The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). 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 nasopharynx cancer and ongoing research in this area.

Purpose/Objective(s) Radiation induced lymphopenia (RIL) is common, but its clinical implications are not well defined. In this secondary analysis of a phase III randomized controlled trial evaluating chemoradiation strategies of intensity modulated proton therapy (IMPT) vs IMRT in patients with advanced stage OPSCC (NCT01893307), we evaluated predictors and clinical implications of RIL. Materials/Methods This is a multi-center, randomized, Phase III non-inferiority trial including OPSCC AJCC 7th stage III-IVA, B, CRT, bilateral neck radiation, and ECOG <3. On-treatment absolute lymphocyte count (ALC) nadir was used to calculate the CTCAE v5 grade of lymphopenia. Covariates including patient characteristics, treatment modality - IMPT vs IMRT, and clinical features were assessed using ANOVA and linear regression with ALC as the dependent variable via per protocol analysis. Covariates demonstrating significant (p<0.05) associations with ALC nadir were selectively introduced in the multivariable analysis (MVA) after being assessed for multicollinearity. Results Three hundred ninety seven of 440 patients from 21 institutions initially assigned patients completed CRT, of whom 338 patients had ALC data evaluable for analysis. The majority experienced Grade 3 (n = 213, 63%) or Grade 4 (n = 75, 22%) lymphopenia. Lymphopenia grade was significantly associated with both ER visits (p<0.001) and hospital admission (p<0.001). Patients who developed Grade 4 lymphopenia presented to the ER 100% more frequently (0.78, 95% CI = 0.55-1.0 vs 0.38, 95% CI = 0.29-0.49, p<0.001) and were admitted 70% more frequently (0.51, 95% CI = 0.35-0.70 vs 0.30, 95% CI = 0.21-0.35 p = 0.001) than those who did not. At a median follow-up of 3.1 years, there was no statistically significant relationship between lymphopenia and 3-year PFS or OS. On univariate analysis, treatment with IMPT was associated with a 68% lower incidence of Grade 4 lymphopenia (11% vs 34%, p<0.001) and a 28% higher ALC nadir (0.32 vs 0.25, p<0.001). ALC nadir was also strongly correlated with baseline ALC (r2 = 0.44, p<0.001), and weakly correlated with CRT (r2 = 0.045, p = 0.032), body mean dose (r2 = 0.045, p<0.001), CTV70 (r2 = 0.041, p<0.001), and V5Gy (r2 = 0.062, p<0.001). MVA (p<0.001) confirmed significant effects of treatment modality (β1 = -0.091, p<0.001), baseline ALC (β2 = 0.14, p<0.001), and CRT with cetuximab (β4 = 0.12, pp = 0.011) and carboplatin (β5 = 0.10, p = 0.039). Conclusion In patients with OPSCC treated with CRT, IMPT was associated with a reduced severity of RIL, while RIL was associated with increased rates of ER visits and HA.

6006 Background: IMPT has unique biologic and physical properties compared with IMRT, limits radiation dose beyond the targeted tumor volumes, and is a novel de-intensification strategy for the management of head and neck tumors. This study was designed to compare the outcomes for patients with OPC after chemoradiation therapy (CRT) with IMRT vs IMPT. Methods: This is a multi-center, randomized, phase III non-inferiority OPC trial Stage III/IV (AJCC 7 th ) squamous cell carcinoma stratified patients by human papillomavirus status, smoking status, and receipt of induction chemotherapy (IC). The primary endpoint was the rate of progression-free survival (PFS) rate at 3 years, where progression was defined as disease recurrence or death. Under the null hypothesis, H0: r ≥ 1.535 established the margin for non-inferiority of IMPT. Secondary endpoints include overall survival (OS), treatment-related malnutrition, and gastrostomy-tube dependence. Analyses were conducted on intent-to-treat (ITT; n=440), per-protocol (PP; n=296), and as-treated (AT; n=397) populations. Results: Patients (n=440) were randomized to undergo IMRT(n=219) or IMPT (n=221) at 21 institutions. The median age was 61 years and HPV/p16 was positive in 95%. IC was the initial treatment in 13% of patients. All patients were treated with CRT to 70 Gy in 33 fx with bilateral neck treatment, and post-CRT surgical lymph node dissection occurred in 8%. The median follow-up was 3.14 years. In the ITT analysis, the hazard ratio (HR) for disease progression or death at 3 y was 0.87 (95%CI 0.56,1.35); p=0.006 and the corresponding HR for death (OS) was 0.63 (95%CI 0.36-1.10) suggesting a protective affect with IMPT. In PP analysis, the PFS HR was 0.85 (95%CI 0.52,1.38); p=0.009 and HR for death (OS) was 0.60 (95%CI 0.32-1.12). In the AT analysis, PFS HR was 0.88 (95%CI 0.56,1.37); p=0.007 and the corresponding HR for death (OS) was 0.70 (95%CI 0.40-1.22). For each analysis above, the null hypothesis was rejected and IMPT was non-inferior to IMRT. PP gastrostomy-tube dependence decreased with IMPT vs. IMRT from 42% to 28% (p=0.019), and more IMPT patients sustained their nutrition with end of treatment weight loss < 5% from baseline: 24% vs 14% (p=0.037). Conclusions: IMPT is non-inferior to IMRT and has emerged as a standard of care CRT approach for OPC that reduces malnutrition and gastrostomy-tube dependence. Clinical trial information: NCT01893307 .

Supplementary Figures S1-S3 from Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma

Purpose: This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. Methods: IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. Results: Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. Conclusion: Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

Supplementary Table S1 from Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma

Supplementary Data from Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer

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.

BACKGROUND:New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS:To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS:In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS:POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY:Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

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.

PURPOSE:This study hypothesized that insurance denial would lead to bias and loss of statistical power when evaluating the results from an intent-to-treat (ITT), per-protocol, and as-treated analyses using a simulated randomized clinical trial comparing proton therapy to intensity modulated radiation therapy where patients incurred increasing rates of insurance denial.METHODS AND MATERIALS:Simulations used a binary endpoint to assess differences between treatment arms after applying ITT, per-protocol, and as-treated analyses. Two scenarios were developed: 1 with clinical success independent of age and another assuming dependence on age. Insurance denial was assumed possible for patients <65 years. All scenarios considered an age distribution with mean ± standard deviation: 55 ± 15 years, rates of insurance denial ranging from 0%-40%, and a sample of N = 300 patients (150 per arm). Clinical success rates were defined as 70% for proton therapy and 50% for intensity modulated radiation therapy. The average treatment effect, bias, and power were compared after applying 5000 simulations.RESULTS:Increasing rates of insurance denial demonstrated inherent weaknesses among all 3 analytical approaches. With clinical success independent of age, a per-protocol analysis demonstrated the least bias and loss of power. When clinical success was dependent on age, the per-protocol and ITT analyses resulted in a similar trend with respect to bias and loss of power, with both outperforming the as-treated analysis.CONCLUSIONS:Insurance denial leads to misclassification bias in the ITT analysis, a missing data problem in the per-protocol analysis, and covariate imbalance between treatment arms in the as-treated analysis. Moreover, insurance denial forces the critical appraisal of patient features (eg, age) affected by the denial and potentially influencing clinical success. In the presence of insurance denial, our study suggests cautious reporting of ITT and as-treated analyses, and placing primary emphasis on the results of the per-protocol analysis.

Purpose We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P = 0.05; and at 2 years, P = 0.04) and composite work impairment scores (at 1 year, P = 0.04; and at 2 years, P = 0.04) were seen in patients treated with IMPT versus those treated with IMRT. Conclusion In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

Hearing loss (HL) after treatment for nasopharyngeal cancer (NPC) is common. Prospective data assessing predictors of ototoxicity are lacking. The purposes of this study were to assess patient-reported and objective hearing function and to determine dosimetric predictors of hearing loss after chemoradiation for NPC.