Gd-GQDs as nanotheranostic platform for the treatment of HPV-positive oropharyngeal cancer.

In this study, we developed new gadolinium-graphene quantum dot nanoparticles (Gd-GQDs) as a theranostic platform for magnetic resonance imaging and improved the efficiency of radiotherapy in HPV-positive oropharyngeal cancer. Based on cell toxicity results, Gd-GQD NPs were nontoxic for both cancer and normal cell lines up to 25 µg/ml. These NPs enhance the cytotoxic effect of radiation only on cancer cells but not on normal cells. The flow cytometry analysis indicated that cell death mainly occurred in the late phase of apoptosis. The immunocytochemical analysis was used to evaluate apoptosis pathway proteins. The Bcl-2 and p53 protein levels did not differ statistically significantly between radiation alone group and those that received irradiation in combination with NPs. In contrast, the combination group exhibited a significant increase in Bax protein expression, suggesting that cells could undergo apoptosis independent of the p53 pathway. Magnetic resonance (MR) imaging showed that Gd-GQD NPs, when used at low concentrations, enhanced T1-weighted signal intensity resulting from T1 shortening effects. At higher concentrations, the T2 shortening effect became predominant and was able to decrease the signal intensity. Gd-GQD appears to offer a novel approach for enhancing the effectiveness of radiation treatment and facilitating MR imaging for monitoring HPV-positive tumors.

Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma.

The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

Results of the study of factors predicting the risk of the development of grade III radiation-induced mucositis during radiation or chemoradiation therapy in patients with oral cavity and oropharynx cancer.

BACKGROUND: Today, a number of methods and ways of prevention and treatment of radiation- -induced mucositis of the oral cavity and oropharynx have been developed, but the represented approaches are still not effective enough. Therefore, to increase the effectiveness of the prevention and treatment of radiation-induced mucositis, it is necessary to approach this problem comprehensively and individually, and to evaluate the factors affecting the development of mucositis. MATERIALS AND METHODS: In this single-center prospective controlled non-randomized clinical trial, the results of clinical observation of the development of complications of radiation and chemoradiation therapy in 105 patients with a newly diagnosed squamous cell cancer of the oral cavity and oropharynx were analyzed. Factors affecting the risk of the development of grade III radiation-induced mucositis including the age, gender of the patients, their general condition before the treatment according to World Health Organisation scales, type of the treatment and its doses, additional use of immunotherapy with alpha/beta defensins, characteristic signs of the tumor process and all indices of the immune status of the patients before the treatment have been analyzed. RESULTS: The method of construction and analysis of one-factor logistic regression models, where 24 indices were analyzed as factorial features, showed that the reduction of the risk of the development of grade III radiation-induced mucositis is predicted by several factors: immunotherapy, gender, serum concentrations of IgG and IgA. A decrease (P < 0.001) in the risk of the development of grade III radiation-induced mucositis was revealed if immunotherapy with alpha/beta defensins (with a total dose of 40 mg) was included into the treatment scheme (relative odds (RO) 0.05; 95% reference interval (RI) 0.02-0.18), in comparison with patients of the groups where it was not present or this immune agent was used in a total dose of 60 mg (P = 0.001, RO 0.06; 95% RI 0.01-0.30). The next factorial sign was gender, namely the risk of the development of grade III radiation-induced mucositis was lower for men (P = 0.003; RO 0.15; 95% RI 0.04-0.53) compared to women. An increase (P = 0.024) in the risk of the development of grade III radiation-induced mucositis with an increase in the initial level of IgG serum concentration was revealed, (RO 1.08; 95% RI 1.01-1.16) for each 1 mg/mL, as well as an increase (P = 0.044) in the possibility of the appearance of grade III radiation-induced mucositis with an increase in the serum concentration of IgA (RO 1.23; 95% RI 1.01-1.50) for every 1 mg/mL also before the beginning of the treatment. Multifactorial analysis has also confirmed that the risk of the development of grade III radiation-induced mucositis increases (P = 0.008) with a high serum IgG concentration before the treatment or with an increase in this index during therapy (RO 1.13; 95% RI 1.03-1.09) for every 1 mg/mL (when standardized by other risk factors). It was determined that when standardizing according to other factors (gender, IgG level), the risk of the development of grade III radiation-induced mucositis in the use of the immune agent alpha/beta defensins in a total dose of 40 mg per course decreases (P < 0.001; RO 0.08; 95% RI 0.02-0.27) compared to patients with oral cavity and oropharynx cancer who were not treated with immunotherapy. The risk of the development of grade III radiation-induced mucositis also decreases (P = 0.001) in the use of immunotherapy in a higher dose, i.e. 60 mg per course (RO 0.03; 95% RI 0.004-0.24 compared to patients whose treatment did not include immunotherapy (when standardized by other factors). CONCLUSION: As a result of this controlled clinical study, some factors were determined in addition to the radiation as those affecting the risk of the development of grade III radiation-induced mucositis in patients with oral cavity and oropharynx cancer during special treatment. These factors comprise the inclusion of immunotherapy with alpha/beta defensins into the specific treatment; gender, and baseline levels of serum IgG and IgA concentrations suggest a pattern in which the higher the serum IgG and IgA concentrations are before the start of the treatment, the greater is the likelihood of severe radiation-induced mucositis degree during special therapy. The results of the study of humoral state of the immune system in patients with oral cavity and oropharynx cancer before the beginning of chemoradiation therapy can be used as prognostic risk factors for the development of severe gamma-irradiation-induced mucositis of the oropharyngeal area, as well as an indication for the use of immunotherapeutic agents (in particular, alpha/beta defensins) that are able to polarize the immune response towards type 1 T-helpers through their immunomodulatory action.

Survival outcomes and failure patterns for oropharyngeal cancers treated with simultaneous integrated boost in intensity modulated radiotherapy (SIB-IMRT) and concurrent chemotherapy.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes. MATERIAL AND METHODS: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method. RESULTS: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9). CONCLUSION: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

PET/CT based transformer model for multi-outcome prediction in oropharyngeal cancer.

BACKGROUND AND PURPOSE: To optimize our previously proposed TransRP, a model integrating CNN (convolutional neural network) and ViT (Vision Transformer) designed for recurrence-free survival prediction in oropharyngeal cancer and to extend its application to the prediction of multiple clinical outcomes, including locoregional control (LRC), Distant metastasis-free survival (DMFS) and overall survival (OS). MATERIALS AND METHODS: Data was collected from 400 patients (300 for training and 100 for testing) diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) who underwent (chemo)radiotherapy at University Medical Center Groningen. Each patient's data comprised pre-treatment PET/CT scans, clinical parameters, and clinical outcome endpoints, namely LRC, DMFS and OS. The prediction performance of TransRP was compared with CNNs when inputting image data only. Additionally, three distinct methods (m1-3) of incorporating clinical predictors into TransRP training and one method (m4) that uses TransRP prediction as one parameter in a clinical Cox model were compared. RESULTS: TransRP achieved higher test C-index values of 0.61, 0.84 and 0.70 than CNNs for LRC, DMFS and OS, respectively. Furthermore, when incorporating TransRP's prediction into a clinical Cox model (m4), a higher C-index of 0.77 for OS was obtained. Compared with a clinical routine risk stratification model of OS, our model, using clinical variables, radiomics and TransRP prediction as predictors, achieved larger separations of survival curves between low, intermediate and high risk groups. CONCLUSION: TransRP outperformed CNN models for all endpoints. Combining clinical data and TransRP prediction in a Cox model achieved better OS prediction.

Comparison of Doses to Parotid, Temporomandibular Joint, and Pharyngeal Constrictor Muscles Using Different Techniques in Radiotherapy for Oropharyngeal Cancer.

OBJECTIVE: The purpose of this research was to compare two treatment techniques for oropharyngeal cancers: conventional linac-based static intensity-modulated radiotherapy (sIMRT) and helical tomotherapy (HT). The study examined several parameters, including target coverage, organs at risk, integral dose, and beam on time. Additionally, the study evaluated the doses to the parotid, temporomandibular joint, and pharyngeal constrictor muscles, which are important for swallowing. METHOD: The present study retrospectively analyzed the data of 13 patients with oropharyngeal cancer who underwent radiotherapy between 2019 and 2021. The treatment plans for each patient were regenerated using both sIMRT and HT treatment planning systems with the sequential boost method. The techniques were evaluated and compared based on dose-volume histogram, homogeneity index, and conformity index parameters. The target coverage and organs at risk were statistically compared for two techniques. Additionally, the doses received by the healthy tissue volume were obtained for integral dose evaluation. The beam on time for each technique was assessed. RESULTS: When considering planning target volume evaluation, there was no difference in Dmeans between the two techniques and sIMRT demonstrated higher D2% values compared to the HT. The HT technique had better results for all organs at risk, such as the parotid, temporomandibular joint, and pharyngeal constrictor muscle. As for integral dose, it has been shown that the sIMRT technique provides better protection compared to HT. In addition, the beam on time was also longer with the HT technique. CONCLUSION: Both techniques may provide optimal target coverage for patients with oropharyngeal cancer. HT conferred notable advantages, especially with regard to critical structures implicated in swallowing, such as the parotid, temporomandibular joint, and pharyngeal constrictor muscle, in comparison to sIMRT.

Efficient proton arc optimization and delivery through energy layer pre-selection and post-filtering.

BACKGROUND: Proton arc therapy (PAT) has emerged as a promising approach for improving dose distribution, but also enabling simpler and faster treatment delivery in comparison to conventional proton treatments. However, the delivery speed achievable in proton arc relies on dedicated algorithms, which currently do not generate plans with a clear speed-up and sometimes even result in increased delivery time. PURPOSE: This study aims to address the challenge of minimizing delivery time through a hybrid method combining a fast geometry-based energy layer (EL) pre-selection with a dose-based EL filtering, and comparing its performance to a baseline approach without filtering. METHODS: Three methods of EL filtering were developed: unrestricted, switch-up (SU), and switch-up gap (SU gap) filtering. The unrestricted method filters the lowest weighted EL while the SU gap filtering removes the EL around a new SU to minimize the gantry rotation braking. The SU filtering removes the lowest weighted group of EL that includes a SU. These filters were combined with the RayStation dynamic proton arc optimization framework energy layer selection and spot assignment (ELSA). Four bilateral oropharyngeal and four lung cancer patients' data were used for evaluation. Objective function values, target coverage robustness, organ-at-risk doses and normal tissue complication probability evaluations, as well as comparisons to intensity-modulated proton therapy (IMPT) plans, were used to assess plan quality. RESULTS: The SU gap filtering algorithm performed best in five out of the eight cases, maintaining plan quality within tolerance while reducing beam delivery time, in particular for the oropharyngeal cohort. It achieved up to approximately 22% and 15% reduction in delivery time for oropharyngeal and lung treatment sites, respectively. The unrestricted filtering algorithm followed closely. In contrast, the SU filtering showed limited improvement, suppressing one or two SU without substantial delivery time shortening. Robust target coverage was kept within 1% of variation compared to the PAT baseline plan while organs-at-risk doses slightly decreased or kept about the same for all patients. CONCLUSIONS: This study provides insights to accelerate PAT delivery without compromising plan quality. These advancements could enhance treatment efficiency and patient throughput.

Systematic evaluation and meta-analysis of the prognosis of down-staging human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma using cetuximab combined with radiotherapy instead of cisplatin combined with radiotherapy.

Objective: To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC). Design: Meta-analysis and systematic evaluation. Data sources: The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com. Eligibility criteria for selecting studies: Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV+ OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE). Data extraction and synthesis: Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data. Results: A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV+ OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV+ OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], P = 0.0004; HR = 1.79, 95% CI [1.40-2.29], P < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], P < 0.0001; HR = 1.66, 95% CI [1.07-2.58], P = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], P = 0.28). Conclusions: Cisplatin + radiotherapy remains the standard treatment for HPV+ OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV+ OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies. Prospero registration number: CRD42023445619.

Tubarial gland sparing with intensity modulated radiation therapy for oropharyngeal cancers: A pilot study of dosimetric feasibility.

BACKGROUND: Tubarial glands are a new organ at risk for head and neck cancer radiation therapy (RT). We aimed to study the feasibility of sparing them using intensity-modulated radiation therapy (IMRT). METHODS: Tubarial glands were delineated for 17 patients with oropharyngeal carcinoma receiving definitive RT, and treatment plans were re-optimized to spare dose to the tubarial glands while maintaining target coverage. A paired t test was performed to compare the mean dose of tubarial glands and target coverage. RESULTS: The difference in mean doses was 4.9 and 7.0 Gy for the ipsilateral and contralateral tubarial glands, respectively (p < 0.01). The mean dose to tubarial gland was ≤39 Gy in 35% versus 47% (ipsilateral) and 70% versus 100% (contralateral) in clinical and re-optimized plans, respectively. Re-optimized ipsilateral tubarial gland mean ≤39 Gy was achieved more commonly in patients with base of tongue versus tonsil primaries (86% vs. 20%, p = 0.02). CONCLUSION: This pilot study demonstrates the dosimetric feasibility of tubarial gland sparing with IMRT. Dosimetric constraints need to be determined with larger studies.

Translational risk-adapted approaches to de-escalated radiation for human papillomavirus-positive oropharyngeal cancer: Past, present, and future.

Interest in the use of de-escalated radiation to treat patients with newly diagnosed human papillomavirus (HPV)-positive oropharyngeal cancer has grown dramatically with the publication of prospective trials demonstrating the efficacy of such an approach. While the rationale for de-escalation--- namely to decrease treatment-related toxicity while maintaining the excellent rates of disease control historically observed in patients with this disease-is inherently obvious, uncertainty exists regarding how to best select patients for de-escalation. Consequently, risk-adapted strategies using a variety of translational and clinical platforms have been increasingly popularized to better refine treatment. These have integrated contemporary methods of mid-treatment response assessment using advanced technologies and molecular assays to customize the radiation dose. By monitoring the response as patients actively proceed through treatment, risk-adapted protocols have the potential to provide insight into the biological behavior of tumors and make individualized therapy possible. The purpose of this review is to summarize the evidence to date on risk-adapted approaches to de-escalated radiation-- highlighting the clinical, radiological, and biological data which may ultimately help usher the principles of precision medicine into practice for patients with HPV-positive oropharyngeal cancer.

Quality of life outcomes comparing primary Transoral Robotic Surgery (TORS) with primary radiotherapy for early-stage oropharyngeal squamous cell carcinoma: A systematic review and meta-analysis.

BACKGROUND: Transoral Robotic Surgery (TORS) and radiotherapy are considered oncologically equivalent primary treatment options for early-stage HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Quality of Life (QoL) and Patient Reported Outcome Measures (PROMs) are therefore imperative in supporting clinical decision-making and optimising patient-centred care. The aim of this article is to evaluate how these primary treatment modalities compare in terms of QoL. MATERIALS AND METHODS: Systematic review and meta-analysis of studies comparing primary TORS and primary radiotherapy for OPSCC using validated QoL tools. Swallowing and global QoL were the primary endpoints with secondary endpoints including all other QoL domains. An inverse variance random-effects model was employed to calculate the weighted estimate of the treatment effects across trials. RESULTS: A total of six studies collectively reporting on 555 patients were included (n = 236 TORS and n = 319 radiotherapy). Meta-analysis showed no significant difference for swallowing (mean difference = -0.24, p = 0.89) and global QoL (mean difference = 4.55, p = 0.14). For the remaining QoL domains (neck/shoulder impairment, neurotoxicity, voice, xerostomia, speech, and distress), the scarcity of data did not permit meta-analysis. However, the existing data showed no significant difference for any except for xerostomia where TORS appears favourable in the sole study reporting on this. CONCLUSIONS: TORS and radiotherapy appear to be comparable primary treatment options for early stage OPSCC when it comes to QoL. However, a substantial proportion of patients in the TORS group received adjuvant (chemo)radiotherapy rendering it difficult to establish the 'true' QoL outcomes following surgery alone. There are also minimal studies reporting QoL outcomes beyond swallowing and global QoL. Further research is therefore needed, including more randomised trials adequately powered to detect differences in QoL outcomes.

Assessment of the Dosimetric Index from IMRT and Rapid arc Plan for Oropharyngeal Cancer with Simultaneous Integrated Boost (SIB) Technique in Combination with EUD-based NTCP and TCP Radiobiological Models.

PURPOSE: The current research compared radiobiological and dosimetric results for simultaneous integrated boost (SIB) plans employing RapidArc and IMRT planning procedures in oropharyngeal cancer from head-and-neck cancer (HNC) patients. MATERIALS AND METHODS: The indigenously developed Python-based software was used in this study for generation and analysis. Twelve patients with forty-eight total plans with SIB were planned using Rapid arc (2 and 3 arcs) and IMRT (7 and 9 fields) and compared with radiobiological models Lyman, Kutcher, Burman (LKB) and EUD (Equivalent Uniform Dose) along with physical index such as homogeneity index(HI), conformity index(CI) of target volumes. RESULTS: These models' inputs are the dose-volume histograms (DVHs) calculated by the treatment planning system (TPS). The values obtained vary from one model to the other for the same technique and patient. The maximum dose to the brainstem and spinal cord and the mean dose to the parotids were analysed both dosimetrically and radiobiologically, such as the LKB model effective volume, equivalent uniform dose, EUD-based normal tissue complication probability, and normal tissue integral dose. The mean and max dose to target volume with conformity, homogeneity index, tumor control probability compared with treatment times, and monitor units. CONCLUSION: Rapid arc (3 arcs) resulted in significantly better OAR sparing, dose homogeneity, and conformity. The findings indicate that the rapid arc plan has improved dose distribution in the target volume compared with IMRT, but the tumor control probability obtained for the two planning methods, Rapid arc (3 arcs) and IMRT (7 fields), are similar. The treatment time and monitor units for the Rapid arc (3 arcs) were superior to other planning methods and considered to be standard in head & neck radiotherapy.

Sparing Swallowing-Related Structures Reduces Post-Radiotherapy Dysphagia in Oropharyngeal Cancer.

OBJECTIVE: To identify swallowing-related structures (SRSs) predicting post-radiotherapy dysphagia in oropharyngeal carcinoma patients. MATERIAL AND METHODS: Between September 2020 and October 2022, oropharyngeal cancer patients who had completed radiotherapy at least one year before without recurrence or residuals were selected. They underwent flexible endoscopic evaluation of swallowing (FEES) assessments and dysphagia grading. The mean radiation doses delivered to their SRSs were recalculated. The correlation between radiation doses to each SRS and FEES scores was analysed. RESULTS: Twenty-nine participants, aged 51-73 years, were enrolled. Six patients had received two-dimensional radiotherapy, eight had undergone three-dimensional conformal radiotherapy, and fifteen had received intensity-modulated radiation therapy. Radiation doses to the inferior pharyngeal constrictor, cricopharyngeus and glottic larynx significantly predicted dysphagia for both semisolids (p = 0.023, 0.030 and 0.001) and liquid diets (p = 0.021, 0.013 and 0.002). The esophageal inlet significantly predicted swallowing outcomes for only the liquid diet (p = 0.007). CONCLUSIONS: This study supports that SRS-sparing during radiotherapy for oropharyngeal cancers improves swallowing outcomes.

Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Association of adjuvant radiation and survival in human papilloma virus-positive oropharynx squamous cell carcinoma with lymphovascular invasion as the sole adverse pathologic feature.

BACKGROUND: Postoperative radiotherapy radiation therapy (PORT) for early-stage human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) with positive lymphovascular invasion (LVI) has an unclear association with overall survival (OS). METHODS: This retrospective cohort study queried the National Cancer Database for surgically treated, T1-2, N0-1 HPV+ OPSCC from 2010 to 2019. Primary exposures were LVI and PORT, and the main outcome was 5-year OS. Odds ratios and hazard ratios (HR) with 95% confidence intervals (CIs) were generated using multivariable models and Cox proportional hazard models, respectively. RESULTS: Of 2768 patients, average age was 59.3 years, 2207 (79.7%) were male, and 386 (13.9%) had LVI. Of patients with LVI as their sole adverse pathologic feature, 220 (57.0%) received PORT, which was not associated with 5-year OS (HR, 1.13; CI, 0.65-1.19). CONCLUSIONS: Patients with surgically treated, early-stage HPV+ OPSCC and positive LVI as their only pathologic adverse feature may not require PORT.

Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

Upfront surgery versus definitive radiotherapy: competing risk analyses for cancer-specific and noncancer mortality in oropharyngeal cancer.

PURPOSE: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT). METHODS: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts. RESULTS: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009). CONCLUSION: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings.