Elective Irradiation of Retropharyngeal Lymph Nodes as an Indication for Adjuvant Radiation Therapy After Transoral Surgery for Tonsil Cancer.

Treatment of squamous cell carcinoma of the tonsil involves primary radiation therapy (RT) or surgical resection. Historically, if RT was the primary or adjuvant treatment modality, most of the bilateral retropharyngeal lymph nodes (RPLNs) were treated electively with a therapeutic dose for subclinical disease, regardless of whether radiographically pathologic lymph nodes were seen on initial diagnostic imaging. De-escalation strategies include the incorporation of transoral surgery with the goal to either eliminate or reduce the dose of adjuvant RT or chemotherapy. Transoral surgery does not include elective removal of the RPLNs, and no guideline or outcome paper recommends adjuvant RT specifically to electively treat RPLNs. In this Topic Discussion, we discuss pertinent literature and suggest management decisions. The management decisions discussed in this Topic Discussion pertain to only tonsillar primaries and not those of the soft palate or base of the tongue.

Total Nasal Reconstruction: Advances in Free Tissue Transfer for Internal Lining and Structural Support.

Total nasal reconstruction is a complex challenge due to the need to establish new internal lining, internal structural support, and external skin covering that is both functional and esthetic. The medial femoral condyle corticoperiosteal free flap represents an innovative option for restoration internal structure and internal nasal lining. When used in conjunction with a paramedian forehead flap, acceptable results in both function and esthetics can be achieved.

Preliminary Results from Retrospective Correlation of Circulating Tumor DNA (ct-DNA) with Imaging for HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

The role of molecular markers is increasingly being recognized for head and neck tumors, ranging from benign lesions like paragangliomas to malignancies like squamous cell carcinomas. Multiple studies have recently validated blood tests for circulating tumor tissue-modified viral human papillomavirus DNA (HPV ct-DNA) for posttreatment surveillance of HPV-driven oropharyngeal squamous cell carcinomas. This technology quantifies fragments of circulating DNA that are shed into the blood stream with very high (>95%) positive and negative predictive values and are also highly sensitive in distinguishing tumor HPV-DNA from a noncancerous source. This study has a cohort of 34 patients with HPV-driven oropharyngeal squamous cell carcinomas, having at least 3 sequential imaging studies and ct-DNA values. The study showed a strong positive correlation between the imaging findings and the ct-DNA level in recurrent HPV-positive oropharyngeal squamous cell carcinomas. Findings also include the 100% negative predictive value of HPV ct-DNA tests to rule out tumor recurrence. At our institution, we are now routinely performing the ct-DNA assay for surveillance of treated HPV oropharyngeal squamous cell carcinomas. Correlation among clinical, radiologic, and biomarker findings are now part of routine discussions during the multidisciplinary tumor boards.

Circulating tumor HPV DNA as an alternative method to determine HPV status in oropharyngeal squamous cell carcinoma.

Human Papilloma Virus (HPV) testing is mandatory for all newly diagnosed oropharyngeal squamous cell carcinoma (OPSCC) due to its importance for prognostication and aiding in treatment decision making. Fine needle aspiration (FNA) is a widely used and accepted diagnostic tool for OPSCC. Although FNA can accurately determine histological diagnosis, results are often indeterminate or lack insufficient samples for HPV testing. For samples with an indeterminant FNA, we propose an alternate method for determining HPV status using circulating tumor tissue modified HPV DNA (ctHPVDNA). We report three cases that confirmed HPV status using ctHPVDNA following an indeterminate FNA. If validated, this non-invasive assay could prevent the need for repeat FNAs or operative biopsies for the sole purpose of determining HPV status.

Osseointegration and Bone Resorption of Scapula Tip Free Flaps in Mandibular Reconstruction.

OBJECTIVES: Bone resorption of more conventional vascularized bone grafts have been well described showing minimal resorption over time. Few studies have evaluated osseous union and bone resorption in scapula tip free flaps (STFF) in the reconstruction of mandibulectomy defects. We aimed to describe our series on STFF with respect to osseous union and bone resorption over time. METHODS: Retrospective chart review of patients receiving STFF from January 2014-January 2017 (n = 25). A neuroradiologist analyzed follow-up CT scans to assess (1) STFF complete, partial, or no osseous union with native mandible and (2) STFF volume change over time in a subset with multiple follow-up scans (n = 18). RESULTS: Twenty-three of 25 patients (92%) showed complete or partial STFF osseous union with native mandible either distally or proximally. STFF volume change ranged from +4.8 to -54% (median -0.5%) over median follow-up interval of 23 months. History of chemoradiation therapy, bisphophonate use, sex, age, or smoking history did not correlate with bone resorption. CONCLUSIONS: STFFs shows high rates of osseous union and limited bone resorption that is equivalent to, or less than, vascularized fibular and iliac crest flaps. Clinically, this translates into both optimal healing and functional and cosmetic outcomes, especially in the setting of prior therapies. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2597-2602, 2023.

Diagnostic accuracy of FNA to determine HPV status in HPV-associated oropharyngeal squamous cell carcinoma.

PURPOSE/OBJECTIVE(S): Accurate diagnosis of human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma (OPSCC) affects prognosis and can alter the treatment plan. We evaluated the diagnostic accuracy of FNA biopsies to determine malignancy and HPV status in OPSCC at our institution. METHODS: Pathology samples from consecutive patients with pathologically confirmed HPV-associated OPSCC who underwent FNA of a cervical lymph node during initial diagnostic work-up were retrospectively analyzed between November 2015 and August 2021. RESULTS: Initial FNA was diagnostic for malignancy in 109/148 (73.6%) patients and non-diagnostic in 39/148 (26.4%). P16 staining of FNAs positive for malignancy showed: 54/109 (49.5%) p16 positive, 6/109 (5.5%) p16 negative, 49/109 (45.0%) p16 indeterminate. In patients with an initial non-diagnostic sampling or p16 indeterminate, repeat FNA was performed in 30/88 (34.1%) patients. Of the 30 repeat FNAs: 23/30 (76.7%) were diagnostic of malignancy and 7/30 (23.3%) remained non-diagnostic for malignancy. Of the 23 repeat FNAs diagnostic of malignancy: 16/23 (69.6%) were p16 positive and 7/23 (30.4%) were p16 indeterminate. In summary, 88/148 (59.5%) initial FNAs and 14/30 (46.7%) of repeat FNAs were non-diagnostic of malignancy or p16 indeterminate. Final yield of FNA biopsies (initial and first repeat FNA) to diagnose malignancy and p16 status was 70/148 (47.3%). CONCLUSIONS: Fine needle aspirations of lymph nodes in patients with HPV-associated OPSCC are frequently non-diagnostic for malignancy or indeterminate for p16 status, requiring repeat FNA or biopsy of the primary site. This can potentially cause treatment delay and increase morbidity and cost to the patient.

Reconstruction of oral cavity defects using myogenous-only scapular tip free-flaps.

Background: Oral cavity reconstruction is very challenging anatomical subsite to reconstruct. Large defects often require free tissue reconstruction to provide the best chance of form and function. Additionally, free tissue reconstruction aids to prevent fistula formation. We aimed to determine outcomes of oral cavity defect reconstruction using scapular tip free flaps with a myogenous intraoral component. Methods: All patients with a mandibular or maxillary bony defect that included a disruption of the intraoral mucosa component between 07/1/14 and 07/31/17. Patients were reconstructed with a scapular tip free flap, which included a muscular component that was used to recreate the oral mucosa. The primary study outcomes were flap success rates, development of orocutaneous or oronasal fistula, rate of resuming oral diet as well as the occurrence of medical and surgical complications in the first month following surgery. The tested hypothesis was formulated before data collection began. Results: Twenty-five patients were identified by the study criteria. There was one (4%) flap that failed, while orocutaneous fistula occurred in two patients (8%). Prior history of osteoradionecrosis was a statistically significant predictor of overall complication (p < .05). Conclusions: Intraoral myogenous reconstruction allows for re-mucosalization of the oral cavity defect and is associated with high viability and low-complication rates. In patients with amenable oral mucosal defects, a myogenous scapular tip free flap is a suitable reconstructive option.

Near-total mandibular reconstruction following osteoradionecrosis with double scapula tip free flap: A case report.

Near-total mandibular reconstruction poses many challenges to reconstructive surgeons. The purpose of this article is to present a challenging case in a patient with osteoradionecrosis of the mandible requiring a near-total mandibular reconstruction using bilateral scapula tip free tissue reconstruction. A 68-year-old African-American male with a history of T2N0M0 squamous cell carcinoma of the tonsil presented with advanced stage osteoradionecrosis of the mandible. Reconstruction was planned using 3D Systems (Denver, CO), mandibular osteotomies were planned inferior to the sigmoid notch on the ascending rami. Neither fibula flap was amenable for harvesting due to poor vasculature of the patient's lower extremities, and bilateral scapula tip free flaps were subsequently planned. The post-operative course was complicated by venous congestion in the right scapula flap which required revision to the venous anastomosis on POD 1. The patient had intraoral breakdown that required debridement in the operating room and application of a cellular matrix. The patient fully recovered from the acute surgery and was discharged home without a tracheostomy. At the last follow up visit, the patient was taking 100% of diet peroral and had no signs of oral incompetence, mental projection was satisfactory, and the ability to verbally communicate was unimpaired. We report a complex case of near-total mandibular reconstruction using simultaneous bilateral scapula tip free flaps. While we do not advocate simultaneous bilateral scapula tip free flaps as the standard of care for large mandibulectomy defects, it may be considered for patients in which traditional osseous free flaps are not available.

Prognostic impact of socioeconomic status compared to overall stage for HPV-negative head and neck squamous cell carcinoma.

OBJECTIVE: To estimate the relative prognostic ability of socioeconomic status (SES) compared to overall stage for HPV-negative head and neck squamous cell carcinoma (HNSCC) MATERIALS AND METHODS: Data were obtained from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE). An empirical 4-category SES classification system was created. Cox proportional hazards models, survival gradients, Bayesian information criterion (BIC), and Harrell's C index were used to estimate the prognostic ability of SES compared to stage on overall survival (OS). RESULTS: The sample consisted of 1229 patients with HPV-negative HNSCC. Patients with low SES had significantly increased risk of mortality at 5 years compared to patients with high SES (HR 3.11, 95% CI 2.07-4.67; p < 0.001), and the magnitude of effect was similar to overall stage (HR 3.01, 95% CI 2.35-3.86; p < 0.001 for stage IV versus I). Compared to overall stage, the SES classification system had a larger total survival gradient (35.8% vs. 29.1%), similar model fit (BIC statistic of 7412 and 7388, respectively), and similar model discriminatory ability (Harrell's C index of 0.61 and 0.64, respectively). The association between low SES and OS persisted after adjusting for age, sex, race, alcohol, smoking, overall stage, tumor site, and treatment in a multivariable model (HR 2.96, 95% CI 1.92-4.56; p < 0.001). CONCLUSION: SES may have a similar prognostic ability to overall stage for patients with HPV-negative HNSCC. Future research is warranted to validate these findings and identify evidence-based interventions for addressing barriers to care for patients with HNSCC.

Genomic heterogeneity and copy number variant burden are associated with poor recurrence-free survival and 11q loss in human papillomavirus-positive squamous cell carcinoma of the oropharynx.

BACKGROUND: Human papillomavirus-positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States. Favorable treatment outcomes have led to increased interest in treatment de-escalation to reduce treatment morbidity as well as the development of prognostic markers to identify appropriately low-risk patients. Intratumoral genomic heterogeneity and copy number alteration burden have been demonstrated to be predictive of poor outcomes in many other cancers; therefore, we sought to determine whether intratumor heterogeneity and genomic instability are associated with poor outcomes in HPV+ OPSCC. METHODS: Tumor heterogeneity estimates were made based on targeted exome sequencing of 45 patients with HPV+ OPSCC tumors. Analysis of an additional cohort of HPV+ OPSCC tumors lacking matched normal sequencing allowed copy number analysis of 99 patient tumors. RESULTS: High intratumorally genomic heterogeneity and high numbers of copy number alterations were strongly associated with worse recurrence-free survival. Tumors with higher heterogeneity and frequent copy number alterations were associated with loss of distal 11q, which encodes key genes related to double-strand break repair, including ATM and MRE11A. CONCLUSIONS: Both intratumor genomic heterogeneity and high-burden copy number alterations are strongly associated with poor recurrence-free survival in patients with HPV+ OPSCC. The drivers of genomic instability and heterogeneity in these tumors remains to be elucidated. However, 11q loss and defective DNA double-strand break repair have been associated with genomic instability in other solid tumors. Copy number alteration burden and intratumoral heterogeneity represent promising avenues for risk stratification of patients with HPV+OPSCC.

Clinical Outcomes of Patients With pT1-T2N0 Oral Tongue Squamous Cell Carcinoma.

OBJECTIVE: The objective of this study was to evaluate the clinical outcomes in a cohort of patients with early-stage oral tongue squamous cell carcinoma (OTSCC). MATERIALS AND METHODS: We conducted a retrospective analysis of patients with pT1-T2N0 (American Joint Committee on Cancer [AJCC] seventh edition) OTSCC treated from 2000 to 2018. Two-year actuarial rates of local regional control, cancer-specific survival, and overall survival were calculated for the entire cohort and patients with/without adjuvant radiation. RESULTS: Ninety-six patients met the criteria with a median follow-up of 4 years; 14 had adjuvant radiation, while 82 had surgery alone. Two-year local regional control was 82.7% (75.4% to 90.8%) for the entire cohort, 84.9% (77.8% to 93.2%) for surgery only, and 70.7% (50.2% to 99.6%) for patients with adjuvant radiation. Two-year progression-free survival was 82.7% (75.3% to 90.8%). Of the 20 patients with recurrence, 11 (55%) were successfully salvaged. CONCLUSION: Local regional recurrence remains modest in early-stage OTSCC, but salvage is possible with high survival rates. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Academic Affiliation and Surgical Volume Predict Survival in Head and Neck Cancer Patients Receiving Surgery.

OBJECTIVE: To determine whether the academic affiliation or surgical volume affects the overall survival (OS) of human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) patients receiving surgery. METHODS: A retrospective study of 39 North Carolina Medical Centers was conducted. Treatment centers were classified as academic hospitals, community cancer centers, or community hospitals and were divided into thirds by volume. The primary outcome was 5-year OS. Hazard ratios (HR) were determined using Cox proportional hazard models, adjusting for demographics, tumor site, stage, insurance status, tobacco use, alcohol use, stage, chemotherapy, and radiation therapy. Patients were also stratified by stage (early stage and advanced stage). RESULTS: Patients treated at community cancer centers had significantly better 5-year OS (HR 0.68, 95% confidence interval [CI] = 0.48-0.98), and patients treated at academic hospitals trended toward better 5-year OS (HR 0.72, 95% CI = 0.50-1.04) compared to patients treated at community hospitals. The effect for academic affiliation on survival was more pronounced for patients with advanced stage cancer at diagnosis (HR 0.60, 95% CI = 0.37-0.95). There were no significant survival differences among early stage patients by treatment center type. Top-third (HR = 0.64, 95% CI = 0.42-0.96) centers by surgical volume had significantly better 5-year OS, and middle-third (HR = 0.71, 95% CI = 0.51-1.03) centers by volume trended toward better 5-year OS when compared to the bottom-third centers by volume. CONCLUSION: Patients treated at academic hospitals, community cancer centers, and hospitals in the top third by case volume have favorable survival for HPV-negative HNSCC. The effect for academic hospitals is most pronounced among advanced stage patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E479-E488, 2021.

Decline in circulating viral and human tumor markers after resection of head and neck carcinoma.

BACKGROUND: DNA sequencing panels can simultaneously quantify human and viral tumor markers in blood. We explored changes in levels of plasma tumor markers following surgical resection of head and neck carcinoma. METHODS: In preresection and postresection plasmas, targeted DNA sequencing quantified variants in 28 human cancer genes and levels of oncogenic pathogens (human papillomavirus [HPV], Epstein-Barr virus [EBV], Helicobacter pylori) from 21 patients with head and neck squamous cell carcinoma. RESULTS: Preresection, 11 of 21 patients (52%) had detectable tumor markers in plasma, most commonly TP53 mutation or HPV genome. Several days postresection, levels fell to undetectable in 8 of 10 evaluable patients, while two high-stage patients retained circulating tumor markers. CONCLUSIONS: Modern sequencing technology can simultaneously quantify human gene variants and oncogenic viral genomes in plasma. Falling levels of cancer-specific markers upon resection can help identify viral and human markers to track at subsequent timepoints as a means to evaluate efficacy of interventions.

Socioeconomic Status Drives Racial Disparities in HPV-negative Head and Neck Cancer Outcomes.

OBJECTIVES/HYPOTHESIS: To determine drivers of the racial disparity in stage at diagnosis and overall survival (OS) between black and white patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective cohort study. METHODS: Data were examined from of a population-based HNSCC study in North Carolina. Multivariable logistic regression and Cox proportional hazards models were used to assess racial disparities in stage at diagnosis and OS with sequential adjustment sets. RESULTS: A total of 340 black patients and 864 white patients diagnosed with HPV-negative HNSCC were included. In the unadjusted model, black patients had increased odds of advanced T stage at diagnosis (OR 2.0; 95% CI [1.5-2.5]) and worse OS (HR 1.3, 95% CI 1.1-1.6) compared to white patients. After adjusting for age, sex, tumor site, tobacco use, and alcohol use, the racial disparity persisted for advanced T-stage at diagnosis (OR 1.7; 95% CI [1.3-2.3]) and showed a non-significant trend for worse OS (HR 1.1, 95% CI 0.9-1.3). After adding SES to the adjustment set, the association between race and stage at diagnosis was lost (OR: 1.0; 95% CI [0.8-1.5]). Further, black patients had slightly favorable OS compared to white patients (HR 0.8, 95% CI [0.6-1.0]; P = .024). CONCLUSIONS: SES has an important contribution to the racial disparity in stage at diagnosis and OS for HPV-negative HNSCC. Low SES can serve as a target for interventions aimed at mitigating the racial disparities in head and neck cancer. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1301-1309, 2021.

Age and risk of recurrence in oral tongue squamous cell carcinoma: Systematic review.

The incidence of oral tongue squamous cell carcinoma has been increasing in young patients (≤45 years) without a clear etiologic driver. It is unknown if younger patients have an increased risk of recurrence compared to older patients. A literature search was conducted through January 2020 using PubMed/MEDLINE, Embase, Cochrane, Scopus, Science Direct, and clinicaltrials.gov. This review was registered with PROSPERO (ID: CRD42020167498) and the PRISMA statement was followed. Studies were eligible for inclusion if they assessed risk of recurrence by age using a time-to-event analysis, used an age cutoff of ≤45 years or less for the younger cohort, and limited the analysis to the oral tongue subsite. Data were extracted independently by two reviewers using a form with a prespecified list of variables. There were 13 articles that met criteria for the qualitative synthesis (n = 1763 patients). The reported 5-year rates of disease-free survival ranged from 30% to 72% for the younger cohorts and 42% to 81% for the older cohorts. Three studies reported a statistically significant increased risk of recurrence in younger patients, three studies reported a nonsignificant increased risk in younger patients, and seven studies reported a similar risk in younger patients based on the time-to-event analyses. There may be an increased risk of recurrence for younger patients with oral tongue cancer. A definitive conclusion is precluded by limitations among individual studies, and additional research is warranted to examine this question.

Novel induction therapy transoral surgery treatment paradigm with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck - Mature clinical and functional outcomes.

OBJECTIVE: Induction chemotherapy in head and neck squamous cell carcinoma (HNSCCA) has principally been studied prior to radiation therapy. We evaluated pre-operative induction therapy followed by surgery followed by risk-adapted adjuvant therapy. This report details the mature 5-year survival statistics, clinical and functional outcomes. METHODS: An IRB-approved single institution prospective phase II clinical trial from October 2012 to November 2016 was conducted for patients with transorally-resectable American Joint Committee on Cancer 7th ed. stage III/IV HNSCCA. Patients were treated once weekly for six weeks with a multi-drug induction regimen of carboplatin, paclitaxel and daily lapatinib followed by transoral surgery and neck dissection. Patients were then stratified based on pathologic response to either observation or adjuvant therapy. Survival statistics and functional patient outcomes were analyzed. Specifically, peri-operative outcomes were analyzed and compared to a matched surgical cohort. RESULTS: 38/40 enrolled patients completed trial therapy. Median hospital stay was 3 days with 9/38 patients receiving a PEG (median 46 days). Median NPO status was 1 day, with a median return to a regular diet in 16 days. Mean patient weight was well preserved from pretreatment to 1 year after surgery (85.1 kg (95% CI 79.6-90.7) vs 83.1 kg (95% CI 77.7-88.6 kg) respectively). Of the 38 patients who completed trial therapy; DSS, PFS and OS were 100%, 97% and 97% respectively with median follow up of 4.9 years (3.33-7.25). CONCLUSION: Transoral surgery was feasible following this novel induction regimen with excellent peri-operative, functional and longterm survival outcomes.

Intraparotid Superficial Temporal Artery Arteriovenous Malformation Causing Persistent Pulsatile Tinnitus.

OBJECTIVES: This article discusses the diagnosis, imaging workup, and management of a rare cause of pulsatile tinnitus: intraparotid arteriovenous malformation. PATIENT: A single patient with a superficial temporal arteriovenous malformation diagnosed by carotid duplex causing pulsatile tinnitus that failed initial surgical management. Repeat imaging failed to identify a cause for the persistent tinnitus. INTERVENTION: Reoperation with a parotid approach based on physical exam findings. RESULTS: Removal of a more proximal arteriovenous malformation in the parotid gland resulted in long-term resolution of the patient's pulsatile tinnitus. CONCLUSIONS: Physical examination is essential in the workup and management of pulsatile tinnitus. Imaging is a useful adjunct in the diagnosis of pulsatile tinnitus but should not be solely relied upon.

Access to preventive care services and stage at diagnosis in head and neck cancer.

BACKGROUND: Decreased access to preventive care services has been proposed as a mechanism for the association between low socioeconomic status (SES) and advanced stage at diagnosis in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Retrospective analysis of patients diagnosed with HNSCC in North Carolina between 2002 and 2006. RESULTS: A total of 1108 patients with HNSCC were included in the study. In the multivariable analysis, use of annual routine dental services (OR 0.7, 95% CI 0.5-0.9) and colonoscopy in the past 10 years (OR 0.7, 95% CI 0.5-0.9) were associated with lower odds of advanced T stage at diagnosis. Having no insurance (OR 1.8, 95% CI 1.1-2.9), an income <$20 000 (OR 1.6 95% CI 1.03-2.6), and >10 pack-years tobacco use (OR 1.5, 95% CI 1.04-2.2) were associated with advanced T stage at diagnosis. CONCLUSION: Use of preventive care services and SES independently predict stage at diagnosis in HNSCC.

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication.

PURPOSE: Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. PATIENTS AND METHODS: This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. RESULTS: Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%-84%) and 75% (51%-88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. CONCLUSIONS: Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.