436 For example, analyses of patients with oropharyngeal cancer who were enrolled in RTOG 9003 or 0129 (n=165) showed that smoking was associated with decreased OS and PFS, regardless of p16 status.34 An analysis of data compiled from 4 cooperative group trials estimated that never smokers had a 51% (hazard ratio [HR], 0.40; 95% CI, 0.33–0.75) reduction in risk of cancer progression when compared with former and current smokers with HPV-positive SCCHN.36 A retrospective analysis from a clinical trial (RTOG 0129) showed no difference in the rate of distant metastasis in patients with p16-positive versus p16-negative disease.23 Additional analyses have suggested that individuals with T4 or N3 disease or radiographically detectable matted lymph nodes may have a worse prognosis, and therefore should be excluded from deintensification trials.3740 These studies on prognostic and predictive factors in HPV-positive oropharyngeal cancers form the basis for RT deintensification studies. Moreover, the striking difference in prognosis for HPV-positive versus HPV-negative SCCHN led to the creation of new AJCC staging criteria in 2018 (see later section on “Treatment,” page 228).

HPV Testing

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers recommend tumor HPV testing by p16 immunohistochemistry (IHC) in all patients diagnosed with an oropharyngeal cancer. There are currently no diagnostic tests with regulatory approval. A few HPV testing options are available for use in the clinical setting. Expression of p16 as detected by IHC is a widely available surrogate biomarker that has very good agreement with HPV status as determined by HPV E6/E7 mRNA expression.33,4144 Other tests include HPV detection by PCR and in situ hybridization (ISH).33,42 Sensitivity of IHC staining for p16 and PCR-based assay is high, although specificity is highest for ISH.42 Analyses of HPV testing methods have shown that sensitivity and specificity of p16 IHC range from 94% to 97% and 83% to 84%, respectively, with sensitivity and specificity of HPV16 ISH ranging from 85% to 88% and 88% to 95%.33,43 The reduced specificity for p16 IHC may be due to the presence of p16-positive tumors that do not have evidence of HPV DNA, whereas the reduced sensitivity for HPV16 ISH may be due to the presence of other high-risk HPV types in the tumor. Due to variations in sensitivity and specificity values of testing options, multiple methods may be used in combination for HPV detection.6,42,43,45,46 Sufficient pathologic material for HPV testing can be obtained by fine-needle aspiration.6,47 Guidelines for HPV testing have been published by the College of American Pathologists.48 HPV testing may prompt questions about prognosis and sexual history that the clinician should be prepared to address.

Treatment

Expert consensus is that HPV status should be used as a stratification factor in clinical trials, or clinical trial eligibility should be restricted to one or the other patient population.4951 With some exceptions, the treatment algorithms in the NCCN Guidelines for Head and Neck Cancers for p16-negative and p16-positive oropharyngeal cancer are identical. It is the stance of the panel that there is currently no evidence that the staging criteria published in the 8th edition of the AJCC Cancer Staging Manual52 should drive clinical decision-making, as it is currently unknown how to therapeutically address the vast biologic differences between the 2 distinct cancers. The panel urges that patients with HPV-positive cancers be enrolled in clinical trials evaluating biologic and treatment-related questions.5355

Some clinicians have suggested that less-intense treatment may be adequate for HPV-positive oropharyngeal cancers (ie deintensification).38 Although not considered deintensification, other RT-based strategies that may be used to potentially minimize harm in patients with p16-positive oropharyngeal cancer include use of image-guided RT and consideration of unilateral neck irradiation in disease that is well-lateralized.56 Available data supporting these assertions are limited by retrospective analyses, single-institution phase III trials, variability in HPV testing method used, and short follow-up periods.38,54,57,58 Deintensification treatment protocols for HPV-positive locally advanced oropharyngeal cancer are being investigated in ongoing clinical trials. Strategies under active investigation include reducing or using response-stratified RT dose, using RT alone versus chemoradiation, using less invasive surgical procedures such as transoral laser microsurgery or transoral robotic surgery (TORS), using sequential systemic therapy/RT, and using immunotherapy.54,56,59

Early-stage (ie, T1–T2N0) p16-positive oropharyngeal cancers may be treated with definitive RT or resection of the primary with neck dissection6063 (see ORPHPV-1, page 226). Tumors at or approaching the midline (ie, tumors in the base of the tongue, posterior pharyngeal wall, soft palate, and tonsil invading the tongue base) are at risk for contralateral metastasis and warrant bilateral treatment. The randomized phase II ORATOR trial aimed to compare swallow-related QoL outcomes in patients with early-stage T1–T2,N0–2 oropharyngeal cancer treated with primary RT or systemic therapy/RT versus those treated with TORS with neck dissection with or without adjuvant RT or systemic therapy/RT.64 The study enrolled 68 patients from 6 hospitals in Canada and Australia (88% were p16-positive), and compared MD Anderson Dysphagia Inventory (MDADI) scores between the 2 groups at 1 year. Swallow-related QoL outcomes reached statistical significance favoring the primary RT cohort; however, this difference did not meet criteria for a clinically meaningful change, and with long-term follow-up the difference in scores became less pronounced with the passage of time.64,65 Study results showed that there were excellent and similar PFS and OS rates in both arms. The authors concluded that “RT- and TORS-based approaches were associated with clinically similar QoL outcomes, but differing spectra of toxicities, and differences in QoL between arms decreased over time. Clinicians and patients should be involved in shared decision-making, in a multidisciplinary context, to individualize treatment of oropharyngeal squamous cell carcinoma.”65 Additional randomized trials of minimally invasive transoral surgery or RT for oropharyngeal cancer are ongoing or have been presented in abstract form (ClinicalTrials.gov identifiers: NCT02984410, NCT05144100, and NCT0321010366).

Results from multiple phase II trials show that RT deintensification is associated with promising PFS rates in patients with p16-positive oropharyngeal cancer.6771 A phase II randomized trial of low-risk HPV-associated oropharyngeal cancer (≤10 pack years, T1–2N1 or T3N0–1) demonstrated that de-escalated RT to 60 Gy with concurrent cisplatin was associated with a 2-year PFS rate of 90.5%, and accelerated RT alone to 60 Gy was associated with a 2-year PFS rate of 87.6%.72 The former, but not the latter, regimen met criteria for further study and is the subject of an ongoing cooperative group phase II/III randomized trial on dose de-escalation. Similarly, a nonrandomized phase II study of definitive RT to 60 Gy ± concurrent cisplatin in 114 patients with T0–3N0–2M0 p16-positive oropharyngeal cancer demonstrated a 2-year PFS of 86% and 2-year OS of 95%.70 Analyses of quality of life (QoL) outcomes from one of these trials68 showed that RT deintensification was associated with a quicker and more robust return to baseline-level functioning.73 A prospective phase II trial of initial TORS followed by risk-adapted adjuvant treatment demonstrated a 2-year PFS rate of 96.9% for low-risk disease with TORS alone, 94.9% for intermediate-risk disease with 50 Gy adjuvant RT, 96% for intermediate-risk disease with 60 Gy adjuvant RT, and 90.7% for high-risk disease with 66 Gy adjuvant RT with concurrent weekly cisplatin.74

Research on the impact of adverse features such as extranodal extension and number of involved nodes on outcomes in patients with p16-positive disease who have undergone resection is rapidly evolving. Analyses from the RTOG 950175 and EORTC 22931 trials,76 prior to the era of p16/HPV testing, showed that extranodal extension is associated with poor prognosis and demonstrated benefit to adjuvant systemic therapy/RT in patients with locally advanced SCCHN who have undergone surgical resection.77 Data suggesting equivalent outcomes of adjuvant RT and systemic therapy/RT for p16-positive oropharyngeal cancer with extranodal extension are restricted to retrospective trials,35,49,7883 although clinical trials are being conducted to validate the revised AJCC staging52 for clinical decision-making. Secondary to a lack of high-quality, prospective clinical evidence in the modern era, systemic therapy/RT is a category 2A option for patients with p16-positive disease and extranodal extension. Adjuvant systemic therapy/RT remains a category 1 recommendation for patients with nonoropharyngeal SCCHN who have extranodal extension. Because patients with p16-positive oropharyngeal cancer have a generally favorable prognosis and may live longer, toxicity and QoL are concerns for these patients.54,55 On the other hand, they are also younger, with fewer comorbidities, so they can probably tolerate combined adjuvant therapy better. Omitting systemic therapy and administering RT alone is a category 2B option for patients with p16-positive cT0–2, cN0–1 disease (single node ≤3 cm) who have extranodal extension following surgery. For patients with positive or close margins, reresection (if feasible), RT, and systemic therapy/RT are treatment options.84 For patients with other risk features such as pT3 or pT4 primary, one positive node >3 cm or multiple positive nodes, nodal disease in levels IV or V, perineural invasion, vascular invasion, or lymphatic invasion, adjuvant treatment options include RT or systemic therapy/RT (category 2B) (see ORPHPV-1 and ORPHPV-2, pages 226 and 227, respectively).

For locally advanced resectable disease (T0–2cN1 [single node >3 cm, or ≥2 ipsilateral nodes ≤6 cm] or T0–2N2, or T3N0–3, or T4, treatment recommendations include concurrent systemic therapy/RT84,85 and resection of the primary and neck dissection (with appropriate adjuvant therapy [systemic therapy/RT or RT]), in addition to enrollment in clinical trials (see ORPHPV-3 and ORPHPV-4, pages 228 and 229, respectively). As with early-stage disease, tumors at or approaching the midline should be strongly considered for bilateral treatment of the neck. The panel asserts that concurrent systemic therapy/RT is preferred in patients with locoregionally advanced HPV-positive disease who have clinical evidence of fixed or matted nodes or obvious extranodal extension, because surgery is not recommended for these patients. Induction chemotherapy (followed by RT or systemic therapy/RT) is listed as a treatment option for these patients,60,62,86 but is a category 3 option due to lack of consensus among NCCN Member Institutions. Panel concerns are based on absence of consistent benefit of induction chemotherapy in randomized clinical trials and concerns that use of better-tolerated—but potentially less effective—concurrent regimens or poorer patient compliance with RT may compromise outcomes. For more detail, see the Discussion section in the full version of the NCCN Guidelines for Head and Neck Cancers (available at NCCN.org). Patients with cN2–3 disease who are treated with initial surgery have a high likelihood of extranodal extension, which warrants adjuvant systemic therapy/RT treatment. Triple modality management is associated with increased toxicity. Beginning treatment with concurrent systemic therapy/RT may help decrease the need for triple modality therapy and additional treatment-induced morbidity. Therefore, definitive concurrent systemic therapy/RT is preferred over up-front surgery for p16-positive cT4 or cN3 oropharyngeal cancer (see ORPHPV-4 , page 229).

In 3 randomized phase III trials, cetuximab + RT was compared with cisplatin + RT as a deintensification treatment strategy for HPV-positive locally advanced oropharyngeal cancer, but cetuximab + RT proved to be inferior to cisplatin (in terms of OS) and was not better tolerated.87,88 In the RTOG 1016 noninferiority trial, 849 patients with locally advanced HPV-positive oropharyngeal cancer were randomized to receive accelerated intensity-modulated RT (IMRT) with either cetuximab or cisplatin.87 After a median follow-up of 4.5 years, the cetuximab arm did not meet the criterion for noninferiority (based on 5-year OS). Five-year OS was 77.9% for the cetuximab arm and 84.6% for the cisplatin arm. PFS and risk of locoregional failure were significantly worse in the cetuximab arm compared with the cisplatin arm (HR, 1.72; 95% CI, 1.29–2.29; P<.001 for PFS; HR, 2.05; 95% CI, 1.35–3.10; P<.001 for locoregional failure), with 5-year PFS and locoregional failure rates being 67.3% and 17.3% for the cetuximab arm, and 78.4% and 9.9% for the cisplatin arm, respectively. In the randomized phase III De-ESCALaTE HPV trial, cetuximab + RT was compared with cisplatin + RT in 334 patients with locally advanced p16-positive oropharyngeal squamous cell carcinoma.88 Patients treated with cisplatin + RT had significantly better 2-year OS (97.5% vs 89.4%, respectively; HR, 5.0; 95% CI, 1.7–14.7; P=.001) and a lower recurrence rate (6.0% vs 16.1%, respectively; HR, 3.4; 95% CI, 1.6–7.2; P<.001) than those treated with cetuximab + RT. In the multicenter TROG 12.01 trial, 189 patients with intermediate-risk HPV-positive oropharyngeal cancer were randomized to receive 70 Gy RT with either weekly cisplatin or cetuximab.89 The 3-year failure-free survival was 93% in the RT/cisplatin arm and 80% in the RT/cetuximab arm (P=.015). These 3 phase III trials demonstrated that cetuximab and RT was inferior to cisplatin and RT in patients with HPV-positive oropharyngeal cancer.8789 When concurrent systemic therapy/RT is recommended for treatment of locoregionally advanced p16-positive cancer of the oropharynx, the panel asserts that high-dose cisplatin is the preferred systemic agent, although weekly cisplatin is also an option. An NRG Oncology trial is currently in progress for comparing high-dose cisplatin to weekly cisplatin in locally advanced SCCHN (ClinicalTrials.gov identifier: NCT05050162).

RT Fractionation

IMRT is preferred for radiation treatment of oropharynx cancer, because it is associated with decreased toxicity.90,91 There is an ongoing randomized trial comparing IMRT with intensity-modulated proton therapy in oropharyngeal cancer (ClinicalTrials.gov identifier: NCT01893307). A fractionation schedule of 66 to 70 Gy at 2 Gy/fraction daily (Monday–Friday) for 6 to 7 weeks is recommended for patients with gross disease. Hypofractionation, hyperfractionation, or accelerated fractionation is acceptable in patients with early-stage oropharyngeal cancer and may be associated with improved locoregional control.84,92 For elective nodal treatment, a biologically equivalent dose of approximately 40 to 50 Gy in 2 Gy/fraction is recommended.84,93 The complete list of recommended schedules for radiation treatment of p16-positive oropharynx cancer are shown in the algorithm (see “Principles of Radiation Therapy,” ORPH-A 1 and 2, pages 230 and 231). Despite the evidence that RT dose deintensification may improve long-term function while preserving PFS in patients with p16-positive disease,6769,73 more studies are needed in this area. The majority of clinical trials in this space have been single-arm phase II and need to be compared with the standard of care in randomized trials. Currently, enrollment of patients with low-risk HPV-positive oropharyngeal cancer is in progress for the randomized phase II/III NRG HN-005 trial, which will compare de-escalated 60 Gy with cisplatin, 60 Gy with nivolumab, and 70 Gy with cisplatin (NCT03952585).

Summary

The incidence of HPV-positive oropharyngeal cancer is increasing in the United States, and patients with locally advanced HPV-positive SCCHN have improved outcomes relative to patients with HPV-negative tumors. The NCCN Guidelines for Head and Neck Cancers recommend tumor HPV testing in all patients with oropharyngeal cancer. Treatment deintensification (eg, dose-reduced RT) is an active area of research with promising preliminary results. However, definitive data from randomized phase III trials must be available before RT deintensification for HPV-positive cancers is considered a standard option. Ongoing clinical trials specific to this unique subset of head and neck cancers are anticipated to further inform these NCCN Guidelines.

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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 of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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