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.
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: 0836-0000-17-006-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/81262; and 3) view/print certificate.
Release date: June 10, 2017; Expiration date: June 10, 2018
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
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 cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Treatment is complex for patients with head and neck (H&N) cancers. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation, indications for systemic therapy). Single-modality treatment with surgery or radiation therapy (RT) is generally recommended for the approximately 30% to 40% of patients who present with early-stage disease (stage I or II). The 2 most commonly used modalities, surgery and RT, result in similar survival in these individuals. The choice of surgery or RT is often based on local institutional expertise and/or perceived relative morbidity of these treatment options. With evolving techniques of systemic therapy/RT and less invasive surgery, morbidity is also a moving target. Combined modality therapy is generally recommended for the approximately 60% of patients with locally or regionally advanced disease at diagnosis. Participation in clinical trials is a preferred or recommended
HPV and H&N Cancer
HPV infection is associated with an estimated 4.8% of global cancers.3 HPV is now well accepted as a cause of squamous cancers of the oropharynx (particularly cancers of the tonsils and tongue base).4–11 The overall incidence of HPV-positive H&N cancers is increasing in the United States, whereas the incidence of HPV-negative (primarily tobacco- and alcohol-caused) cancer is decreasing.12 Patients with HPV-associated H&N cancer tend to be younger.11,13 The HPV-attributable fraction in newly diagnosed oropharyngeal cancer is estimated at 60% to 70% in the United States and parts of the European Union.12,14–17 Oral HPV type 16 (HPV16) infection increases the risk of oropharyngeal cancer4,10,18,19 and a strong causal relationship has been established4,18; HPV types 18, 31, and 33 are responsible for the vast majority of the remaining fraction.11 Expression of HPV E6 and E7 oncogenes inactivates the tumor-suppressor proteins p53 and pRb, respectively, which leads to the development of cancer.20
Prophylactic HPV vaccination strongly decreased the incidence of cervical intraepithelial neoplasia in prospective clinical trials.21,22 Recent data from one of these trials suggest that HPV vaccination has the potential to prevent HPV-attributed oropharyngeal cancer.23 An unplanned analysis demonstrated a statistically significantly lower prevalence of oral HPV 16/18 infection 4 years after vaccination among HPV-vaccinated versus hepatitis A–vaccinated
The association of tumor HPV status with patient prognosis has led to clinical utility (discussed later). However, 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 immunohistochemistry (IHC) is a widely available surrogate biomarker that has very good agreement with HPV status as determined by HPV E6/E7 mRNA expression.24–26 Other tests include HPV detection through PCR and in situ hybridization (ISH).24,26 Sensitivity of IHC staining for p16 and PCR-based assay is high, although specificity is highest for ISH.26 A validation study of HPV testing methods showed that the sensitivity and specificity of p16 IHC was 96.8% and 83.8%, respectively, with the sensitivity and specificity of HPV16 ISH being 88.0% and 94.7%.24 Agreement between p16 IHC and ISH was good. The reduced specificity for p16 IHC may have been due to the presence of p16-positive tumors that do not have evidence of HPV DNA, whereas the reduced sensitivity for HPV16 ISH may been 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.11,26–28 Sufficient pathologic material for HPV testing can be obtained through fine-needle aspiration.11,29
NCCN Recommendations: For the 2016 update, the panel revised the footnote regarding HPV testing as part of the evaluation for oropharyngeal cancer to take into account that p16 IHC is widely available and highly correlated with HPV status (ORPH-1; page 763). The footnote was also revised to take into account the option of using either ISH- or PCR-based assay. Panel members note that HPV testing may prompt questions about prognosis (ie, a favorable or a less favorable forecast) and sexual history that the clinician should be prepared to address.
HPV and Treatment of Oropharyngeal Cancer
Analyses from clinical trials indicate that patients with locally advanced HPV-positive H&N cancers experience improved response to treatment and overall survival (OS) and progression-free survival (PFS) when compared with HPV-negative tumors,30–34 with one analysis showing that p16-positive nonoropharyngeal squamous H&N cancers have a better prognosis compared with p16-negative nonoropharyngeal cancers.35 Treatment response is improved in patients receiving both chemoradiation30,31 and conventional RT.36 A systematic review including 56 prospective or retrospective studies showed that patients with p16-positive oropharyngeal cancer had a better prognosis and fewer rates of adverse events compared with those with p16-negative disease.37 Further, patients with p16-negative disease had worse outcomes after RT relative to surgery (hazard ratio [HR], 1.66; 95% CI, 1.26–2.18; P<.001), and this difference was not statistically significant for patients with p16-positive disease (HR, 1.33; 95% CI, 0.94–1.87; P=.114).
There may also be an association between HPV status and survival in patients with recurrent or metastatic disease. Retrospective analyses from the phase III RTOG 0129 and 0522 trials30,38 included patients with disease progression after platinum-based chemoradiotherapy (n=154) and showed that patients with p16-positive disease had greater OS relative to those with p16-negative disease (HR, 0.48; 95% CI, 0.31–0.74; P<.001).33 An archival analysis from 2 ECOG trials (E139539 and E330140), which included 129 patients with recurrent or metastatic H&N squamous cell carcinoma, showed that both HPV status (12.9 vs 6.7 months for HPV-positive vs HPV-negative; P=.014) and p16-positive disease (11.9 vs 6.7 months for p16-positive vs p16-negative; P=.027) were associated with greater median survival.41 These studies provide substantial evidence that there is a clinically relevant prognostic difference in recurrent or metastatic disease.
Because patients with locally advanced HPV-positive oropharyngeal cancer may live longer, late toxicity and quality of life are concerns for these patients.42,43 Therefore, consensus is increasing that HPV status should be used as a stratification factor or be addressed in separate trials (HPV-related vs -unrelated disease) for which patients with oropharyngeal cancer are eligible.44–46 Some clinicians have recently suggested that less-intense treatment may be adequate for HPV-positive oropharyngeal cancers (ie, deintensification)47; however, the available data supporting this assertion are limited by retrospective analyses, variability in HPV testing method used, and short follow-up periods.42,47–49 Deintensification treatment protocols for HPV-associated, 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 robotic surgery, using sequential systemic therapy/RT, and using immunotherapy and targeted therapy agents such as cetuximab.42,43,50 The ECOG-ACRIN phase II E1308 trial, in which patients with stage III–IV HPV16 and/or p16-positive oropharyngeal cancer (N=80) received induction chemotherapy followed by reduced-dose RT and weekly cetuximab, recently reported results showing that RT deintensification may result in equivalent or similar responses in selected patients compared with full-dose RT.51
The relationship between HPV and other prognostic or predictive factors such as smoking history and stage has been investigated.52,53 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.52 A retrospective analysis from a clinical trial showed no difference in the presence of distant metastasis in patients with p16-positive disease compared with those with p16-negative disease.30 Additional analyses have suggested that individuals with matted nodes or N2c disease may have worse prognosis, and therefore should be excluded from deintensification trials.47,54,55
The panel currently recommends adjuvant systemic therapy/RT in patients with squamous cell carcinoma of the oropharynx in the presence of the adverse pathologic features of extracapsular nodal spread with (or without) positive mucosal margins. This recommendation is primarily based on results from RTOG 9501 and EORTC 22931.56–58 However, in a review of published data from these randomized controlled trials, it was noted that the panel's recommendations are based on studies that did not investigate the impact of HPV or p16 status.59 However, the investigators from RTOG 9501 and EORTC 22931 point out that the prevalence of HPV-positive/p16-positive tumors was likely to be low in these trials.60 Other limitations noted in this review included unplanned subgroup analyses, the grouping of multiple H&N subsites, inconsistent quantitative reporting, and lack of reporting on tumor and lymph node classification, treatment effect sizes, multivariable analyses, and quality-of-life outcomes. Therefore, the investigators who performed this review argued that these trials lack the generalizability necessary to rationalize the use of adjuvant systemic therapy/RT in patients with p16-positive disease.
Recent retrospective studies have not observed a statistically significant association between extracapsular spread and survival in patients with HPV-positive oropharyngeal cancer.44,53,61–64 For example, a study of 220 patients with p16-positive oropharyngeal cancer who received surgical resection with or without adjuvant treatment showed that the presence of ≥5 metastatic nodes is associated with disease recurrence and survival, but extracapsular spread was not significantly associated with outcomes in this sample.63 Recent studies of patients with p16-positive oropharyngeal cancer treated with surgery show that soft tissue metastasis may be associated with poor survival outcomes, especially in patients with T3–T4 disease.53,65 These results suggest that patients with p16-positive disease with extracapsular spread could potentially be treated differently than those with p16-negative disease and extracapsular spread.
NCCN Recommendations: The panel deliberated regarding the strength and limitations of the evidence supporting the use of adjuvant systemic therapy/RT in patients with oropharyngeal cancer who have extracapsular spread. Before the 2016 update, adjuvant systemic therapy/RT for patients with extracapsular spread was a category 1 recommendation for cancer of the oropharynx, lip, oral cavity, hypopharynx, larynx, and unknown primary. For the 2016 update, the panel revised its recommendation for adjuvant systemic therapy/RT in patients with oropharyngeal cancer who have extracapsular spread from category 1 to category 2A (see ORPH-2; page 764; revisions also apply to ORPH-3 and ORPH-4). This change in category was based on a lack of high-quality, prospective clinical evidence and controversy. Adjuvant systemic therapy/RT remains a category 1 recommendation for patients with other types of H&N cancer who have extracapsular spread, including HPV-negative oropharynx cancer. Where the panel recommends adjuvant systemic therapy/RT for patients with oropharyngeal cancer and extracapsular spread, a footnote was added noting that this treatment recommendation is based on randomized studies in which HPV status was unknown, consistent with a conclusion of the review by Sinha et al.59
Because HPV status is a strong predictor of oropharyngeal cancer prognosis, the AJCC recently released separate staging systems for p16-positive and p16-negative oropharyngeal cancer.66,67 However, as the panel meeting to discuss the 2017 NCCN Guidelines update was held before publication of the newest edition of the AJCC Staging Manual, the most recent version of the NCCN Guidelines for Cancer of the Oropharynx does not take into account differential staging between p16-positive and p16-negative disease. Deintensification treatment protocols for patients with HPV-related oropharyngeal cancer are currently being investigated (eg, ClinicalTrials.gov identifiers: NCT01154920, NCT01706939, NCT01302834, and NCT01855451). Panel members urge that patients with HPV-related cancers be enrolled in clinical trials evaluating biological and treatment-related questions.42,43,68
Immunotherapy for Recurrent and Metastatic H&N Cancer
Updates to systemic therapy recommendations made in 2016 include the addition of 2 immunotherapy agents: nivolumab and pembrolizumab (see CHEM-A 2 of 5; page 765). Nivolumab, an anti–PD-1 antibody, was assessed in a phase III randomized clinical trial including 361 patients with recurrent H&N squamous cell cancer whose disease had progressed within 6 months after platinum-based chemotherapy.69 With a median follow-up of 5.1 months (range, 0–16.8 months), OS was significantly greater in patients randomized to receive nivolumab versus standard second-line, single-agent systemic therapy with either methotrexate, docetaxel, or cetuximab (HR, 0.70; 97.73% CI, 0.51–0.96; P=.01). One-year survival was also greater for patients who received nivolumab versus standard therapy (36.0% vs 16.6%, respectively) and the response rate was higher (13.3% vs 5.8%, respectively), but median PFS was not significantly different between the groups (2.0 vs 2.3 months, respectively; P=.32). In prespecified exploratory analyses, the OS benefit in patients treated with nivolumab appeared to be confined to those with a tumor PD-L1 expression level of ≥1% (n=149; 8.7 vs 4.6 months; HR, 0.55; 95% CI, 0.36–0.83). In patients with tumor PD-L1 expression level <1% (n=111), no OS advantage was demonstrated for those treated with nivolumab (5.7 vs 5.8 months; HR, 0.89; 95% CI, 0.54–1.45). Grade 3 or 4 treatment-related adverse events occurred in 13.1% of patients who received nivolumab compared with 35.1% of those who received standard therapy. These results indicate that nivolumab prolongs survival in patients with recurrent or metastatic squamous cell H&N cancer that has progressed after platinum-based chemotherapy compared with those who receive standard single-agent systemic therapy.
Pembrolizumab, another anti–PD-1 antibody, was initially studied at a dose of 10 mg/kg given every 2 weeks in the squamous cell H&N cancer cohort of the KEYNOTE-012 trial.70 Clinical activity was identified and the possibility that responses could be durable was suggested. A lower, fixed-dose schedule using pembrolizumab, 200 mg every 3 weeks was subsequently assessed in a phase Ib expansion cohort of 132 patients with recurrent or metastatic squamous cell H&N cancer71; 82% of these patients had previously received systemic therapy for their recurrent or metastatic disease. At 6 months, the OS rate was 59% and PFS was 23%, with an overall response rate of 18%. Observed responses appeared durable, although follow-up was limited (median, 9 months). Through scoring both tumor and immune cells, the response rate in patients who were PD-L1–positive (≥1% expression) was significantly greater than in patients who were PD-L1–negative (22% vs 4%, respectively; P=.021), and responses were seen in both HPV-associated and non–HPV-associated disease. Pembrolizumab was generally well tolerated, with grade 3/4 toxicities reported in only 9%, and no treatment-related deaths.70
Based on these studies, nivolumab and pembrolizumab received FDA approval in 2016 for use in patients with recurrent or metastatic squamous cell H&N cancer that has progressed on or after platinum-based chemotherapy. The NCCN panel recommends nivolumab for patients with this indication as a category 1 recommendation based on high-quality evidence,69 whereas pembrolizumab is a category 2A recommendation based on results from nonrandomized trials.70,71 Despite the ambiguities of PD-L1 testing and definitions, PD-L1 expression may be associated with better outcomes from treatment with immunotherapy for recurrent or metastatic squamous cell H&N cancer (ie, greater likelihood of response to pembrolizumab and greater survival benefit in response to nivolumab).
The incidence of HPV-positive oropharyngeal cancer is increasing in the United States, and patients with locally advanced HPV-positive H&N cancers have improved outcomes compared with those with HPV-negative tumors. However, currently there are insufficient data to recommend that patients with HPV-positive oropharyngeal cancers receive less-intense treatment relative to patients with HPV-negative cancers. HPV status is a prognostic factor, and panel members urge that patients with HPV-related cancers be enrolled in clinical trials evaluating biological and treatment-related questions. Evidence to support adjuvant systemic therapy/RT for patients with oropharyngeal cancer and extracapsular spread is based on randomized studies in which HPV status was unknown. Other recent updates to the NCCN Guidelines for H&N Cancers include the addition of the immunotherapy agents nivolumab and pembrolizumab for the treatment of patients with recurrent or metastatic H&N cancer who have progressed on or after platinum-based chemotherapy.
RTOG 0522: a randomized phase III trial of concurrent accelerated radiation and cisplatin versus concurrent accelerated radiation, cisplatin, and cetuximab [followed by surgery for selected patients] for stage III and IV head and neck carcinomas. Clin Adv Hematol Oncol2007;5:79–81.
MarurSLiSCmelakAJ. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx-ECOG-ACRIN Cancer Research Group[published online ahead of print December 28 2016]. J Clin OncolJCO2016683300.
ChowLQHaddadRGuptaS. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort[published online ahead of print September 19 2016]. J Clin Oncolpii: JCO681478.