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PURPOSE Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus–associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( P = .04). For IMRT, 2-year PFS was 87.6% ( P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( P = .56). CONCLUSION The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981–2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks.

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals – the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab – for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S. Electronic supplementary material The online version of this article (10.1186/s40425-019-0662-5) contains supplementary material, which is available to authorized users.

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.

PurposePersistent oral human papillomavirus (HPV) infection increases risk for oropharyngeal carcinoma, and people living with HIV have higher rates of oral HPV infection and related cancers. Some prescription medications have immunomodulatory effects, but the impact of medication use on oral HPV natural history is unknown.MethodsScope® oral rinse-and-gargle samples were collected semi-annually from 1,666 participants and tested for 37 types of oral HPV DNA using PCR; 594 HPV-infected participants with 1,358 type-specific oral HPV infections were identified. Data were collected on recent (past 6months) use of medications. The relationship between medication use and oral HPV clearance was evaluated using Wei-Lin-Weissfeld regression, adjusting for biologic sex, prevalent versus incident infection, age, HIV status and CD4+T cell count.ResultsOut of 11 medications examined, oral HPV clearance was significantly reduced in participants reporting recent use of antipsychotics (HR 0.75, 95% CI 0.57-0.99), anxiolytics/sedatives (HR 0.78, 95% CI 0.63-0.96) and antidepressants (HR 0.82, 95% CI 0.67-0.999). Among antipsychotics users, effect modification by HIV status was observed, with reduced clearance in HIV-infected (HR 0.67, 95% CI 0.49-0.91), but not HIV-uninfected participants (p-interaction=0.009). After adjusted analysis, antipsychotic use remained significantly associated with reduced oral HPV clearance overall (aHR 0.75, 95% CI 0.57-0.99), and when restricted to only HIV-infected participants (aHR 0.66, 95% CI 0.48-0.90). After adjustment, anxiolytic/sedative use and antidepressant use were no longer significantly associated with reduced oral HPV clearance.ConclusionsSome medications were associated with decreased oral HPV clearance, most notably antipsychotic medications. These medications are prescribed for conditions that may have immunomodulating effects, so characteristics of underlying illness may have partially contributed to reduced oral HPV clearance.

Purpose Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx. Patients and Methods p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics. Results p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes. Conclusion Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

Purpose To report results of a randomized phase II trial (Radiation Therapy Oncology Group RTOG-0234) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) with high-risk pathologic features. Patients and Methods Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and/or extracapsular nodal extension and/or two or more nodal metastases. Patients were randomly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m2 or docetaxel 15 mg/m2 once per week. Results Between April 2004 and December 2006, 238 patients were enrolled. With a median follow-up of 4.4 years, 2-year overall survival (OS) was 69% for the cisplatin arm and 79% for the docetaxel arm; 2-year disease-free survival (DFS) was 57% and 66%, respectively. Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors. Grade 3 to 4 myelosuppression was observed in 28% of patients in the cisplatin arm and 14% in the docetaxel arm; mucositis was observed in 56% and 54%, respectively. DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial (Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck), which had a hazard ratio of 0.76 for the cisplatin arm versus control (P = .05) and 0.69 for the docetaxel arm versus control (P = .01), reflecting absolute improvement in 2-year DFS of 2.5% and 11.1%, respectively. Conclusion The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity. The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial.

Tumor human papillomavirus (HPV) status is a prognostic factor for oropharyngeal cancer, but classification methods are not standardized. Here we validate the HPV classification methods used in US cooperative group trials. Tumor DNA and RNA purified from 240 paraffin-embedded oropharyngeal cancers diagnosed from 2000 to 2009 were scored as evaluable if positive for DNA and mRNA controls by quantitative polymerase chain reaction (PCR). Eighteen high-risk (HR) HPV types were detected in tumors by consensus PCR, followed by HR-HPV E6/7 oncogene expression analysis by quantitative reverse transcriptase PCR. The sensitivity (S), specificity (SP), and positive (PPV) and negative predictive values (NPV) of p16 expression detected by immunohistochemistry (IHC) and HPV16 detected by in situ hybridization (ISH) were evaluated in comparison with HR-HPV E6/7 oncogene expression. Interrater agreement among 3 pathologists was evaluated by κ statistics. Of 235 evaluable tumors, 158 (67%; 95% confidence interval, 61.2-73.3) were positive for HR-HPV E6/7 oncogene expression [HPV type 16 (92%), 18 (3%), 33 (3%), 35 (1%), or 58 (1%)]. p16 IHC had high sensitivity (S 96.8%, SP 83.8%, PPV 92.7%, and NPV 92.5%), whereas HPV16 ISH had high specificity (S 88.0%, SP 94.7%, PPV 97.2%, and NPV 78.9%) for HR-HPV oncogene expression. Interrater agreement was excellent for p16 (κ=0.95 to 0.98) and HPV16 ISH (κ=0.83 to 0.91). Receiver operating curve analysis determined the cross-product of p16 intensity score and percentage of tumor staining to optimally discriminate HR-HPV E6/7-positive and HR-HPV E6/7-negative tumors. p16 IHC and HPV16 ISH assays show excellent performance, with high sensitivity and specificity, respectively. A new validated H-score for p16 IHC assessment is proposed. Appropriate assay choice depends on clinical implications of a false-positive or false-negative test.