Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. EXPERIMENTAL DESIGN: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12-17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46-119.5; P = 0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.

Perspectives on Referral Pathways for Timely Head and Neck Cancer Care.

Importance: Timely diagnosis and treatment are of paramount importance for patients with head and neck cancer (HNC) because delays are associated with reduced survival rates and increased recurrence risk. Prompt referral to HNC specialists is crucial for the timeliness of care, yet the factors that affect the referral and triage pathway remain relatively unexplored. Therefore, to identify barriers and facilitators of timely care, it is important to understand the complex journey that patients undertake from the onset of HNC symptoms to referral for diagnosis and treatment. Objective: To investigate the referral and triage process for patients with HNC and identify barriers to and facilitators of care from the perspectives of patients and health care workers. Design, Participants, and Setting: This was a qualitative study using semistructured interviews of patients with HNC and health care workers who care for them. Participants were recruited from June 2022 to July 2023 from HNC clinics at 2 tertiary care academic medical centers in Boston, Massachusetts. Data were analyzed from July 2022 to December 2023. Main Outcomes and Measures: Themes identified from the perspectives of both patients and health care workers on factors that hinder or facilitate the HNC referral and triage process. Results: In total, 72 participants were interviewed including 42 patients with HNC (median [range] age, 60.5 [19.0-81.0] years; 27 [64%] females) and 30 health care workers (median [range] age, 38.5 [20.0-68.0] years; 23 [77%] females). Using thematic analysis, 4 major themes were identified: the HNC referral and triage pathway is fragmented; primary and dental care are critical for timely referrals; efficient interclinician coordination expedites care; and consistent patient-practitioner engagement alleviates patient fear. Conclusions and Relevance: These findings describe the complex HNC referral and triage pathway, emphasizing the critical role of initial symptom recognition, primary and dental care, patient information flow, and interclinician and patient-practitioner communication, all of which facilitate prompt HNC referrals.

Patient Experience of Head and Neck Surgery With Free Flap Reconstruction.

Importance: Major head and neck surgery with microvascular free tissue transfer reconstruction is complex, with considerable risk of morbidity. Little is known about patients' experiences, including decision-making prior to, and regret following, free flap surgery. Objective: To characterize patient experiences and decision regret of patients undergoing head and neck reconstructive free flap surgery. Design, Setting, and Participants: This mixed-methods cohort study comprising semistructured interviews was conducted June to August 2021 at a single tertiary academic cancer center. Participants underwent head and neck reconstructive surgery with microvascular free tissue transfer (flap) more than 3 months before recruitment (range, 3 months to 4 years). Interview transcripts were qualitatively analyzed for themes. Participants also completed a Decision Regret Scale questionnaire. Exposure: Microvascular free flap surgery for head and neck reconstruction. Main Outcomes and Measures: Thematic analysis of interviews, decision regret score. Results: Seventeen participants were interviewed. Median (IQR) age was 61 (52-70) years. Overall, 7 participants were women (49%), and 10 of 17 were men (59%). The most common free flap was fibula (8/17, 47%). Three major themes with 9 subthemes were identified: theme 1 was the tremendous effect of preoperative counseling on surgical decision-making and satisfaction, with subthemes including (1) importance of clinical care team counseling on decision to have surgery; (2) emotional context colors preoperative understanding and retention of information; (3) expectation-setting affects satisfaction with preoperative counseling; and (4) desire for diversified delivery of preoperative information. Theme 2 was coexisting and often conflicting priorities, including (1) desire to survive above all else, and (2) desire for quality of life. Theme 3 was perception of surgery as momentous and distressing, including (1) surgery as a traumatic event; (2) centrality of mental health, emotional resolve, and gratitude to enduring surgery and recovery; and (3) sense of accomplishment in recovery. On the Decision Regret Scale, most participants had no regret (n = 8, 47%) or mild regret (n = 5, 29%); 4 had moderate-to-severe regret (24%). Conclusions and Relevance: In this mixed-methods cohort study, patient experiences surrounding major head and neck reconstructive free flap surgery were described. Opportunities to improve support for this complex and vulnerable population, and to mitigate decision regret, were identified.

Primary Classic Kaposi Sarcoma of the Parotid Gland in an HIV-Negative Patient.

This case report describes an HIV-negative man in his 60s of Mediterranean descent with hypertension, Hashimoto thyroiditis, nephrolithiasis, and gout who presented with a lump on the right side of his face and was subsequently diagnosed with Kaposi sarcoma.

Personal Social Networks and Care-Seeking for Head and Neck Cancer: A Qualitative Study.

OBJECTIVES: To investigate the role of patients' personal social networks (SNs) in accessing head and neck cancer (HNC) care through patients' and health care workers' (HCWs) perspectives. STUDY DESIGN: Qualitative study. SETTING: Tertiary HNC centers at 2 academic medical centers, including 1 safety net hospital. METHODS: Patients with newly diagnosed HNC, and HCWs caring for HNC patients, aged ≥18 years were recruited between June 2022 and July 2023. Semistructured interviews were conducted with both patients and HCWs. Inductive and deductive thematic analysis was performed with 2 coders (κ = 0.82) to analyze the data. RESULTS: The study included 72 participants: 42 patients (mean age 57 years, 64% female, 81% white), and 30 HCWs (mean age 42 years, 77% female, 83% white). Four themes emerged: (1) Patients' SNs facilitate care through various forms of support, (2) patients may hesitate to seek help from their networks, (3) obligations toward SNs may act as barriers to seeking care, and (4) the SN composition and dedication influence care-seeking. CONCLUSION: Personal SNs play a vital role in prompting early care-seeking among HNC patients. SN-based interventions could enhance care and improve outcomes for HNC patients.

Circulating tumor-tissue modified HPV DNA testing in the clinical evaluation of patients at risk for HPV-positive oropharynx cancer: The IDEA-HPV study.

OBJECTIVES: While survival outcomes are favorable for Human Papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs), early diagnosis may minimize treatment-related morbidity and mortality. This study evaluated circulating tumor tissue-modified viral (TTMV)-HPV DNA plasma testing to facilitate early diagnosis of HPV-positive OPSCCs. METHODS: In this prospective exploratory cohort study, patients presenting to an Otolaryngology-Head and Neck Surgery clinic with unexplained signs or symptoms considered high-risk for HPV-positive OPSCC were recruited between March 2021-October 2022. Circulating TTMV-HPV DNA testing was performed, and results were shared with subjects and treating clinicians. Clinicians were surveyed regarding the perceived clinical utility of the test. RESULTS: Thirty-nine subjects were included. Most subjects were women (N = 23, 59 %), white (N = 32, 82 %) and never-smokers (N = 20, 51 %) with median age 60 years. Circulating TTMV-HPV DNA was detected in 2/39 subjects, both subsequently diagnosed with HPV-positive OPSCC. Both were white men aged 70-80 years with a neck mass. One subject with undetectable TTMV-HPV DNA was also diagnosed with HPV-positive OPSCC through excisional neck mass biopsy. Other eventual diagnoses included 3 HPV-negative head and neck squamous cell carcinomas and 4 other malignancies. Testing was perceived as helpful in clinical decision-making for 26/38 (68 %) subjects, and useful for similar future patients for 32/37 (86 %) subjects. CONCLUSION: Circulating TTMV-HPV DNA testing is feasible and holds potential as a diagnostic aid for HPV-positive OPSCC alongside standard clinical workup. Clinicians should be cognizant of its limitations, as a negative test does not necessarily indicate the absence of disease. Further studies to evaluate its utility are warranted.

Variations in Payer-Negotiated Prices for Head and Neck Reconstructive Surgery.

OBJECTIVE: Little is known about pricing for reconstructive procedures of the head and neck. As of January 2021, the Centers for Medicare and Medicaid Services requires hospitals to disclose payer-negotiated prices for services, offering new insight into prices for privately insured patients. STUDY DESIGN: Cross-sectional analysis. SETTING: Turquoise database. METHODS: Payer-negotiated facility fees for 41 reconstructive surgeries were grouped by procedure type: primary closure, skin grafts, tissue rearrangement, locoregional flaps, or free flaps. Prices were normalized to account for local labor costs, then calculated as percent markup in excess of Medicare reimbursement. The mean percent markup between procedure groups was compared by the Kruskal-Wallis test. Subset analyses were performed to compare mean percent markup using a Student's t test. We also assessed price variation by calculating the ratio of 90th/10th percentile mean prices both across and within hospitals. RESULTS: In total, 1324 hospitals (85% urban, 81% nonprofit, 49% teaching) were included. Median payer-negotiated fees showed an increasing trend with more complex procedures, ranging from $379.54 (interquartile range [IQR], $230.87-$656.96) for Current Procedural Terminology (CPT) code 12001 ("simple repair of superficial wounds ≤2.5 cm") to $5422.60 ($3983.55-$8169.41) for CPT code 20969 ("free osteocutaneous flap with microvascular anastomosis"). Median percent markup was highest for primary closure procedures (576.17% [IQR, 326.28%-1089.34%]) and lowest for free flaps (99.56% [37.86%-194.02%]). Higher mean percent markups were observed for rural, for-profit, non-Northeast, nonteaching, and smaller hospitals. CONCLUSION: Wide variation in private payer-negotiated facility fees exists for head/neck reconstruction surgeries. Further research is necessary to better understand how pricing variation may correlate with out-of-pocket costs and quality of care.

Hospital-Negotiated Pricing of Cochlear Implants.

Access to cochlear implantation can be restricted by financial burden, and little is known about the extent to which cochlear implant (CI) devices prices may vary between hospitals or manufacturers. We performed a cross-sectional analysis of private payer-negotiated prices for CI devices. In total, 161 hospitals were analyzed. Prices varied widely across hospitals and between payers. Despite clinical equipoise between manufacturers with regards to CI user outcomes, significant differences in prices were identified, with higher prices for MED-EL ($38,478 ± 2633) than for Cochlear Ltd. ($34,150 ± 2418, p < .001). Markup analysis for Cochlear Ltd. devices revealed a mean 58.5% ± 7.4% markup in excess of the company's average sales price ($24,649). Negotiated prices were also at least $5000 lower when all 3 brands were offered at the same center (p < .05). Further research examining the influence of patient outcomes and hospital volume on prices are needed.

Variation in the Price of Head and Neck Surgical Oncology Procedures.

Health care costs can present a significant strain on patients with head and neck cancer. It remains unclear how much prices may vary among hospitals providing care and what factors lead to differences in prices of surgical procedures. A cross-sectional analysis of private payer-negotiated prices was performed for 10 commonly performed head and neck surgical oncology procedures. In total, 896 hospitals disclosed prices for at least 1 common head and neck surgical oncology procedure. Wide variation in negotiated surgical prices was identified. Across-center ratios ranged from 6.2 (partial glossectomy without primary closure) to 22.8 (excision of tongue lesion without closure). For-profit hospital ownership structure and geographic region outside of the northeast United States were associated with increased prices. For example, private payer-negotiated prices for direct laryngoscopy with biopsy were on average $2083 greater at for-profit hospitals when compared with nonprofit hospitals ($5215 vs $3132, P < .001). Further research comparing prices and outcomes is needed.

Hospital Prices for Pediatric Tympanostomy Tube Placement and Adenotonsillectomy in 2021.

OBJECTIVES: Hospital prices vary substantially for myringotomy with tympanostomy tube placement (M&T) and adenotonsillectomy (T&A). The Centers for Medicare and Medicaid Services recently implemented hospital price transparency requirements to help families make financially informed decisions about where to seek care. We sought to determine price availability and the extent of price variation for these procedures. METHODS: We performed a cross-sectional analysis of the Turquoise Health Hospital Rates Data Platform, which extracts prices for facility fees from publicly available hospital chargemasters. We determined the proportion of hospitals serving pediatric patients that published payer-specific prices for M&T and T&A. We additionally characterized the extent of variation in payer-specific prices both across and within hospitals. RESULTS: Approximately 40% (n = 909 of 2,266 hospitals) serving pediatric patients disclosed prices for M&T or T&A. Among disclosing hospitals, across-center ratios (adjusted for Medicare hospital wage indices) ranged from 11.0 (M&T; 10th percentile adjusted median price: $536.80 versus 90th percentile adjusted median price: $5,929.93) to 23.4 (revision adenoidectomy age >12 years; 10th percentile: $393.82 versus 90th percentile: $9,209.88). Median within-center price ratios for procedures ranged from 2.2 to 2.7, indicating that some private payers reimbursed the same hospital more than twice as much as other payers for the same procedure. CONCLUSION: The majority of hospitals serving pediatric patients were non-compliant with federal requirements to disclose prices for M&T and T&A. Among disclosing hospitals, there was wide variation in payer-specific prices between and within institutions. Further research is necessary to understand whether disclosure of prices will enable families to make more financially informed decisions. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:948-955, 2023.

Hospital-Administered Cancer Therapy Prices for Patients With Private Health Insurance.

Importance: The federal Hospital Price Transparency final rule, which became effective in 2021, requires hospitals to publicly disclose payer-specific prices for drugs. However, little is known about hospital markup prices for parenterally administered therapies. Objective: To assess the extent of price markup by hospitals on parenterally administered cancer therapies and price variation among hospitals and between payers at each hospital. Design, Setting, and Participants: A cross-sectional analysis was conducted of private payer-specific negotiated prices for the top 25 parenteral (eg, injectable or infusible) cancer therapies by Medicare Part B spending in 2019 using publicly available hospital price transparency files. Sixty-one National Cancer Institute (NCI)-designated cancer centers providing clinical care to adults with cancer were included. The study was conducted from April 1 to October 15, 2021. Exposures: Estimated hospital acquisition costs for each cancer therapy using participation data from the federal 340B Drug Pricing Program. Main Outcomes and Measures: The primary outcome was hospital price markup for each cancer therapy in excess of estimated acquisition costs. Secondary outcomes were the extent of across-center price ratios, defined as the ratio between the 90th percentile and 10th percentile median prices across centers, and within-center price ratios, defined as the ratio between the 90th percentile and 10th percentile prices between payers at each center. Results: Of 61 NCI-designated cancer centers, 27 (44.3%) disclosed private payer-specific prices for at least 1 top-selling cancer therapy as required by federal regulations. Median drug price markups across all centers and payers ranged between 118.4% (sipuleucel-T) and 633.6% (leuprolide). Across-center price ratios ranged between 2.2 (pertuzumab) and 15.8 (leuprolide). Negotiated prices also varied considerably between payers at the same center; median within-center price ratios for cancer therapies ranged from 1.8 (brentuximab) to 2.5 (bevacizumab). Conclusions and Relevance: Most NCI-designated cancer centers did not publicly disclose payer-specific prices for cancer therapies as required by federal regulation. The findings of this cross-sectional study suggest that, to reduce the financial burden of cancer treatment for patients, institution of public policies to discourage or prevent excessive hospital price markups on parenteral chemotherapeutics might be beneficial.

Unusual presentation of HPV-positive squamous cell carcinoma of the nasolacrimal duct as carcinoma of unknown primary.

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.

Private Payer-Negotiated Prices for Outpatient Otolaryngologic Surgery.

In January 2021, the Centers for Medicare & Medicaid Services began requiring hospitals to publish price transparency files listing all prices negotiated with payers. We performed a cross-sectional analysis of payer-negotiated prices for commonly performed outpatient otolaryngology surgery at all hospitals scored by the US News & World Report in otolaryngology. We compared prices among hospitals (across-center ratios) and among payers at the same hospital (within-center ratios). Price disclosure rates were low overall for otolaryngologic surgery (maximum, 26.7% for bronchoscopy). Across-center ratios ranged from 3.5 (adjacent tissue transfer/rearrangement <10 cm2; raw median price range, $1384-$7047) to 18.6 (cochlear implant placement; raw median price range, $2417-$60,255). Median within-center ratios ranged between 2.7 (intraoperative navigation) and 5.4 (total thyroidectomy). Although price variation may signal opportunities for cost savings, patients may have limited ability to comparison shop due to hospital nondisclosure. Further investigation is necessary to examine the factors affecting price variation for otolaryngologic procedures.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling. RESULTS: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders. CONCLUSIONS: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Cancer of the Oropharynx and the Association with Human Papillomavirus.

Squamous cell carcinoma of the oropharynx (OPC) consists of human papillomavirus (HPV)-negative disease caused by tobacco and alcohol use, and HPV-positive disease caused by the sexually transmitted infection HPV. These entities have unique but overlapping risk factors, epidemiologic trends, staging systems, and survival outcomes. HPV-positive tumor status confers a significant survival benefit compared with HPV-negative disease. OPC treatment entails a combination of surgery, radiation, and chemotherapy. Ongoing trials will determine whether treatment of HPV-related disease may be safely deintensified to decrease morbidity. Emerging HPV-related biomarkers are under study as tools to inform screening, diagnosis, treatment, and surveillance for HPV-positive OPC.

Single-surgeon parotidectomy outcomes in an academic center experience during a 15-year period.

OBJECTIVE: As large single-surgeon series in the literature are lacking, we sought to review a single-surgeon's experience with parotidectomy in an academic center, with a focused analysis of pathology, technique, and facial nerve (FN) weakness. Benchmark values for complications and operative times with routine trainee involvement and without continuous FN monitoring are offered. MATERIALS AND METHODS: All patients who underwent parotidectomy, performed by D. G. D., for benign and malignant disease between January 2004 and December 2018 at an academic center were reviewed. RESULTS: A total of 924 parotidectomies, with adequate evaluatable data were identified. The majority of patients had benign tumors (70.9%). Partial/superficial parotidectomy was the most common approach (65.7%). Selective FN branch sacrifice was rare (12.3%), but significantly more common among patients with malignant pathology (33.8% vs 3.5% for benign, P < .0001). Among patients with intact FN, post-operative short- and long-term FN weaknesses were rare (6.5% and 1.7%, respectively). These rates were lower among patients with benign tumors (5.4% and 1.3%). Partial/superficial parotidectomy for benign tumors was associated with a low rate of short- and long-term FN weaknesses (2.7% and 0.9%). Mean OR time was 185 minutes. CONCLUSION: This is the largest single-surgeon series on parotidectomy, spanning 15 years. We demonstrate excellent long- and short-term FN paresis rates with acceptable operative times without regular use of continuous FN monitoring and with routine trainee involvement. These findings may provide valuable insight into parotid tumor pathology, FN outcomes, and feasibility and expectations of performing parotidectomy in an academic setting. LEVEL OF EVIDENCE: 4.

Complications of Transoral Robotic Surgery.

This article summarizes major and minor complications following transoral robotic surgery in the head and neck. Overall, transoral robotic surgery is extremely safe; however, surgeons must recognize inherent risks associated with major and severe bleeding, dysphagia, and minor complications, including injury to nerves, mucosal surfaces, teeth, and the eyes. This article briefly discusses prevention and management strategies for common complications.