Head and neck squamous cell carcinoma (HNSCC) remain a major clinical challenge due to its high heterogeneity and limited therapeutic response, resulting in a 5-year overall survival rate of only ~50%. Identifying molecular pathways that drive tumor progression while suppressing anti-tumor immunity is therefore critical for developing more effective therapies. N-acetyltransferase 10 (NAT10) is the only known enzyme responsible for catalyzing the RNA modification N4-acetylcytidine (ac4C) on rRNA, tRNA, and mRNA, and has been implicated in tumor progression in several cancers. In this study, we identify NAT10 as a key suppressor of tumor-intrinsic immune signaling in HNSCC. NAT10 expression was significantly elevated in tumor tissues and HNSCC cell lines and was associated with poor overall survival. Moreover, high-risk HPV, a major etiological factor in HNSCC, upregulated NAT10 protein expression through the viral oncoproteins E6 and E7. Functional inhibition of NAT10, either by genetic depletion or the small-molecule inhibitor Remodelin, activated tumor-intrinsic innate immune responses, as evidenced by increased IRF3 phosphorylation and induction of type I/II interferons and interferon-stimulated genes. Depletion of NAT10 was able to suppress tumorigenic phenotypes, including cell proliferation, migration, and colony formation in HNSCC cells. Importantly, activation of the STING signaling pathway using agonist cyclic di-GMP further amplified immune activation in NAT10-inhibited cancer cells. Together, our findings establish NAT10 as a previously unrecognized negative regulator of tumor-intrinsic immunity in HNSCC and support NAT10 targeting, particularly in combination with STING agonists, as a promising immunotherapeutic strategy.

Abstract Background: a/mHNSCC exhibits poor prognosis and limited immunotherapy efficacy. Weekly low-dose chemotherapy may enhance immunogenicity while reducing toxicity. We conducted a phase II trial of weekly low-dose chemotherapy plus cemiplimab as first-line treatment in a/mHNSCC, with integrated genomic profiling to explore molecular correlates of outcome. Patients received weekly carboplatin (AUC 1) and paclitaxel (30 mg/m2) plus cemiplimab (350 mg q3w). Forty-two patients were enrolled from Dec 2021-Dec 2024. Median age was 68 (range 42-81); 38/42 were male, and 27 (64%) were HPV-positive. Median OS (27 events) was 16.4 months (95% CI, 12.6-23.9); median PFS (36 events) was 5.62 months (95% CI, 5.0-10.3). Objective response rate (ORR) was 43% (18/42, PR or CR). The treatment was well-tolerated. These results were previously presented at ESMO 2025. We aim to present an exploratory analysis of pathogenic genomic mutations in this cohort and their correlation with ORR, PFS, and OS. Methods: Of the 42 enrolled patients, genomic analysis (Tempus xT/xF) was performed in 29. The 4 most prevalent pathogenic alterations were analyzed separately, while all genes with detected pathogenic alterations were grouped and analyzed by pathway or functional group, with time-to-event outcomes assessed via Kaplan-Meier and log-rank, and Cox models when appropriate. Prevalence of tumor mutations between responder groups (CR/PR versus PD as ORR) and extreme PFS groups (<3 versus >12 months) was performed with odds ratio. P-values< 0.05 were deemed statistically significant. Due to the hypothesis-generating nature of this report, p-value adjustments for multiple tests were not performed. Results: Pathogenic alterations included TP53 (N=14), CDKN2A (N=11), TERT promoter (N=8), and FGF3/FGF4 copy number gains (CNG; N=17). Mutations in NOTCH pathway genes (NOTCH1/3, FBXW7; N=7) were enriched in patients with primary progression (p = 0.02) and those with PFS <3 months versus >12 months (p = 0.03). NOTCH alterations conferred inferior PFS (HR 3.6; 95% CI, 1.4-9.3; p < 0.01) and OS (HR 2.9; 95% CI, 1.05-8.0; p = 0.04). TERT promoter mutations were associated with worse OS (HR 4.9; 95% CI, 1.7-14.5; p < 0.01) and trended toward poor PFS (HR 2.2; 95% CI, 0.9-5.2; p = 0.08). FGF3/FGF4 CNGs also trended toward inferior PFS (HR 2.6; 95% CI, 0.9-7.4; p = 0.08) and were associated with worse OS (HR 2.5; 95% CI, 1.0-6.6; p = 0.04). Conclusions: Weekly low-dose chemotherapy plus cemiplimab shows promising activity in a/mHNSCC. Exploratory genomic profiling suggests NOTCH pathway mutations may be markers of poor prognosis and resistance. TERT and FGF3/4 alterations may also confer inferior outcomes and warrant further study. Citation Format: Mateus Trinconi Cunha, Fahad Rind, Priyanka Bhateja, Esmerina Tili, David Konieczkowski, Darrion Mitchell, Sujith Baliga, Sung Jun Ma, Simeng Zhu, Gogineni Emile, John Grecula, Nolan Seim, Catherine Harring, Lauren Miller, Abberly Lott Limbach, Kang Stephen, James W. Rocco, Christian Rolfo, Dukagjin Blakaj, Marcelo Bonomi. Molecular correlates of response and survival in a phase II trial of weekly carboplatin/paclitaxel plus cemiplimab (wCP+C) in advanced/metastatic mucosal head and neck squamous cell carcinoma (a/mHNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3871.

PURPOSE National Comprehensive Cancer Network guidelines recommend weekly cisplatin and weekly carboplatin with paclitaxel as alternative concurrent systemic therapy regimens among patients with head and neck cancer undergoing definitive chemoradiation. However, there is a paucity of literature comparing outcomes with these two regimens. We performed an observational cohort study of patients with head and neck cancer treated with definitive chemoradiation receiving either cisplatin or carboplatin with paclitaxel. METHODS A single-institution database was queried for patients with head and neck cancer diagnosed between October 2011 and December 2023 who underwent chemoradiation with either once a week cisplatin (40 mg/m 2 ) or once a week carboplatin (AUC 1) with paclitaxel (30 mg/m 2 ). Cox multivariable analysis (MVA), Kaplan-Meier, Fine-Gray MVA, logistic MVA, and propensity score matching were performed to evaluate treatment outcomes. RESULTS A total of 488 patients were identified. Median follow-up was 43.1 months (95% CI, 41.0 to 45.4). The majority of patients received at least five cycles. Those with older age, former smoking history, and worse performance status were more likely to undergo carboplatin and paclitaxel. Carboplatin and paclitaxel were associated with no statistically significant overall survival (adjusted hazards ratio [aHR], 1.12 [95% CI, 0.69 to 1.82]; P = .64), progression-free survival (aHR, 1.45 [95% CI, 0.96 to 2.19]; P = .08), locoregional failure (aHR, 1.91 [95% CI, 0.85 to 4.32]; P = .12), and distant failure (aHR, 1.33 [95% CI, 0.70 to 2.54]; P = .39) compared with cisplatin. Similar findings were noted on 109 matched pairs as well as subgroups stratified by p16 status. CONCLUSION Our study suggested that those treated with weekly carboplatin and paclitaxel had no statistically significant survival and tumor control outcomes compared with those with weekly cisplatin. Older age and poor performance status were independently associated with the receipt of weekly carboplatin and paclitaxel.

Although adjuvant treatments are preferred to begin within 6 weeks after surgery for patients with head and neck cancer, both the National Comprehensive Cancer Network guideline and ongoing cooperative group phase III clinical trials, such as NRG HN009, do not current specify when definitive treatments should start after the initial diagnosis of head and neck cancer. In addition, patients have various levels of healthcare access based on their health insurance among other social determinants of health. We performed an observational cohort study to evaluate whether treatments delays are associated with types of health insurance and clinical outcomes among patients with head and neck cancer receiving definitive radiation or chemoradiation. Our single institution database was queried for patients with non-metastatic head and neck cancer diagnosed between October 2011 and December 2023 who received definitive radiation or chemoradiation. In addition to clinically relevant variables, primary health insurance and the dates of initial diagnosis and first radiation treatment were available for analysis. Those with induction systemic therapies, surgery, or palliative-intent treatments were excluded. Treatment delays were defined as more than 8 weeks between the initial diagnosis and the first radiation treatment. Cox multivariable analysis (MVA) and Fine-Gray MVA were performed for survival and tumor recurrence outcomes, respectively. Propensity score matching was also performed to reduce selection bias. Logistic MVA was used to identify variables associated with treatment delays. A total of 694 patients met our criteria. Of these patients, 302 patients (43.5%) had treatment delays. Median duration between the initial diagnosis and the first radiation treatment was 54 days (interquartile range 41-68). Median follow up was 46.8 months (95% confidence interval [CI] 45.5-49.2). Compared to those without treatment delays, patients with treatment delays had worse overall survival (OS; adjusted hazards ratio [aHR] 1.36, 95% CI 1.01-1.84, p=0.04), but not progression-free survival (PFS; aHR 1.15, 95% CI 0.88-1.50, p=0.31), locoregional failure (LRF; aHR 1.02, 95% CI 0.59-1.75, p=0.94), or distant failure (DF; aHR 0.75, 95% CI 0.45-1.24, p=0.26). Similar findings were noted among 274 matched pairs (OS: HR 1.43, 95% CI 1.03-1.98, p=0.03; PFS: HR 1.18, 95% CI 0.89-1.58, p=0.25; LRF: HR 1.20, 95% CI 0.65-2.22, p=0.56; DF: HR 0.85, 95% CI 0.52-1.38, p=0.51). On logistic MVA, Medicaid insurance was the only variable associated with treatment delays (vs private insurance; adjusted odds ratio [aOR] 2.35, 95% CI 1.41-3.94, p=0.001). Our study suggested that nearly half of patients had treatment delays and that treatment delays were an independent, adverse prognostic factor for survival outcomes. It also suggested that those with Medicaid insurance were more likely to experience treatment delays than others with private insurance. Alec Kotler, Matthew Nguyen, Sung Jun Ma, Wayne Rutherford, Melissa Moore, Kevin Agner, Darien Reed, Jacob Wells, Om Desai, Frida Calderon Gutierrez, Krithik Tella, Daniel Alvarez, Andrew Koempel, Simeng Zhu, Priyanka Bhateja, Emile Gogineni, Sujith Baliga, David Konieczkowski, Darrion Mitchell, Sachin Jhawar, John Grecula, Matthew Old, James Rocco, Marcelo Bonomi, Lauren Miller, Dukagjin Blakaj. Association of treatment delays with health insurance and clinical outcomes among patients with head and neck cancer receiving definitive treatments [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A143.

Background: Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a median survival of six months. While immunotherapy (IT) has improved outcomes in other solid tumors, its role in ATC remains unclear. This study evaluated whether receipt of IT was associated with improved overall survival (OS) in the initial treatment of patients with newly diagnosed ATC. Methods: We performed a retrospective study of patients with metastatic and nonmetastatic ATC from the National Cancer Database (2008-2020) treated with surgery, radiation, chemotherapy, or a combination. Patient outcomes were stratified between those who received IT at any point in their treatment compared with those who did not. The primary outcome was OS, compared between cohorts receiving IT and those who did not. Survival analyses were performed using Kaplan-Meier estimates, long-rank tests, and multivariable models. Results: Among 3318 patients with ATC, 87 (2.6%) received IT. Rates of surgical resection (46%) and radiation therapy (64% vs. 57%, p = 0.133) were similar across groups. IT recipients were younger (mean = 66.7 vs. 70.2 years, p = 0.005), more often diagnosed in recent years (2017-2019 vs. 2008-2016, p = 0.0001), and more frequently received chemotherapy (65.5% vs. 46.3%, p = 0.0007). Charlson Comorbidity Index scores were similar (p = 0.551). Median OS was 9.1 months (confidence interval [CI] 7.06-14.9) for those receiving IT versus 3.78 months (CI: 3.52-4.01) for those who did not (p < 0.005). Five-year OS was 18% (CI: 5-36%) with IT versus 9% (CI: 8-10%) without (p < 0.0001). Among 23 patients who received trimodality therapy (surgery, IT, and radiation), 5-year OS was 35% (CI: 16-55%) versus 9% in patients who did not. Conclusions: IT was associated with prolonged survival in patients with ATC, although confounding factors, such as the retrospective design of the study, lack of detailed IT drug details, and sequencing of therapy, preclude definitive conclusions on its efficacy. The efficacy of IT for ATC as a stand-alone treatment is uncertain. Further studies could indicate which combination of therapies best increases OS in patients with ATC.

e18099 Background: Definitive chemoradiation for head and neck cancers is a common treatment with a high toxicity burden. There is an urgent need to identify toxicity biomarkers and develop mitigation or amelioration strategies. Recently, the microbiome was observed to associate with various cancer treatment outcomes, including response and toxicity. In this prospective trial, we aimed to determine whether the oral microbiome at baseline could predict treatment-related toxicities after chemoradiation. Methods: We collected pre-treatment oral swabs from 34 patients on the OROMIC trial (OSU-20074). Patients received definitive chemoradiation (CRT) in 33-35 fractions for oropharyngeal cancer. Patient swabs were collected using an OMR-110 kit containing a nucleic acid stabilizing solution. Samples were processed for total RNAseq, human ribodepleted, and sequenced by Illumina Nextseq 2×150bp to a depth greater than 50 million reads/sample. Metatranscriptomes were aligned to a custom database using Kraken2. We compared differences in oral microbiome based on toxicity grade (low-grade [CTCAE 0-1] vs high-grade [CTCAE 2-3]) to evaluate correlations with acute toxicity and microbes in this cohort. Results: The most common treatment-related toxicities were dysphagia, secretions, oral mucositis, and dermatitis and patients who developed high-grade for these adverse effects had higher abundances of Kineobactrum , Musicloa , and Opituts genera pre-treatment (adjusted p values < 0.0001). Conversely, the presence of Stanieria and Paroceanicella genera seemed protective and related to low grade dermatitis, secretions, and dysgeusia (p value < 0.0001). Several microbes demonstrated more variable relationship to acute toxicity. For example, Ureaplasma demonstrated an association with high-grade mucositis, but also correlated with low-grade dysphagia and secretions (p value < 0.0001). Similarly, Trabulseilla appeared to relate to high-grade dysgeusia and low-grade xerostomia (p value < 0.0001). Conclusions: Overall, a widespread diversity was observed between the relationship between the pre-treatment microbial abundance in the oral cavity and acute toxicity severity in patients undergoing definitive chemoradiation for oropharynx cancer. While the presence of some organisms seems consistently detrimental and the presence of others is generally protective, others still demonstrate variability in influencing acute toxicity outcomes. These findings need to be validated and further analysis of the microbial composition and flux in the oral microbiome is required through longitudinal data which we will present as this study continues to mature. These findings will help in identifying potential biomarkers and therapeutic targets within the oral to improve response to acute toxicity and adverse effects from to chemoradiation for oropharynx.

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is clinically and biologically distinct from HPV-negative counterparts, differing in prognosis, failure patterns, and patient demographics. Although outcomes are generally favorable for HPV-OPSCC, large randomized trials have not confirmed the safety or efficacy of treatment de-escalation. Liquid biopsy approaches, particularly those measuring circulating tumor HPV DNA (ctHPVDNA), have emerged as promising tools for risk stratification, treatment response monitoring, and early recurrence detection. Technologies such as droplet digital PCR and next-generation sequencing offer high sensitivity and specificity in detecting ctHPVDNA, supporting their potential utility in clinical management. Baseline ctHPVDNA levels correlate with tumor burden, HPV integration status, and clinical outcomes. Notably, rapid clearance of ctHPVDNA during radiation therapy is a strong predictor of disease control, whereas persistent or detectable ctHPVDNA after surgery is associated with a heightened risk of recurrence. For surveillance, ctHPVDNA demonstrates high positive and negative predictive values, in some studies surpassing the performance of conventional imaging modalities. Despite these encouraging findings, standardization of assay methodologies and further clinical validation are essential before ctHPVDNA can be fully incorporated into personalized treatment algorithms for HPV-OPSCC.

BACKGROUND AND PURPOSE:Reirradiation for recurrent or second primary head and neck cancer (HNC) can result in radiation-induced brachial plexopathy (RIBP), a debilitating side effect. This study aims to identify factors associated with the development of RIBP in patients undergoing reirradiation for recurrent or second primary HNC. MATERIALS AND METHODS:This retrospective cohort study included 48 patients treated from 2015 to 2022 at a single National Cancer Institute-Designated Comprehensive Cancer Center, with a median follow-up duration of 22.7 months post-reirradiation. Patients underwent conventionally fractionated reirradiation, and a total of 72 brachial plexi that received overlapping courses of radiation were analyzed. Primary outcomes measured were the incidence of RIBP and factors contributing to increased risk, including EQD2 (equivalent dose in 2 Gy fractions) maximum point dose (Dmax, defined as 0.03 cc) and volumetric brachial plexus (BP) dosimetric endpoints (V80-V120), comorbidities, time between radiation courses, receipt of systemic therapy, and neck dissection. BP EQD2 was calculated using an alpha/beta of 3 Gy. RESULTS:The crude incidence of RIBP was 23 %, occurring at a median of 9.5 months after reirradiation, with 12- and 24-month rates of 11 % and 16 %, respectively. On univariate analysis, concurrent cisplatin during the second course of radiation (hazard ratio [HR] 9.04, 95 % confidence interval [CI]: 2.70-30.40, p < 0.001) and cumulative EQD2 BP Dmax ≥ 103 Gy2 (HR 1.10, CI: 1.04-1.17, p < 0.001) were significantly associated with RIBP. These factors remained significant on multivariable analysis. RIBP incidence was significantly associated with all cumulative volumetric BP endpoints from V80-V120, with higher RIBP rates for V80 ≥ 1.94 cc, V100 ≥ 1.35 cc, V120 ≥ 0.89 cc, and EQD2 Dmax ≥ 103 Gy2. CONCLUSIONS:This study, the largest to date investigating rates of RIBP in patients with HNC treated with conventionally fractionated reirradiation, found that cumulative EQD2 maximum dose, and the use of concurrent cisplatin during the second RT course, were associated with increased rates of RIBP. Understanding these factors may guide clinicians in the setting of reirradiation, potentially leading to improved patient outcomes.

Purpose/Objective(s)Head and neck re-irradiation treatment approach can lead to various side effects like radiation induced brachial plexopathy (RIBP). Factors contributing to brachial plexus injury in the re-irradiation setting need further assessment. We aim to identify these factors to help tailor treatment management.Materials/Methods71 BP sites with 48 patients (pts), treated with re-irradiation between 2015 and 2022 for recurrent head and neck cancer, were assessed. Reverse Kaplan-Meier and logistic regression were used to test the correlation between variables and outcomes. Common terminology criteria of adverse events (CTCAE v5.0) was used to define brachial plexus injury.ResultsThe median age of pts was 65 (range, 29-79), 65% of pts were males, and 88% had ECOG performance status of 0-1. All pts received 1.64-2.12 Gy per fraction with one fraction per day and 5 fractions per week via VMAT. 15% additionally received IORT during salvage treatment ranging from 10-15Gy. 27% of patients in the first course and 88% in the second course of pts had surgery, with RT delivered in the adjuvant setting; the remainder had definitive-intent radiation without surgery. Concurrent chemotherapy was delivered to 67% of pts in the first course (Cisplatin 40%, Cetuximab 17%, Carboplatin +/- Paclitaxel 10%) and 62% in the second course (Carboplatin/Paclitaxel 38%, Cisplatin 16%, Cetuximab 6%, Nivolumab 2%). The median duration between RT courses was 34 months (4.6-216). With a median follow-up of 20.1 months, the cumulative incidence of RIBP at 1- and 2- year for the whole cohort was 9% and 17%, respectively. The cumulative incidence of RIBP was lower in pts with a cumulative Dmax of less than 116Gy, (1-year: 2% vs 22%, p <.001), Dmean of less than 70Gy, (1-year: 4% vs 18%, p .003). When V80 less than 1.9cc, V90 less than 1.5cc and V100 less than 1.3cc, the 1-year cumulative incidence of RIBP was 3% vs 18% p .004, 2% vs 20% p 0.001, and 6% vs 18% p .023, respectively. The 1- year cumulative incidence of RIBP in correlation with concurrent cisplatin was 62% vs 3%, p <.001. 1- year cumulative incidence of RIBP with age less than 65 was 18% vs 2%, p .002. 1-year cumulative incidence of RIBP with positive neck lymph node was 22% vs 3% p <.001. On multivariate analysis, age below 65 (HR 9.7 [CI 1.7-57], p .012), Dmax above 116Gy (HR 23 [CI 2.2-245], p .009) and positive neck lymph node during second radiation (HR 6.1 [CI 1.1-33], p .039] continued to show increasing risk of RIBP.ConclusionRIBP was higher in younger pts, pts received concurrent cisplatin during the 2nd course, positive neck lymph node, cumulative Dmax 116Gy, mean 70Gy, V80 1.9cc, V90 1.5cc and V100 1.3cc. We identified 10 cases with brachial plexopathy. six pts had grade I, 3 pts had grade II and one pt had grade III brachial plexopathy. Median time to develop RIBP was 9.5 months (range, 1-17.1). Prospective study, longer follow up, and higher numbers are warranted.

BACKGROUND:The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. METHODS:We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. FINDINGS:We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. INTERPRETATION:We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. FUNDING:NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Background and purpose: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. Materials and methods: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0–69.96). Results: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25–90%). The median dose homogeneity index was 1.07 (range: 1.03–1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0–75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. Conclusions: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

HPV viral E6 and E7 onco-proteins play a well-known role in carcinogenesis. Host genomic alterations also play a key role in the development of HPV-related oropharyngeal cancer and have been under-recognized. We describe a case series of 6 metastatic/locoregionally recurrent HPVOPSCC patients with FGFR alterations. HPVOPSCC presents with distinct pattern of spread both temporally and sites of recurrence compared to  non-HPV-related oropharyngeal cancer. Identification and reporting of genomic alterations in HPV are crucial to the understanding of disease biology and could aid in development of novel therapeutics for these patients. In addition, use of circulating tumor DNA may lead to early detection and supplement imaging in the follow up of these patients. Loco-regional treatments may also play a key role in the management of metastatic HPV OPSCC depending on the pattern of presentation. Our case series highlights all these novelties that could lead to better treatment outcomes.

Purpose/Objective(s)Volumetric Modulated Arc Therapy (VMAT) has become a staple of modern head and neck (HN) radiation planning, but there may exist unexpected failure modes in which VMAT plans are less robust than typically expected. We identify and characterize one such potential instability (to our knowledge not previously described) that can occur at the interface between target volume (e.g. a mucosal primary tumor) and internal air (e.g. pharyngeal lumen, sinuses, nasal cavity, etc.), where the lack of a sufficient region for full dose buildup can lead to development of unexpected hotspots with even minor variations in target geometry.Materials/MethodsPlans for ten HN patients treated with curative-intent VMAT radiation therapy (RT) at our institution in 2023 were reviewed. All patients received 60-69.96 Gy in 30-33 daily fractions with 6MV photons, with plans created in a technology company treatment planning system and calculated with an advanced dose calculation algorithm (version 16.1). To model the effect of swelling or tumor growth at the internal air/tumor interface, verification plans were run in which internal air within 3 mm of the planning target volume (PTV) was overridden to soft tissue density (Hounsfield Unit [HU] = 0), and resulting hotspots were assessed. A modified planning technique was employed to increase robustness, wherein the plan was initially optimized with the luminal air density on CT overridden to HU = -300, before being re-calculated and re-normalized with the original CT HU values. Finally, the modified plan was then assessed for robustness in the event of tissue filling by again overriding luminal air to HU = 0.ResultsAlthough hotspots were well controlled in clinically treated plans at baseline (median 110%, range 109%-114%), relatively minor changes at the tumor-air interface (within 3 mm of PTV) resulted in development of significant unexpected hotspots (median 131%, range 115%-155%). With the proposed robust planning technique, plans were similar at baseline (median hotspot 110%, range 108%-114%, p=0.275 relative to original plan), but significantly more robust in the event of changes at the internal air-tumor interface (median hotspot 110%, range 108%-114%, p=0.001 relative to non-robust plan) while maintaining stable target coverage (D95% of 99.1% to 100.2%).ConclusionIn cases requiring full dose to the interface between target volume and luminal air, standard VMAT plans can exhibit unstable behavior due to insufficient region for dose buildup, resulting in clinically unacceptable hotspots with even minor variations in target geometry—variations that are well under thresholds that would conventionally trigger replanning. A density override planning technique can mitigate this effect, creating VMAT plans that differ minimally at baseline but are substantially more robust against the development of unexpected hotspots. This technique is worthy of further consideration, particularly for HN plans with high dose regions abutting luminal air.

Purpose/Objective(s) RTOG 0129 suggested 200 mg/m2 as a minimum cumulative dose to be effective when using concurrent cisplatin given every 3 weeks. However, it remains unclear whether this threshold applies to weekly cisplatin. We performed an observational cohort study of patients with head and neck cancer treated with definitive chemoradiation receiving weekly cisplatin to determine if the number of cycles were associated with oncologic outcomes. Materials/Methods A single-institution database was queried for patients with head and neck cancer diagnosed between December 2011 and March 2020 who underwent chemoradiation and had weekly cisplatin of 40 mg/m2 with at least 200 mg/m2 total. Patients with <5 cycles of weekly cisplatin were excluded. Cox multivariable analysis (MVA), Fine-Gray MVA, and Kaplan-Meier were performed to evaluate the treatment outcomes among >6, 6, and 5 cycles. Reasons for missing cisplatin cycles were also recorded. For subgroup analysis, Cox and Fine-Gray MVA were repeated among those with p16-negative and p16-positive subgroups. Bonferroni correction was performed, with p value of 0.025 considered as statistically significant. Results A total of 142 patients were identified (n = 34 with 5 cycles [n = 8 for p16-negative; n = 26 for p16-positive], n = 58 with 6 cycles [n = 10 for p16-negative; n = 48 for p16-positive], and n = 50 with >6 cycles [n = 14 for p16-negative, n = 36 for p16-positive]). Median follow up was 46.8 months (interquartile range 40.8-55.6). Among 92 patients with missing cisplatin cycles, 79 patients (85.9%) had 92 reasons for lower adherence to chemotherapy available for review. Three most common reasons were low blood counts (n = 42/92, 45.7%), failure to thrive (n = 26/92, 28.3%), and fever or infection (n = 13/92, 14.1%). Outcomes were comparable between >6 cycles and 6 cycles (overall survival [OS]: adjusted hazards ratio [aHR] 0.62, p = 0.39; progression-free survival [PFS]: aHR 0.92, p = 0.86; locoregional failure [LRF]: aHR 0.29, p = 0.20; distant failure [DF]: aHR 0.83, p = 0.83). However, OS was worse for patients who received 5 cycles than those who received >6 cycles (aHR 3.37, p = 0.02), while PFS (aHR 2.72, p = 0.05), LRF (aHR 0.38, p = 0.42), and DF (aHR 2.03, p = 0.38) outcomes were comparable. On subgroup analysis, among those with p16-negative tumors (n = 32), 5 cycles were associated with worse OS (aHR 145, p = 0.02) than >6 cycles, but comparable PFS (aHR 56, p = 0.05). However, among those with p16-positive tumors (n = 110), OS and PFS outcomes were comparable between those treated with 5 cycles versus >6 cycles (OS: aHR 0.95, p = 0.95; PFS: aHR 1.36, p = 0.68). Conclusion Patients who received 5 weekly cisplatin cycles had lower overall survival than those with >6 cycles, while oncologic outcomes were comparable. This finding was primarily driven by patients with p16-negative tumors, while outcomes for patients with p16-positive tumors were not associated with the number of cisplatin cycles. Cytopenia represented the most common reason for missing cisplatin cycles.

ImportanceNational Comprehensive Cancer Network guidelines recommend weekly cisplatin as an alternative concurrent systemic therapy for definitive chemoradiation in patients with head and neck cancer. However, the impact of different levels of adherence to weekly cisplatin on outcomes stratified by human papillomavirus p16 status remains unclear.ObjectiveTo evaluate the association between the number of weekly cisplatin cycles and outcomes.Design, Setting, and ParticipantsThis retrospective, observational, single-institution cohort study at The Ohio State Comprehensive Cancer Center included patients with a diagnosis of nonmetastatic head and neck cancer between December 1, 2011, and March 30, 2020, who received chemoradiation. Data analysis was performed between March and May 2024.ExposureA total of 5, 6, or 7 to 8 weekly cisplatin cycles.Main Outcomes and MeasuresThe primary outcomes were overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Cox multivariable analysis was performed for variables associated with OS and PFS, and Fine-Gray multivariable analysis was performed for variables associated with LRF and DF.ResultsA total of 142 patients met the criteria (119 men [83.8%]; median [IQR] age, 59 [54-63] years). Median (IQR) follow-up was 46.8 (40.8-55.6) months. Among 92 patients with reasons for cisplatin interruption reported, the most common reason was low blood counts (42 patients [45.7%]). Those who missed weekly cisplatin cycles had worse OS (adjusted hazard ratio [aHR], 2.22; 95% CI, 1.19-4.17; P = .01) and PFS (aHR, 1.83; 95% CI, 1.06-3.15; P = .03) than those who received 7 to 8 cycles. Cancer control outcomes were comparable between these groups (LRF aHR, 0.53; 95% CI, 0.15-1.93; P = .34; DF aHR, 1.51; 95% CI, 0.60-3.82; P = .38). Patients with p16-negative tumors who missed weekly cisplatin cycles had worse OS (for every missing cisplatin cycle, aHR, 11.34, 1.51-84.94; P = .02) than those treated with 7 to 8 cycles. However, for those with p16-positive tumors, there were no statistically significant differences in OS between those who missed weekly cisplatin cycles vs others who received 7 to 8 cycles (aHR, 1.21; 95% CI, 0.47-3.14; P = .69).Conclusions and RelevanceIn this cohort study of patients with head and neck cancer who received definitive chemoradiation, those with p16-negative tumors who missed weekly cisplatin cycles had lower OS than those who received 7 to 8 cycles, although OS was comparable between these groups for p16-positive tumors. Cytopenia represented the most common reason for cisplatin interruption.

AIM:The response rates to immune checkpoint inhibitors (ICI) remain low (13%-20%) in metastatic head and neck cancer patients, indicating an urgent need to better understand factors predictive of response to these agents. This study explored the impact of smoking status, marijuana use, and alcohol consumption on treatment outcomes in recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with ICI. METHODS:A retrospective analysis was performed on 201 R/M HNSCC patients treated with ICI between January 15th 2016 and April 9th 2020 at a single institution. RESULTS:Gender: 154 male (77%), 47 female (23%). Median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), nivolumab + ipilimumab 10 (5%). Line of therapy: first: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), larynx 26 (13%), other sites 46 (23%). p16 tumor status: negative 132 (66%), positive 69 (34%). Smoking status: former 111 (55%), never 54 (27%), current 36 (18%), median pack-year 18 (IQR: 0-37). Alcohol use: yes 110 (55%), no 91 (54%). Marijuana use: yes 47 (23%), no 154 (77%). Overall response rate: 36 (18%). Median OS: 12 months (95% CI: 9.4-14.8). Tobacco: former (HR: 0.75, 95% CI: 0.50, 1.11), current (HR: 0.58, 95% CI: 0.33, 1.02). Marijuana: yes (HR: 0.93, 95% CI: 0.58, 1.49). Alcohol: yes (HR: 1.04, 95% CI: 0.72, 1.49). CONCLUSION:In our cohort, smoking status, marijuana use, and alcohol consumption did not have a statistically significant impact on OS in patients with R/M HNSCC treated with ICI.

Purpose/Objective(s) Circulating tumor HPV DNA (ctHPVDNA) has emerged as a promising biomarker in human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). However, the impact of ctHPVDNA kinetics on disease outcomes during chemoradiation (CRT) remains unclear. The objective of this study was to assess ctHPVDNA clearance kinetics during CRT and its relationship with progression in HPV-OPSCC. Materials/Methods We retrospectively identified patients diagnosed with AJCC 8th edition cT1-4, N0-N3, M0, HPV-OPSCC who underwent plasma ctHPVDNA testing before, during and after curative intent CRT between June 2021 to February 2023 (n = 82). All patients had pre-, end of, and post-treatment ctHPVDNA collected, while a subset of patients (n = 70) also had ctHPVDNA collected during week 4 (mid-treatment) of CRT. Patients with an initial ctHPVDNA of ≥200 copies/mL and >95% clearance by week 4 were considered favorable risk and those who did not achieve this clearance profile were classified as unfavorable risk. The primary objective was to evaluate the relationship between ctHPVDNA clearance during CRT and its impact on progression free survival (PFS). The association of this clearance status with PFS was evaluated using the Kaplan-Meier estimator. Results The median follow up was 14.7 months. Of the 82 patients, 75 (91.4%) had HPV16, 4 (5%) had HPV33, 2 (2.4%) had HPV18, and 1 (1.2%) had HPV35 subtype of disease. Of the 70 patients who had a ctHPVDNA drawn at mid and end of treatment, 31 (37.8%) and 48 (58.5%) completely cleared their ctHPVDNA at those respective time points. At 3 months post CRT, 73 (89%) had complete clearance of their ctHPVDNA. Of the clinical risk factors, only nodal stage was associated with a higher ctHPVDNA score at baseline and the median scores were 128 copies/mL, 778 copies/mL and 1219 copies/mL for patients with N0/1, N2a-b, and N3 disease, respectively (p = 0.01). Patients with a favorable risk clearance profile had a trend toward superior PFS compared to those with unfavorable risk disease at 1 (92.9% vs 87.7%) and 2-years (89.3% vs 67.5%) (log rank, p = 0.17). Patients who had persistent ctHPVDNA at the end of CRT had an inferior PFS compared to those who cleared their ctHPVDNA at 1 (95.5% vs 91.7%) and 2 years (85.5% vs 73.2%) (log rank, p = 0.05). There were no loco-regional or distant failures in patients who had ≤10 pack year smoking history and a favorable risk clearance profile. Conclusion Our study demonstrates that rapid clearance of ctHPVDNA during or after CRT predicts excellent disease control for HPV-OPSCC patients, whereas persistent ctHPVDNA post-CRT indicates unfavorable outcomes. Thus, monitoring ctHPVDNA clearance kinetics is a promising approach for adjusting intra-radiation therapy, potentially allowing therapy de-escalation for low-risk patients and escalation for high-risk cases. Prospective clinical trials are necessary to fully assess the utility of ctHPVDNA as a predictive biomarker for treatment stratification.

6521 Background: Contemporary anticancer drugs frequently have different efficacy and side effects in men and women. Yet, whether women are well-represented in pivotal trials supporting contemporary anticancer drugs is unknown. The objective of this study was to characterize the representation of women in trials supporting the use of contemporary anticancer drugs. Methods: We retrospectively evaluated all pivotal (phase II and III) trials supporting FDA-approval of anticancer drugs from 1998 to 2018, derived from Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available FDA-drug reviews. Expected population rates were derived from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, and US Census databases. The primary outcome was the report of any gender-specific analysis of efficacy and/or safety, irrespective of treatment-arm. The secondary outcome was the proportional representation of women across trials, evaluated by a participation-to-prevalence ratio (PPR) of 0.85, according to cancer-type. Female representation was also assessed as change across time. Differences in pooled binary endpoint hazard ratios, by the presence or absence of adequate female representation, were also assessed. Results: In total, there were 97,566 participants, enrolled in 189 clinical trials, evaluating 123 anticancer therapies. Gender was reported in 182 (96.3%) clinical trials, of which 43.4% (42,299) were women, compared to 55.6% (55,267) men ( P < 0.01). Overall, women were under-represented in clinical trials of anticancer therapies by a mean of 16.5% compared to the proportional incidence of all cancers in women. Women were the most under-represented in gastric (PPR = 0.821) and liver (PPR = 0.619) cancer trials. Sex-based drug efficacy analysis was only published in 36.8% of trials. Over time, the trend of percentage women recruited into clinical trials increased, but not at a rate comparable to prevalence (-5.0 to -5.5% of prevalence), and the gap in under-representation of women in anticancer therapy clinical trials is widening. Conclusions: Among pivotal clinical trials supporting contemporary FDA-approved cancer drugs, women were frequently under-represented. Additional studies are needed to understand the impact of under-representation on contemporary anticancer therapy outcomes.