PURPOSE:RTOG 1016 was a noninferiority phase III trial comparing the efficacy of radiation with either cisplatin (RT + Cis) or cetuximab (RT + Cetux) for patients with Humman Papillomavirus (HPV)+ oropharyngeal cancer (OPC). Perceived hearing handicap was included as a patient-reported outcome (PRO) secondary endpoint. The primary hypothesis was that perceived hearing handicap would be greater for patients receiving RT + Cis compared with RT + Cetux. METHODS AND MATERIALS:Perceived hearing handicap was measured at baseline, end of treatment, and 3, 6, and 12 months posttreatment using the Hearing Handicap Inventory for Adults Screening Version (HHIA-S), a 10-item self-assessment questionnaire designed to measure patients' reactions to their hearing loss. Mixed ordinal logistic models were used to determine the treatment effect on HHIA-S scores and handicap categories (2-sided α = 0.05). RESULTS:The PRO substudy included 375 eligible patients. No significant differences in patient/tumor characteristics were found between patients who participated in the HHIA-S study versus those excluded. For total HHIA-S scores and social and emotional subscales, RT + Cetux had significantly lower (ie, better) scores from end of treatment. Change score from baseline to end of treatment for RT + Cis (4.32; 95% confidence interval [CI], 2.57-6.07]) was greater than RT + Cetux (0.08; 95% CI, -1.15 to 1.31). For hearing handicap category, RT + Cis had a significantly higher percentage of mild/moderate and severe cases at the end of treatment (32%) compared with RT + Cetux (20%) (P < .0001). Adjusted conditional odds of higher self-perceived hearing handicap category for RT + Cis compared with RT + Cetux was 3.73 (95% CI, 2.10-6.62). CONCLUSION:Patients have significantly worse self-perceived hearing handicap after receiving RT + Cis treatment than with RT + Cetux. This was consistent across time through 1 year posttreatment. These findings inform hearing-related outcomes for patients with HPV-associated OPC and indicate the need for ototoxicity monitoring with RT + Cis treatment.

Dynamic biomarkers that guide de-escalation strategies in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remain an unmet need. In this study, we evaluated the kinetics of plasma cell-free HPV (cfHPV) DNA and oral gargle HPV DNA during radiotherapy in patients with low-risk HPV-related OPSCC. Data were obtained from a trial evaluating an adaptive model optimizing radiation fractionation in patients with low-risk (T0-2N0-1M0) HPV-related OPSCC undergoing radiotherapy. The primary objective was to determine whether week 4 plasma cfHPV DNA or oral gargle HPV DNA clearance is associated with reduction of target tumor volume (TTV) at week 4. A total of 325 plasma and 334 oral gargle samples from 50 patients with available baseline samples were analyzed. Higher baseline plasma cfHPV DNA was associated with higher nodal staging (P = 0.002), whereas oral gargle HPV DNA was detected more frequently in the tonsil or soft palate than occult or base of tongue primary tumors (P = 0.039). Week 4 plasma but not oral gargle HPV DNA clearance was associated with higher reduction of TTV at week 4 (P = 0.0063). Whereas week 4 plasma and oral gargle HPV DNA clearance was not associated with progression-free survival, a lower baseline plasma cfHPV DNA was associated with superior progression-free survival (P = 0.027). Week 4 plasma cfHPV DNA clearance aligns with reduction in TTV, and future studies are warranted to determine the role of early plasma cfHPV DNA clearance in biomarker-adapted de-escalation strategies.Significance: Our findings may inform appropriate patient selection for low-risk HPV-related OPSCC based on cfHPV DNA in future deintensification studies, aimed at preventing or minimizing treatment-related toxicities in patients who may have lower risk of recurrence.

PURPOSE:Locoregionally recurrent squamous cell carcinoma of the head and neck and second primary tumors (SPTs) in previously irradiated fields, if not resectable, are virtually always fatal. Chemotherapy alone yields a median survival of 10 to 11 months and 5-year overall survival (OS) rates of <5%. Concurrent reirradiation and chemotherapy constitutes an alternative, nonstandard strategy. Herein, we report the long-term outcomes of NRG Oncology Radiation Therapy Oncology Group 9911, a phase II trial of split-course radiation therapy (RT) and concurrent paclitaxel and cisplatin. METHODS AND MATERIALS:Eligibility stipulated measurable, recurrent squamous cell carcinoma of the head and neck or SPT in previously irradiated fields, performance status 0-1, and adequate end-organ indices. Patients received split course, twice-daily RT (1.5 Gy/fraction twice a day × 5 days every 2 weeks ×4), plus cisplatin (15 mg/m2every day × 5) and paclitaxel (20 mg/m2every day ×5) every 2 weeks for 4 cycles. Granulocyte colony-stimulating factor was administered on days 6 to 13 of each 2-week cycle. The primary endpoint was OS relative to historical control, NRG Oncology Radiation Therapy Oncology Group 9610. Secondary endpoints included progression-free survival, toxicities, and patterns of failure. RESULTS:Between March 2000 and June 2003, 105 patients were enrolled; 100 patients were analyzable (76% male, median age 60 years). Oropharynx (41%) and oral cavity (27%) were the predominant primary sites. A total of 23% had SPT. Median prior RT dose was 65.7 Gy. Overall, 73% of patients completed all chemotherapy. Nine treatment-related deaths (9%) occurred: 5 in the acute and 4 in the late setting. Survival was significantly improved over historical control (P = .01) with 5-year survival increased from 3.8% (95% CI, 0.0-8.0) to 14.9% (95% CI, 7.9-21.9). Five-year progression-free survival was 7.0% (95% CI, 2.0-12.0). A total of 64.9% died of incident cancer, 3.2% of SPT, and 22.3% of noncancer or unknown causes. In 1-year survivors, the rate of subsequent late grade 4-5 toxicity was significantly higher than historical control (P = .02), with 5-year cumulative incidence of 22.4% (95% CI, 11.8-35.1) compared with 3.2% (95% CI, 0.2-14.5). CONCLUSIONS:Despite a high incidence of grade 5 toxicity, OS rates for this trial evaluating concurrent split course twice a day reirradiation with cisplatin and paclitaxel exceeded results seen historically with chemotherapy alone.

Survivors of head and neck cancer have complex nutritional and supportive care needs. These needs result from the tumour's proximity to organs essential for normal eating function and the intensive treatment targeting those organs. Despite the crucial role of nutrition and supportive care in head and neck cancer, research and funding are lacking compared with other cancer types. This Review was compiled and written by a team of multidisciplinary medical professionals. Topics include poor access to medical nutrition therapy (MNT), MNT reimbursement policies, long-term survivorship care needs, percutaneous endoscopic gastrostomy tube placement, nutrition literacy, psychological services, speech-language pathology care, and concomitant physical activity. The goal of this work is to define current issues in research and practice, advocate for the expansion of head and neck cancer funding opportunities, and raise awareness of head and neck cancer supportive care needs and challenges. This work provides a roadmap for health-care professionals, researchers, policy makers, and funding agencies to prioritise nutrition in head and neck cancer care, with the overarching goal of improving treatment outcomes and quality of life.

ABSTRACT Background Treatment decision-making in oropharyngeal squamous cell carcinoma (OPSCC) includes clinical stage, HPV status, and smoking history. Despite improvements in staging with separation of HPV-positive and -negative OPSCC in AJCC 8th edition (AJCC8), patients are largely treated with a uniform approach, with recent efforts focused on de-intensification in low-risk patients. We have previously shown, in a pooled analysis, that the genomic adjusted radiation dose (GARD) is predictive of radiation treatment benefit and can be used to guide RT dose selection. We hypothesize that GARD can be used to predict overall survival (OS) in HPV-positive OPSCC patients treated with radiotherapy (RT). Methods Gene expression profiles (Affymetrix Clariom D) were analyzed for 234 formalin-fixed paraffin-embedded samples from HPV-positive OPSCC patients within an international, multi-institutional, prospective/retrospective observational study including patients with AJCC 7th edition stage III-IVb. GARD, a measure of the treatment effect of RT, was calculated for each patient as previously described. In total, 191 patients received primary RT definitive treatment (chemoradiation or RT alone, and 43 patients received post-operative RT. Two RT dose fractionations were utilized for primary RT cases (70 Gy in 35 fractions or 69.96 Gy in 33 fractions). Median RT dose was 70 Gy (range 50.88-74) for primary RT definitive cases and 66 Gy (range 44-70) for post-operative RT cases. The median follow up was 46.2 months (95% CI, 33.5-63.1). Cox proportional hazards analyses were performed with GARD as both a continuous and dichotomous variable and time-dependent ROC analyses compared the performance of GARD with the NRG clinical nomogram for overall survival. Results Despite uniform radiation dose utilization, GARD showed significant heterogeneity (range 30-110), reflecting the underlying genomic differences in the cohort. On multivariable analysis, each unit increase in GARD was associated with an improvement in OS (HR = 0.951 (0.911, 0.993), p = 0.023) compared to AJCC8 (HR = 1.999 (0.791, 5.047)), p = 0.143). ROC analysis for GARD at 36 months yielded an AUC of 80. 6 (69.4, 91.9) compared with an AUC of 73.6 (55.4, 91.7) for the NRG clinical nomogram. GARD ≥ 64.2 was associated with improved OS (HR = 0.280 (0.100, 0.781), p = 0.015). In a virtual trial, GARD predicts that uniform RT dose de-escalation results in overall inferior OS but proposes two separate genomic strategies where selective RT dose de-escalation in GARD-selected populations results in clinical equipoise. Conclusions In this multi-institutional cohort of patients with HPV-positive OPSCC, GARD predicts OS as a continuous variable, outperforms the NRG nomogram and provides a novel genomic strategy to modern clinical trial design. We propose that GARD, which provides the first opportunity for genomic guided personalization of radiation dose, should be incorporated in the diagnostic workup of HPV-positive OPSCC patients.

BACKGROUNDA key objective in managing HPV+ oropharyngeal squamous cell carcinoma (OPSCC) is reducing radiation therapy (RT) doses without compromising cure rates. A recent phase II/III HN005 trial revealed that clinical factors alone are insufficient to guide safe RT dose de-escalation. Our prior research demonstrated that the genomic adjusted radiation dose (GARD) predicts RT benefit and may inform dose selection. We hypothesize that GARD can guide personalized RT de-escalation in HPV+ OPSCC patients.METHODSGene expression profiles were analyzed in 191 HPV+ OPSCC patients enrolled in an international, multi-institutional observational study (AJCC Eighth Edition, stages I-III). Most patients received 70 Gy in 35 fractions or 69.96 Gy in 33 fractions (median dose: 70 Gy; range: 51.0-74.0 Gy). Overall survival (OS) was 94.1% at 36 months and 87.3% at 60 months. A Cox proportional hazards model assessed association between GARD and OS, and time-dependent receiver operating characteristic analyses compared GARD with traditional clinical predictors.RESULTSDespite uniform RT dosing, GARD showed wide heterogeneity, ranging from 15.4 to 71.7. Higher GARD values were significantly associated with improved OS in univariate (HR = 0.941, P = 0.041) and multivariable analyses (HR = 0.943, P = 0.046), while T and N stages were not. GARD demonstrated superior predictive performance at 36 months (AUC = 78.26) versus clinical variables (AUC = 71.20). Two GARD-based RT de-escalation strategies were identified, offering potential survival benefits while reducing radiation exposure.CONCLUSIONGARD predicts OS and outperforms clinical variables, supporting its integration into the diagnostic workflow for personalized RT in HPV+ OPSCC.FUNDINGThis work was supported by the National Cancer Institute through the Cleveland Clinic/Emory ROBIN center (U54-CA274513, project 2), the European Union Horizon 2020 Framework Programme (grant/award 689715), the Italian Association for Cancer Research (AIRC project ID 23573), and the European Research Area Network ERA PerMed JTC2019/Fondazione Regionale per la Ricerca Biomedica project SuPerTreat (Supporting Personalized Treatment Decisions in Head and Neck Cancer through Big Data).

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

PURPOSE:NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses. PATIENTS AND METHODS:We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic squamous cell carcinoma receiving definitive radiotherapy in the NRG/RTOG 9512 trial. A total of 119 patients had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for the presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (two-sided α = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. RESULTS:Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared with those without had significantly more local failure [HR = 3.50; 95% confidence interval (CI), 1.56-7.89; P = 0.0025] and locoregional failure (HR = 3.80; 95% CI, 1.80-8.03; P = 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR = 2.88; 95% CI, 1.46-5.66; P = 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). CONCLUSIONS:NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563.

11066 Background: This study aimed to determine to what extent area-level social determinants of health (SDOH) interact with individual, institutional, and biological factors to predict outcomes in head and neck cancer (HNC) trials. Methods: Five NRG Oncology HNC trials (2635 patients receiving chemoradiation) were analyzed. Area-level SDOH coded by patient ZIP codes included rurality (rural-urban commuting area code), neighborhood socioeconomic deprivation (Area Deprivation Index [ADI] categorized as upper vs. lower quartile), and travel burden (distance and time to treatment site). Individual (demographic, cancer and treatment-related factors), institutional (accrual volume), biological (HPV+/-) factors, and outcomes (overall survival [OS], progression free survival [PFS], quality of life [QOL], and symptoms) were analyzed. Multivariable Cox proportional hazards regression and mediation analysis using logistic regression assessed associations using hazard ratio (HR) or odds ratios (OR) and 95% confidence intervals (CI). Results: Most patients were White (88%), non-Hispanic (92.7%), of mean age of 57 years, HPV+ (64.6%), and received intensity-modulated radiotherapy (95.9%) and cisplatin (94.2%). ADI and rurality were not associated with OS and PFS. OS and PFS were higher in patients with travel time <1 hour (HR=0.85, 95% CI [0.75, 0.98]; HR=0.85, 95% CI [0.73, 0.98]) and travel distance <50 miles (HR=0.84, 95% CI [0.72, 0.96]; HR=0.85, 95% CI [0.73, 0.98]). ADI, travel time, and travel distance were not associated with QOL decline. Patients treated at institutions with high rural accrual volume had worse QOL decline from baseline (OR=0.36, 95% CI [0.15, 0.85]). The impact of travel distance but not time varied by race to influence QOL decline (OR=0.38, 95% CI [0.16, 0.93]). ADI was not associated with symptoms, but patients from institutions with high rural accrual volume had worse symptoms (OR=7.83, 95% CI [1.98, 31.01]). HPV status had a significant indirect effect on the relationship between travel distance and survival at 1 year (estimate [β]=0.03, 95% CI [0.01, 0.05]) and 5 years (β=0.03, 95% CI [0.004, 0.05]), as well as a direct and total mediation effect of travel distance on QOL decline at 1 year (direct β=-0.08, 95% CI [-0.16, -0.004]; total β=-0.89, 95% CI [-0.17, -0.01]). Conclusions: This study showed the impact of area-level SDOH and their interactions with race and institutional accrual volume, which are associated with survival, QOL, and symptom changes. HPV status potentially mediated the effects of travel distance on outcomes. Our findings provide novel approaches to identify patients at risk for poor outcomes, such as those with travel burden at institutions with high rural accrual, to design community-based interventions to improve cancer outcomes.

Background We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM).Methods The study is a phase Ib trial of nivolumab and SRS for BCBM. Clinical trial information: NCT03807765. Key eligibility criteria include BCBM of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performace Status (ECOG-PS)≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and every 4 weeks for flow cytometry and cell-free DNA (cfDNA) assessment.Results A total of 12 patients received SRS to 17 brain metastases. Breast cancer subtypes included triple negative (50%), hormone receptor (HR)+/HER2− (33%), and HR−/HER2+ (17%). Median follow-up from start of protocol therapy is 56 months. No cases of radionecrosis were noted. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12-month control rate of 33%. Median systemic progression-free survival was 7.7 months with a 12-month rate of 42%. Median overall survival (OS) was 24.7 months with a 12-month OS of 75%. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared with baseline (83%), week 25 compared with baseline (89%), and 100% at first follow-up. Intracranial control was associated with lower levels of CD4 regulatory T cells (Treg) (p=0.03) and higher levels of CD4 T effector memory (p=0.04).Conclusions Nivolumab and SRS is a safe and feasible treatment option in BCBM. Long-term follow-up revealed no cases of radiation necrosis.Trial registration number NCT03807765.

Purpose The rate of long-term feeding tube usage for patients treated with definitive (chemo)radiation is unknown. This analysis aims to determine predictive factors of feeding tube use years after treatment completion on NRG Oncology head and neck cancer trials that accrued from 2002 to 2014. Methods and Materials This is an unplanned, post hoc secondary analysis in the long term of both oropharynx cancer (OPC) and all treated patient feeding tube rates 6 months to 9 years after chemoradiation completion for patients treated on the multicenter prospective trialsNRG/RTOG 0129, 0522, and 1016. Results Median (min-max) follow-up was 6.7 years (interquartile range, 3.4-8.2) for OPC patients. Five hundred ninety-eight of 1839 (33%) OPC patients had a feeding tube 6 months after treatment. This decreased to 4% at 1 year and 3% at 9 years. Predictors of a feeding tube posttreatment were treatment with 3D conformal (3DCRT) accelerated chemoradiation with concomitant boost (AFX3DCRT), older age, feeding tube at registration, T4 tumor stage, and >10 pack-years of smoking. AFX3DCRT was independently significantly more associated with feeding tube use when compared to all other regimens. Among all treated patients (n = 2387), the median follow-up was 6.3 years (interquartile range, 2.7-8.2). Intensity modulated radiation therapy (IMRT) regimens had significantly less feeding tubes than 3DCRT (AFXIMRT + Cetux + C: hazard ratios [HR], 0.75 [0.63-0.89]; AFXIMRT + Cetux: HR, 0.81 [0.67-0.98]) for all patients. Primary site did not significantly influence feeding tube utilization (nontonsil/tongue base HR, 0.97 [0.85-1.11]). Conclusions 3DCRT accelerated fractionation chemoradiation is associated with increased posttreatment feeding tube use for both OPC patients and all patients treated when compared to IMRT-based regimens. Other predictors of posttreatment feeding tube use are largely known prior to treatment initiation. Patients treated for nontonsil/tongue base primary tumors did not have higher rates of feeding tube utilization.

Purpose/Objective Stereotactic Radiation Therapy (SBRT) has been implemented for re-iradiation of recurrent or second primary cancers of the head and neck to improve the therapeutic ratio in this difficult scenario. We reviewed our experience at a single institution. Material/Methods After IRB approval, a database of patients receiving re-irradiation was queried. Patients were excluded if receiving conventionally fractionated radiotherapy (RT), non-squamous histology, were enrolled on non-published clinical trials, or metastatic disease. All patients were seen in a multi-disciplinary clinic and/or reviewed in multi-disciplinary tumor board. All patients were ineligible for or refused surgical intervention. Patients were simulated with thermoplastic masks and 2 mm cuts on CT scan with and without contrast. Additional imaging including PET and/or MRI were fused. Gross tumor volume (GTV) was delineated and expanded 2-3 mm for the planning target volume. Elective nodes were not targeted. Minimum dose to PTV was 90% of prescription, with 110 - 130% prescription allowed within GTV/PTV. SBRT was delivered every other day for 5 fractions, with daily cone beam CT imaging, and 6 degree of freedom couch correction. Locoregional control (LRC), progression free survival (PFS), and overall survival (OS) were calculated from the end of RT and estimated via Kaplan-Meier method and comparisons made via log-rank test. Multi-variate cox regression model of OS was performed. Acute (during within three months from completion of treatment) and late (three or more months from completion of treatment) grade 3-5 CTCAE toxicities were collected. Results A total of 76 patients were available for analysis, with a median follow up of 31.5 months for patients alive at last contact, and 12 months for the entire cohort. Median age was 66 (range 36 – 92) with a median RT interval of 29.5 months (range 5 -315). Median dose of initial RT was 70 Gy (range 44 – 79.2 Gy). The majority of patients were former smokers (n=45, 59.2%), followed by never smokers (n=20, 26.3%), and current smokers (n=11, 14.5%). There were 56 men (73.7%) and 20 women (26.3%). Performance status was zero (n=22, 28.9%) and 1-2 (n=54, 71.1%), with 50 patients being recurrent (65.8%) and 26 having a second primary (34.2%). All patients were treated with 5 fractions to a median dose of 40 Gy (range 25 – 40 Gy). Systemic therapy was utilized in 29 patients (38.2%), primarily concurrently (n=27). Concurrent systemic therapy was cisplatin (n=20, 26.3%), cetuximab (n=4, 5.3%), or immunotherapy (n=3, 3.9%). Median gross tumor volume (GTV) was 11.42 cc (range 0.93 – 58.31 cc). Acute grade 3-4 toxicity was seen in 5 patients (6.6%), consisting of feeding tube in 2, aspiration pneumonia in 1, tracheostomy in 1, and stroke in 1. Actuarial rates for the entire cohort at 1 and 2-years for LRC were 43.5% and 33.3%, for PFS, 40.6% and 31.1%, and OS 49.6% and 33.1%. On univariate analysis median GTV, treatment site (nasopharynx/base of skull/neck/skin vs other), and recurrence were prognostic for OS. On multivariate analysis, GTV (HR 1.037, 95% CI 1.018 – 1.056, p < 0.001) and recurrent disease (HR 0.344, 95% CI 0.194 – 0.609, p < 0.001). For the subset of patients (n=26) with a GTV ≤ 11.4 cc and recurrent disease, 2-year OS was 80.1% with a median OS of 37 months. Of 73 patients followed for more than 3 months post treatment, 15 (20.5%) developed a late grade 3-4 toxicity, including feeding tubes in 7, aspiration pneumonia in 3, soft tissue necrosis in 3, or a cranial neve deficit in 3. Conclusion SBRT for re-irradiation for patients with smaller, recurrent squamous cell carcinomas of the head and neck had the best performance. While severe acute toxicities are low, additional studies are needed to improve survival and decrease the risk of late toxicity.

Purpose HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management. Methods The American Society for Radiation Oncology convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and post-treatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. Results Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or one node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins (PSM) or extranodal extension (ENE). Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without PSM and ENE, 5600-6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-D techniques with reduction in dose to critical organs-at-risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography (PET-CT) is recommended approximately 3 months following definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal PET-CT findings, either neck dissection or repeat imaging is recommended. Conclusions The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

PurposeA workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated.MethodsUsing retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc >= 95% (acceptable variation (Delta) >= 90%), V100% >= 95% (Delta >= 90%), and D0.03cc <= 120% (Delta <= 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes.ResultsAll initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc >= 95%, V100% >= 95%, and D0.03cc <= 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively).ConclusionsThis study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Purpose/Objective(s) Chromosomal instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell divisions and is common in cancer. There appears to be a range of CIN that allows for optimal tumor cell fitness, and when increased beyond a maximally tolerated threshold, can lead to cell death due to loss of both copies of one or more essential chromosomes. Radiation induces CIN and we have shown that head and neck cancer cells engineered to have higher CIN at baseline are more sensitive to radiation than their isogenic, wild-type counterparts. We hypothesized that laryngeal cancers from patients enrolled on RTOG 9512 with higher levels of CIN at baseline would be more sensitive to radiation therapy (RT), as reflected by decreased local failure (LF) and locoregional failure (LRF). Materials/Methods RTOG 9512 randomized patients with T2 squamous cell carcinoma of the glottic larynx to hyperfractionated (twice daily) versus standard fractionation (once daily) RT. CIN was quantified by 6-chromosome fluorescence in situ hybridization (FISH). Samples were stained with centromeric probes for chromosomes 3, 4, 7, 9, 10 and 17 and CIN was calculated as the average percentage of cells that deviate from the modal number for each centromeric probe. LF/LRF rates were estimated by the cumulative incidence method. Cox proportional hazards models (stratified by treatment) were used to associate (two-sided 0.10) CIN with LF, LRF, and overall survival (OS). Hazard ratios (HRs) for CIN are presented per 1-standard deviation (SD) increment. Results Of 239 eligible patients from RTOG 9512, 129 had samples available and 107 (44.8%) were of sufficient quality to quantify CIN. There were no notable differences in treatment assignment, patient characteristics, or outcomes between patients included in or excluded from analysis. Mean CIN was 0.48 (SD 0.09) and there was no difference between treatment arms. 5-year LF/LRF rates in this cohort were 23.5% [95% confidence interval (CI) 15.9, 32.0) and 26.3% (95% CI = 18.4, 35.0). CIN was significantly associated with LF (P = 0.04), HR 0.67 (90% CI = 0.48, 0.92), and LRF (P = 0.04), HR 0.68 (90% CI = 0.50, 0.92). After adjustment for covariates, CIN remained significantly associated with LF (P = 0.01), HR 0.58 (90% CI = 0.40, 0.82) and LRF (P = 0.009), HR 0.59 (90% CI = 0.42, 0.82). Before or after adjusting for covariates CIN was not significantly associated with OS (P = 0.61, P = 0.36) with HR 1.07 (90% CI = 0.85, 1.36) and 0.87 (90% CI = 0.68, 1.12). Conclusion Higher CIN in laryngeal tumors from RTOG 9512 was associated with decreased LF/LRF, potentially indicating enhanced radiation sensitivity. This suggests that CIN may serve as a prognostic biomarker for LF/LRF in laryngeal cancers treated with definitive radiation, though further validation is required.

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.

Quality of organ at risk (OAR) autosegmentation is often judged by concordance metrics against the human-generated gold standard. However, the ultimate goal is the ability to use unedited autosegmented OARs in treatment planning, while maintaining the plan quality. We tested this approach with head and neck (HN) OARs generated by a prototype deep-learning (DL) model on patients previously treated for oropharyngeal and laryngeal cancer. Forty patients were selected, with all structures delineated by an experienced physician. For each patient, a set of 13 OARs were generated by the DL model. Each patient was re-planned based on original targets and unedited DL-produced OARs. The new dose distributions were then applied back to the manually delineated structures. The target coverage was evaluated with inhomogeneity index (II) and the relative volume of regret. For the OARs, Dice similarity coefficient (DSC) of areas under the DVH curves, individual DVH objectives, and composite continuous plan quality metric (PQM) were compared. The nearly identical primary target coverage for the original and re-generated plans was achieved, with the same II and relative volume of regret values. The average DSC of the areas under the corresponding pairs of DVH curves was 0.97 ± 0.06. The number of critical DVH points which met the clinical objectives with the dose optimized on autosegmented structures but failed when evaluated on the manual ones was 5 of 896 (0.6%). The average OAR PQM score with the re-planned dose distributions was essentially the same when evaluated either on the autosegmented or manual OARs. Thus, rigorous HN treatment planning is possible with OARs segmented by a prototype DL algorithm with minimal, if any, manual editing.

Supplemental Figure 1 shows the number of non-zero coefficients per variable that was examined in the variable selection processing for the final biomarker panel.