Wilson, Jessica

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.

IMPORTANCE Neoadjuvant chemoimmunotherapy has high rates of pathologic response and improved prognosis among solid tumors. Its role in head and neck squamous cell carcinoma (HNSCC) remains understudied. OBJECTIVE To summarize the efficacy associated with neoadjuvant chemoimmunotherapy regimens in HNSCC and to compare the efficacy associated with neoadjuvant chemoimmunotherapy vs immunotherapy alone in locoregionally advanced resectable HNSCC prior to definitive surgery. DATA SOURCES A librarian-led systematic review was conducted using multiple electronic databases, including Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, following Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. Databases were queried from inception to October 2024. STUDY SELECTION Inclusion criteria included prospective interventional trials that have completed accrual, with results published in English. Only trials of resectable, treatment-naive HNSCC were included. Exclusion criteria included lack of reporting on pathologic response or Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 response. DATA EXTRACTION AND SYNTHESIS Two investigators independently conducted title, abstract, and full-text reviews per PRISMA guidelines. Primary outcomes extracted were major pathologic response (MPR) and complete pathologic response (CPR) at surgery and complete response (CR) on imaging by RECIST 1.1. Secondary outcomes included 1-year overall survival (OS) and toxic effects. MAIN OUTCOMES AND MEASURES A meta-analysis was performed using a binary random-effects model to determine the pooled proportion of primary outcomes in the immunotherapy and chemoimmunotherapy groups. Heterogeneity was reported as I 2 . RESULTS A total of 751 patients (502 [77%] male; age range, 27-87 years) across 23 studies were included in the meta-analysis, including 357 patients (47%) who underwent chemoimmunotherapy, 102 patients (14%) who underwent dual-agent immunotherapy, and 292 patients (39%) who underwent single-agent immunotherapy. Pooled rates of MPR plus CPR were 66% (95% CI, 58%-73%; I 2 = 0.59) for chemoimmunotherapy, 18% (95% CI, 6%-29%; I 2 = 0.65) for dual-agent immunotherapy, and 6% (95% CI, 3%-9%; I 2 < 0.01) for single-agent immunotherapy. Across all groups, 1-year OS rates ranged from 88% to 96% for single-agent immunotherapy, 88% to 96% for dual-agent immunotherapy, and 88% to 100% for chemoimmunotherapy. Grade 3 to 5 adverse events were reported in 61 of 210 patients (29%), 2 of 67 patients (3.0%), and 36 of 210 patients (17%) among the reporting studies in the single-agent immunotherapy, dual-agent immunotherapy, and chemoimmunotherapy groups, respectively. CONCLUSIONS AND RELEVANCE These findings suggest that neoadjuvant chemoimmunotherapy regimens were associated with higher pathologic and radiographic response rates compared with immunotherapy alone in locoregionally advanced HNSCC. These results call for phase 3 trials comparing these neoadjuvant regimens head to head.