Objectives We aimed to examine the effectiveness of platinum-based triplet induction chemotherapy in metastatic squamous cell carcinoma of the head and neck (HNSCC) at diagnosis in terms of tumor human papillomavirus (HPV) status and the clinical relevance of circulating tumor HPV DNA (ctHPVDNA) during induction chemotherapy. Methods  Twenty-one patients were included. ctHPVDNA was longitudinally quantified using optimized digital PCR in a subset of patients. Results HPV-related HNSCC patients (N=7) had a significantly better response to induction chemotherapy than HPV-unrelated HNSCC patients (N=14) (complete or partial response rate, 100% vs. 36%, P = 0.007). Following induction chemotherapy, more HPV-related HNSCC patients than HPV-unrelated patients received radiotherapy (86% vs. 36%, P = 0.06). With a median follow-up of 26 months in surviving patients, the two-year overall survival was 86% in HPV-related HNSCC patients and 43% in HPV-unrelated HNSCC patients (P = 0.04). In two patients, ctHPVDNA levels drastically decreased after the first cycle of induction chemotherapy but turned to continuous increase after the second cycle, suggesting the acquisition of drug resistance by the end of the second cycle. Radiographic imaging after induction chemotherapy failed to identify the drug resistance. In one patient, ctHPVDNA decreased gradually but remained detectable after induction chemotherapy despite no radiographic residual disease. ctHPVDNA became undetectable during radiotherapy. Conclusion HPV-related HNSCC patients with distant metastasis at diagnosis should be treated definitively. The ctHPVDNA level reflects real-time disease activity. ctHPVDNA monitoring during induction chemotherapy could help the decision-making of the therapeutic strategy.

OBJECTIVE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy.
METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle.
RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV.
CONCLUSIONS: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

OBJECTIVE: Blood-based multi-cancer early detection (MCED) tests are now commercially available. However, there are currently no consensus guidelines available for head and neck cancer (HNC) providers to direct work up or surveillance for patients with a positive MCED test. We seek to describe cases of patients with positive MCED tests suggesting HNC and provide insights for their evaluation.
METHODS: Retrospective chart review of patients referred to Otolaryngology with an MCED result suggesting HNC. Patients enrolled in prospective MCED clinical trials were excluded. Cancer diagnoses were confirmed via frozen-section pathology.
RESULTS: Five patients were included (mean age: 69.2 years, range 50-87; 4 male) with MCED-identified-high-risk for HNC or lymphoma. Only patient was symptomatic. After physical exam and follow-up head and neck imaging, circulating tumor HPV DNA testing, two patients were diagnosed with p16 + oropharyngeal squamous cell carcinomas and underwent appropriate therapy. A third patient had no evidence of head and neck cancer but was diagnosed with sarcoma of the thigh. The remaining two patients had no evidence of malignancy after in-depth workup.
CONCLUSIONS: In this retrospective study, 2 of 5 patients referred to Otolaryngology with a positive MCED result were diagnosed with HPV + oropharyngeal squamous cell carcinoma. We recommend that positive HNC MCED work up include thorough head and neck examination with flexible laryngoscopy and focused CT or MRI imaging. Given the potential for inaccurate MCED tissue of origin classification, PET/CT may be useful in specific situations. For a patient with no cancer identified, development of clear guidelines is warranted.

BACKGROUND: De-escalation strategies for newly-diagnosed p16-positive oropharyngeal squamous cell carcinoma (p16+ OPSCC), aim to reduce treatment-related morbidity without compromising disease control. One strategy is neoadjuvant cisplatin and docetaxel chemotherapy (NAC + S) before transoral robotic surgery, with pathology-based risk-adapted adjuvant treatment.
METHODS: We examined the recurrence-free survival (RFS) for patients who received NAC + S.
RESULTS: Comparing outcomes in 103 patients between 2008 and 2023, 92% avoided adjuvant treatment and showed significantly higher 2-year recurrence-free survival (RFS) compared to those with adjuvant treatment (95.9% vs. 43.8%, p = 0.0049) CONCLUSION: Our findings suggest that pathology-based risk-adapted omission of adjuvant treatment following NAC + S does not appear to elevate recurrence risk and that NAC may identify patients with favorable tumor biology, yielding a 2-year RFS probability exceeding 95% without adjuvant treatment. Further, the study identifies a patient subset experiencing disease recurrence despite triple modality therapy. Despite limitations, including a retrospective design and modest sample size, the data advocate for controlled NAC + S studies.

BACKGROUND: This study provides an epidemiological description of cancer in the lip, oral cavity, and oropharynx in the South and South-East Asia region.
METHODS: The number of new cases and deaths was extracted from the GLOBOCAN 2020 and the CI5 series. We present age-standardized incidence and mortality rates per 100,000 inhabitants. To assess temporal trends, we estimated the annual percent change.
RESULTS: The incidence rates (ASR) for lip and oral cavity cancer in South and South-East Asia were highest in Taiwan (30.2), Sri Lanka (16.5), India (14.8), and Pakistan (13.2) among males. For oropharyngeal cancer, the highest rates were found in Taiwan (4.7), Bangladesh, Sri Lanka, and India (4.3, 2.9, and 2.6, respectively). Incidence rates were consistently higher in males compared to females. Overall, trends in lip and oral cavity cancer incidence were either stable or decreasing in most of the populations evaluated. In India, an increase in rates among males contrasted with a decline among females over the study period.
CONCLUSIONS: Incidence and mortality rates of oral cavity cancer in South and South-East Asia are among the highest globally. Our results suggest an optimistic trend of reduction in oral cavity rates in the region, despite an increase in rates among Indian males.

Squamous cell carcinoma (SCC) is the most common malignancy of the oropharynx (OP). Treatment of OP SCC includes chemotherapy, radiation, and/or surgery. OP SCC can spread via direct extension, lymphatics, or hematogenously. Although rare, distant metastases can occur in OP SCC. The most common sites of metastasis include the lungs, bone, and liver. Other less common sites include the skin, bone marrow, brain, kidneys, eyes, and heart. Patients who present with distant metastases usually have a poor prognosis. Sites of bone metastases from more common to less common include the spine, skull, ribs, and axial bones. In this article, we discuss a patient who presents with HPV+ base of tongue SCC with metastases to the lungs and mandible symphysis. Base of tongue SCC metastasizing to the mandible symphysis is a rarely reported location of metastasis.

BACKGROUND: Despite the diverse genetic mutations in head and neck cancer, the chemotherapy outcome for this cancer has not improved for decades. It is urgent to select prognostic factors and therapeutic targets for oropharyngeal cancer to establish precision medicine. Recent studies have identified PSMD1 as a potential prognostic marker in several cancers. We aimed to assess the prognostic significance of PSMD1 expression in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry.
METHODS: We studied 64 individuals with OPSCC tissue from surgery at Seoul National University Bundang Hospital between April 2008 and August 2017. Immunostaining analysis was conducted on the tissue microarray (TMA) sections (4 μm) for p16 and PSMD1. H-score, which scale from 0 to 300, was calculated from each nucleus, cytoplasm, and cellular expression. Clinicopathological data were compared with Chi-squared test, Fisher\'s exact test, t-test, and logistic regression. Survival data until 2021 were achieved from national statistical office of Korea. Kaplan-Meier method and cox-regression model were used for disease-specific survival (DSS) analysis.
RESULTS: H-score of 90 in nucleus was appropriate cutoff value for \'High PSMD1 expression\' in OPSCC. Tonsil was more frequent location in low PSMD1 group (42/52, 80.8%) than in high PSMD1 group (4/12, 33.3%; P = .002). Early-stage tumor was more frequent in in low PSMD1 group (45/52, 86.5%) than in high PSMD1 group (6/12, 50%; P = .005). HPV was more positive in low PSMD1 group (43/52, 82.7%) than in high PSMD1 group (5/12, 41.7%; P = .016). Patients with PSMD1 high expression showed poorer DSS than in patients with PSMD1 low expression (P = .006 in log rank test). In multivariate analysis, PSMD1 expression, pathologic T staging, and specimen age were found to be associated with DSS (P = .011, P = .025, P = .029, respectively).
CONCLUSIONS: In our study, we established PSMD1 as a negative prognostic factor in oropharyngeal squamous cell carcinoma, indicating its potential as a target for targeted therapy and paving the way for future in vitro studies on drug repositioning.

Cancer-related fatigue (CRF) is a common side-effect of cancer and its treatments. For head and neck cancer (HNC), CRF may exacerbate the symptom burden and poor quality-of-life. Using data from the Head and Neck 5000 prospective clinical cohort, we investigated clinically important CRF over a year post-diagnosis, assessing temporal trends, CRF by HNC site and treatment received, and subgroups at higher risk of CRF. Recruitment was undertaken in 2011-2014. Socio-demographic and clinical data, and patient-reported CRF (EORTC QLQ-C30 fatigue subscale score ≥39 of a possible 100) were collected at baseline (pre-treatment) and 4- and 12- months post-baseline. Mixed-effects logistic multivariable regression was used to investigate time trends, compare cancer sites and treatment groups, and identify associations between clinical, socio-demographic and lifestyle variables and CRF. At baseline, 27.8% of 2847 patients scored in the range for clinically important CRF. This was 44.7% at 4 months and 29.6% at 12 months. In the multivariable model, after adjusting for time-point, the odds of having CRF over 12 months were significantly increased in females and current smokers; those with stage 3/4 disease, comorbidities and multimodal treatment; and those who had depression at baseline. The high prevalence of clinically important CRF indicates the need for additional interventions and supports for affected HNC patients. These findings also identified patient subgroups towards whom such interventions could be targeted.

OBJECTIVE: To prospectively compare the impact of treatment modality on patient-reported quality of life (QOL) in human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC).
METHODS: Prospective cohort study.
METHODS: Academic medical center.
METHODS: One hundred one patients with American Joint Committee on Cancer (AJCC) 8th edition T1-3 N0-2 HPV + OPSCC completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire and Head and Neck Module pretreatment and 3-month and 1-year posttreatment. Mean score changes were compared to published minimal clinically important differences.
RESULTS: Patients underwent surgery alone (SA: N = 42, 42%), surgery with adjuvant radiation (S-RT: N = 10, 10%), surgery with adjuvant chemoradiation (S-CRT: N = 8, 8%), definitive radiation (RT: N = 11, 11%), or definitive chemoradiation (CRT: N = 30, 30%). SA, S-[C]RT, and [C]RT patients all reported clinically significant difficulty with sense of taste/smell persisting at 1 year. S-[C]RT and [C]RT patients reported statistically and clinically significant worse salivary dysfunction and problems with social eating at 1 year than SA. S-[C]RT patients reported statistically and clinically significant worse fatigue and head and neck pain compared to [C]RT and SA patients at 3 months, but normalized at 1 year. S-CRT compared to S-RT had statistically and clinically worse physical and role functioning and swallowing difficulties at 3 months but this difference was resolved by 1-year posttreatment.
CONCLUSIONS: HPV + OPSCC patients after SA report the lowest posttreatment QOL impact, whereas after S-CRT report the highest symptom burden. Careful selection for definitive surgery is important given the possibility of adjuvant CRT. Patients can experience persistent sense taste and smell difficulties at 1 year with all treatment modalities.
METHODS: 3 Laryngoscope, 134:1687-1695, 2024.

Intermediate and high-risk features (IRFs/HRFs) for locoregional recurrence following initial surgery for oropharyngeal SCCs (OP-SCCs) were defined prior to the known association of HPV with OP-SCC. There are limited reports on practice patterns and outcomes associated with post-operative radiation therapy (PORT) or chemoradiation (POCRT) for HPV-associated OP-SCCs.
The National Cancer Database was queried for patients with HPV-associated OP-SCCs managed initially with surgery with IRFs or HRFs. IRFs were defined as pT3/T4 disease, pN1-3 disease, and lymphovascular space invasion, and HRFs as positive margins and extranodal extension (ENE). Patients were stratified into no adjuvant therapy, PORT, or POCRT arms. Kaplan-Meier analysis was utilized for comparison of overall survival (OS) between treatment arms followed by a Cox multivariate (MVA) proportional-hazards model and propensity score analyses with inverse probability treatment weighting (IPTW).
We identified 6,301 patients; 51.2% had IRFs only and 48.8% had HRFs. Regarding treatment, 25.5%, 38.2%, and 36.3% of patients received no RT, PORT, and POCRT, respectively. Patients with IRFs who did not receive RT or CRT had inferior 8-year OS (81.1% vs. 87.8%; p < 0.001) that remained significant on IPTW MVA (hazard ratio (HR) = 1.69 (95% CI: 1.27-2.24; p < 0.001). Among patients with HRFs, 8-year OS was not significantly different between patients receiving PORT vs. POCRT (77.3% vs. 79.2%; p = 0.22) that remained insignificant on IPTW MVA (HR = 0.91(0.72-1.17); p = 0.48).
A significant proportion of HPV-associated OP-SCC patients with IRFs or HRFs did not receive PORT, which was associated with inferior OS. We did not demonstrate with statistical power that POCRT vs. PORT was associated with superior OS in patients with HRFs, though prospective studies are warranted.