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Importance Standard adjuvant therapy for human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is radiation therapy 60 Gy with or without cisplatin delivered in 30 fractions during 6 weeks. A phase 3 randomized clinical trial demonstrated decreased toxic effects and improved patient-reported outcomes with de-escalated adjuvant radiation therapy (DART) compared with standard therapy; however, outcomes for patients treated in the clinical practice setting following trial adoption remain unknown. Objective To compare characteristics and oncologic outcomes of patients treated with DART during clinical trials (on study) and in clinical practice settings (off study) and report progression-free survival (PFS) by risk category. Design, Setting, and Participants This retrospective cohort study included patients treated with DART in the MC1273 and MC1675 trials and in clinical practice after study completion at a multisite tertiary care center. Patients with surgically resectable HPV-OPSCC who underwent margin-negative resection between August 20, 2013, and March 21, 2023, and were treated with DART were included in the analysis. Those with prior head and neck cancer, pT0 or pT4 disease, unknown HPV status, metastatic disease at presentation, synchronous primary tumors, induction chemotherapy, or treatment at an outside institution were excluded. Data were analyzed from July 1, 2024, to July 18, 2025. Interventions DART consisting of 30 to 36 Gy in 1.5- to 1.8-Gy fractions twice daily with docetaxel 15 mg/m 2 on days 1 and 8. Main Outcomes and Measures Progression-free survival as measured via Kaplan-Meier analysis. Results A total of 282 patients were included in the analysis: 176 (62.4%) in the on-study group and 106 (37.6%) in the off-study group (252 [89.4%] male; mean [SD] age, 59.1 [9.3] years). Both groups were predominantly male (157 [89.2%] and 95 [89.6%], respectively) and consisted mostly of never smokers (118 [67.0%] and 62 [58.5%], respectively). Pathologic features were similar between groups except for nodal stage (pN1: 155 [88.1%] on study vs 102 [96.2%] off study; pN2: 21 [11.9%] on study vs 4 [3.8%] off study; P = .02). The median follow-up times were 5.2 years (95% CI, 5.2-5.8 years) in the on-study group and 2.2 years (95% CI, 1.9-2.4 years) in the off-study group. Two-year PFS was similar (93% [95% CI, 88%-97%] on study vs 93% [95% CI, 88%-99%] off study). For patients with pN1 and no extranodal extension (ENE), 2- and 5-year PFS were 97% (95% CI, 93%-100%) and 96% (95% CI, 92%-100%), respectively. Patients with pN1 and ENE had a 2- and 5-year PFS of 93% (95% CI, 89%-98%) and 87% (95% CI, 81%-94%), respectively. Conclusions and Relevance In this retrospective cohort study of patients receiving DART on and off study, oncologic outcomes were similar between the 2 groups. Fewer patients with pN2 received DART off study, given the interim results of MC1675. Patients with pN1 and no ENE treated with DART had excellent 2- and 5-year PFS, supporting DART as a compelling treatment option in well-selected patients. An additional study that is currently underway will evaluate biomarker risk-stratified treatment of patients with pN1 and ENE receiving DART.

PURPOSE The ECOG-ACRIN E3311 phase II trial demonstrated outstanding disease control (90.6% 54-month progression-free survival) after transoral surgery (TOS) with de-escalated, risk-based postoperative management in resectable human papillomavirus–associated oropharyngeal cancer. The goal of de-escalation was functional preservation. The objective of this work was to evaluate clinician-graded modified barium swallow (MBS) studies from E3311 over time and across arms for (1) aspiration and high-grade pharyngeal residue rates, (2) differences in swallow safety and efficiency, and (3) accuracy of site clinicians reporting against central MBS review. METHODS Eight hundred eighty-five MBS studies were performed on 314 patients from 50 of 59 sites at baseline, post-TOS, and 6 and 24 months postradiotherapy (RT). Swallow outcomes (aspiration, high-grade residue) were recorded by site clinicians. A subset of 414 MBS studies was centrally graded using penetration-aspiration scale scores and the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. RESULTS Aspiration, residue, and dysphagia rates significantly increased from baseline to post-TOS ( P < .01) and then decreased modestly at 6 and 24 months. At 6 months, swallow outcomes favored the 50- versus 60-Gy arm, with significantly lower aspiration and high-grade dysphagia rates, but this difference was not maintained at 24 months. MBS results reported by site clinicians demonstrated substantial agreement with those assessed by the central laboratory (PABAK, 0.75-0.84; P < .01). CONCLUSION Swallowing worsened after TOS but improved by 6 and 24 months despite adjuvant therapy. De-escalated adjuvant RT at 50 Gy reduced acute aspiration. Site-reported MBS metrics strongly aligned with DIGEST, showing potential as an accessible metric in cooperative group settings.

This phase II trial of transoral surgery (TOS) with deintensified postoperative management in human papillomavirus (HPV)–associated oropharynx cancer (OPC) enrolled patients with resectable cT1-2 stage III/IV American Joint Committee on Cancer (AJCC) seventh edition p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (arm A); those with clear margins, 2-4 + LN, or ENE ≤1 mm were randomly assigned to 50 Gy (arm B) or 60 Gy (arm C); and those with involved margins, >4 + LN, or >1 mm ENE received weekly cisplatin and 60-66 Gy (arm D). Among 359 evaluable patients, the 54-month progression-free (PFS) and overall survival (OS) were 90.6% (90% CI, 87.2% to 93.1%) and 95.3% (93.0% to 96.9%), respectively. The 54-month PFS by arm was A 93.2% (79.6% to 97.8%; all four recurrences among N1 patients), B 94.9% (89.7% to 97.5%), C 90.2% (82.7% to 94.6%), and D 85.5% (77.5% to 90.8%). The 54-month OS by arm was A 97.1% (85.7% to 99.4%), B 97.9% (93.5% to 99.3%), C 95.1% (90.1% to 97.6%), and D 92.5% (86.9% to 95.7%). PFS or OS did not differ by primary site or smoking history. TOS and neck dissection with deintensified postoperative management results in outstanding 54-month PFS and OS. Among patients with favorable pathologic characteristics, those with N1 disease are at risk of late recurrence without radiation.

ImportanceThe De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity.ObjectiveTo determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Design, Setting, and ParticipantsThis was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025.InterventionsThe DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2.Main Outcome and MeasurePFS.ResultsThe analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67).Conclusions and RelevanceThis secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02908477

Abstract Purpose: Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus–associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. Experimental Design: Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell–cell interactions, and niche analyses were performed. Results: In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. Conclusions: In human papillomavirus–associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.

Abstract Objective Margin distance is a significant prognosticator in oral cavity cancer but its role in HPV‐related oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] remains unclear. Here, we investigate the impact of margin distance on locoregional recurrence in HPV(+)OPSCC. Study Design This is a retrospective cohort study of surgically treated HPV(+)OPSCC patients. Patients received either standard of care (at least 60 Gy with or without cisplatin) or de‐escalated adjuvant therapy (30‐36 Gy with concurrent docetaxel). Margin distance was measured in mm from the primary specimen or in combination with separately submitted margins. Kaplan‐Meier survival analysis with univariate and multivariable Cox regressions were conducted to determine the impact of margin distance on risk of local and locoregional recurrence. Setting Setting for this is 3 tertiary centers between January 2010 and February 2024. Results Among 1102 included patients, 33 (3.0%) had positive final margins. 374 patients had adequate margin distance data available. Margin distance was >3 mm in 73.4%, 1 to 3 mm in 24.5%, and <1 mm in 2.2% of patients. Positive final margins, pT4 disease, pN2 disease, and surgery alone as a treatment modality ( P < .02 for all) was associated with higher risk of 5‐year locoregional recurrence. Margin distance did not significantly impact risk of local or locoregional recurrence even after adjusting for de‐escalated adjuvant therapy ( P > .05). Conclusion Positive final margins after TORS without adjuvant radiotherapy for HPV(+)OPSCC carries a high risk of local recurrence. Margin distance does not appear to significantly impact risk of local or locoregional recurrence, even after de‐escalated adjuvant radiotherapy.

Abstract Background Sarcomatoid carcinomas (SC) are rare tumors with both epithelial and mesenchymal characteristics, linked to aggressive behavior and poor prognosis. Sarcomatoid carcinoma of unknown primary (SCUP) is an exceedingly rare subset with limited literature and no standardized management guidelines. This study aims to characterize the clinical presentations, treatment patterns, and genomic landscape of SCUP. Patients and Methods Data were retrospectively collected from the Mayo Clinic Rochester Cancer of Unknown Primary Registry. Patients included had biopsy-proven SC with no identifiable primary tumor despite comprehensive diagnostic evaluations. Baseline characteristics, immunohistochemistry (IHC) results, next-generation sequencing (NGS) data, and treatment outcomes were analyzed. Statistical analyses included descriptive statistics, Kaplan–Meier survival estimates, and Cox proportional hazards regression. Results Fifty-two SCUP patients were identified, with a median age of 60 years. Most patients presented with widely metastatic disease, particularly lytic bone lesions. Elevated alkaline phosphatase (ALP) was noted in nearly half of the patients. IHC showed high positivity for AE1/AE3 and OSCAR antibodies. Tumor NGS revealed 247 alterations, with TP53 being the most common mutation. Patients receiving definitive therapy had a median overall survival (OS) of 72 months, significantly longer than those receiving systemic therapy (14 months). Immunotherapy was a significant prognostic factor, reducing the risk of death by 90%. Conclusions This study provides essential insights into the clinical and genomic characteristics of SCUP, advocating for the integration of definitive therapy and immunotherapy in treatment protocols. Further prospective studies are needed to validate these findings and improve patient outcomes.

Soft tissue aneurysmal bone cysts (STABCs) are rare neoplasms histopathologically identical to aneurysmal bone cysts. These benign lesions are characterized by thin, peripheral ossification and no skeletal continuity. STABC may be difficult to distinguish from myositis ossificans (MO) and malignant entities from imaging and fine needle aspiration, due to rarity and overlapping features. We present a case of a STABC occurring in the paraspinal cervical muscles. The imaging, histopathology, molecular analysis, and treatment are discussed. Four other published cases of STABC of the head and neck are reviewed.

6009 Background: E3311 is a phase II trial of TOS by credentialed surgeons with pathology-driven deintensified post-operative management in HPV+ OPC. Intermediate risk patients were randomized between standard and reduced dose radiation. We present mature outcome data, at median follow up of 52.4 months (m). Methods: Patients were eligible who had resectable cT1-2 stage III/IV AJCC7 p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (Arm A, N=38); those with clear margins, 2-4 + LN, or ENE ≤1mm were randomized to 50Gy (Arm B, N=100) or 60Gy (Arm C, N=108); those with involved margins, >4 + LN, or >1mm ENE received weekly cisplatin 40 mg/m2 and 60-66Gy (Arm D, N=113). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using a log-rank test, stratified by arm for comparisons of primary site and smoking history. Results: Among 359 evaluable patients, 54-m PFS and OS were 90.6% (90% CI: 87.2%, 93.1%) and 95.3% (90% CI: 93.0%, 96.9%). 54-m PFS by arm was: A 93.2% (90% CI: 79.6%, 97.8%); B 94.9% (90% CI: 89.7%, 97.5%); C 90.2% (90% CI: 82.7%, 94.6%) and D 85.5% (90% CI: 77.5%, 90.8%). 54-m OS by arm was: A 97.1% (90% CI: 85.7%, 99.4%); B 97.9% (90% CI: 93.5%, 99.3%), C 95.1% (90% CI: 90.1%, 97.6%) and D 92.5% (90% CI: 86.9%, 95.7%). Among patients in Arm A, 11 had N0 and 27 N1 stage. Median Arm A lymph node yield (LNY) was 29 (11 to 91 LN) and did not differ for patients with/without recurrence (p=0.83). All Arm A recurrences were in N1 patients: 1 at 18 m and 3 at > 40 m. No significant difference in PFS or OS was observed by prescribed radiation dose for intermediate risk patients (Arm B vs. C). Outcome did not differ by primary site of tonsil vs. other OPC (oOPC): 54-m PFS Tonsil 89.3% (90% CI: 84.9%, 92.5%) vs. oOPC 92.9% (90% CI: 87.0%, 96.2%), p=0.28, and 54-m OS Tonsil 94.6% (90% CI: 91.5%, 96.6%) vs oOPC 96.6% (90% CI: 92.4%, 98.5%), p=0.35. Smoking history also did not impact outcome. 54-m PFS was 89.9% (90% CI: 85.9%, 92.9%) for those with ≤10 pack-years (PY) tobacco exposure and 91.7% (90% CI: 83.9%, 95.9%) for those with >10 PY. Conclusions: TOS, neck dissection with deintensified risk-based post-operative management results in outstanding 54-m PFS and OS across all subsites of T1-2 p16+ OPC, irrespective of smoking history. Late recurrence is not increased when post-operative radiation is reduced from 60 to 50Gy for intermediate risk patients. Pathologic >1mm ENE (N=87), involved margin (N=12) or >4 involved LN (N=30) accurately identify patients at increased recurrence risk and outcomes were favorable among such patients. Among patients with favorable pathologic characteristics, a subset with N1 disease are at risk for late recurrence and further characterization of these patients is warranted. Clinical trial information: NCT01898494 .