The incidence of Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has risen over the past two decades, now accounting for 44-75 % of cases in Europe and the USA. This review synthesized data from PubMed, additional academic sources, and ongoing studies to summarize the potential role of proton therapy (PT) role in treating HPV-related OPSCC. In vitro studies support PT radiosensitization of HPV-positive cells and clinical experiences report high locoregional control (LRC) rates of 88.6-97 % with significantly reduced side effects such as xerostomia by 12.5 % and brain necrosis by 2.3 %, compared to intensity-modulated radiation therapy (IMRT). A randomized trial (NCT01893307) has also recently provided level 1 evidence showing that PT is non-inferior to IMRT for tumor control while reducing treatment-related toxicities, such as feeding tube dependence (28 % vs. 42 %, p = 0.019) and facilitating better work resumption outcomes (71 % vs. 52 % at 2 years). Despite the success of radiation de-escalation achieving LRC up to 95 %, recent trials indicate potential survival risks when standard treatments are modified. Failure pattern analysis showed that up to 70 % of locoregional recurrences occurred in-field, highlighting the potential role of PT in achieving LRC while minimizing toxicity. PT could also play a role in the reirradiation of recurrent OPSCC, with reported 1-year LRC rates of 71.8-80.8 %, 2-year LRC rates of 72.8-80.3 %, 1-year overall survival (OS) rates of 65.2-81.3 %, 2-year OS rates of 32.7-69 %, and late grade ≥2 toxicities of 11.9-36.3 %. Methodologies improving reRT approaches include dose/volume histogram comparisons, which recommended PT when it resulted in lower predicted toxicities.

To compare plan quality among photon volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT) with robustness using three different proton beam delivery systems with various spot size (σ) ranges: cyclotron-generated proton beams (CPBs) (σ: 2.7-7.0 mm), linear accelerator proton beams (LPBs) (σ: 2.9-5.5 mm), and linear accelerator proton mini beams (LPMBs) (σ: 0.8-3.9 mm) for the treatment of head and neck (HN) cancer with bilateral neck irradiation.

Ten patients treated for oropharynx cancer with bilateral neck irradiation were planned using CPBs, LPBs, LPMBs, and VMAT. The homogeneity index (HI), mean body dose, and defined volumetric doses for selected critical organs-at-risk (OARs) were compared. Set-up uncertainties of ±3 mm and ± 3.5% range uncertainties were included in robust evaluation using V95%Rx > 95% (Volume that covers 95% of the target volume at 95% of the prescription (Rx) dose) to high dose and low dose CTV volumes (CTV_70 Gy and CTV_56 Gy). VMAT and proton plans were compared in terms of OAR doses and mean body dose only. Homogeneity Indices were compared among IMPT plans in addition to OAR doses. The Wilcoxon signed-rank test was used to evaluate statistical differences between evaluation metrics for VMAT plans and all proton plan types.

OAR dose metrics were improved by 2% to 30% from CPB plans to LPB or LPMB plans. Compared to photon VMAT plans, all OAR doses except for mandible dose metrics were improved by 2% to 53% for all proton plans. The mean body dose was also improved by 7.5% from CPB to LPB and by 10.8% from CPB to LPMB. In addition, the mean body dose was also improved by 44% from VMAT to CPB, by 48% from VMAT to LPB, and by 50% from VMAT to LPMB plans. Compared to CPB plans, HI was significantly better (p < 0.05) for the LPB and LPMB plans. HI also improved considerably from VMAT to CPB, LPB, and LPMB. For both CTV_70 Gy and CTV_56 Gy, average robust evaluation across all worst-case scenarios was slightly better for CPB plans, with an average of V95%Rx of the CTV_70 Gy of 97.6% ± 1.22%, followed by 97.2% ± 1.31% and 97.2% ± 1.35% for LPB and LPMB plans, respectively. Robustness for CTV_56 Gy showed comparable robustness across all proton plan types, with an average V95%Rx of 97.4% ± 0.87% for CPB, 97.4% ± 1.21%, and 97.5% ± 1.08% for CPB, LPB, and LPMB plans, respectively.

With decreased spot size, the LPB and LPMB are excellent alternatives to VMAT and CPB therapy and can significantly reduce the dose to normal tissue.

Secondary cancer is a serious side effect from external beam radiotherapy (EBRT). Conventional EBRT is performed using a beam of photons, however, due to their ability to produce more conformal dose distributions, the use of protons is becoming more wide-spread. Due to this sparing it would be expected that proton therapy could be associated with lower secondary cancer rates compared to photon therapy. However, since proton therapy data is still being accumulated and the follow-up period is often relatively short thus far, simulation studies can complement the existing data and extrapolate to longer time frames.

This study aims to estimate and compare the risk of secondary cancer when treating head-and-neck cancer patients with proton therapy or photon therapy, while combining a whole-body computational human phantom with the patient treatment planning computed tomography (CT) scan in order to study organs that are partially or fully outside of the treatment planning CT. In addition, proton therapy secondary cancer rates are investigated further by including variable relative biological effectiveness (RBE) models.

For 20 head-and-neck cancer patients, two clinical radiotherapy treatment plans were created, one for proton therapy and one for photon therapy. For proton therapy, linear energy transfer (LET) distributions were simulated and used to calculate the variable RBE-weighted dose distributions for six different variable RBE models, in addition to the constant RBE of 1.1 widely used clinically. In order to obtain the dose deposited outside the treatment planning CT scan, an adjustable whole-body digital reference phantom was stitched to the treatment planning CT. Based on the resulting dose distributions, the risk of secondary cancer was calculated for each modality.

Averaged across all patients and relevant organs, photon therapy compared to proton therapy with a constant RBE of 1.1 was estimated to be 1.8 times more likely to cause secondary cancer. This risk ratio varied between 1.6 and 2.0, depending on the variable RBE model used. Cases with lifetime attributable risk (LAR) values below 0.1% were excluded from this analysis to prevent the benefits of proton therapy (the ratioL A R p h o t o n L A R p r o t o n $\frac{LAR_{photon}}{LAR_{proton}}$ ) from being artificially elevated in cases in whichL A R p r o t o n ≈ 0 $LAR_{proton}\approx 0$ .

Proton therapy was associated with lower estimated secondary cancer rates compared to photon therapy when treating head-and-neck cancer patients. This trend was observed even when considering different variable RBE models to calculate the proton therapy dose distributions.

Historically, spot-scanning proton therapy (SSPT) treatment planning uses dose-volume constraints and linear-energy-transfer (LET) volume constraints separately to balance tumor control and organs-at-risk (OARs) protection. We propose a novel dose-LET-volume constraint (DLVC)-based robust optimization (DLVCRO) method for SSPT in treating prostate cancer to obtain a desirable joint dose and LET distribution to minimize adverse events.

DLVCRO treats DLVC as soft constraints that control the shapes of the dose-LET volume histogram (DLVH) curves. It minimizes the overlap of high LET and high dose in OARs and redistributes high LET from OARs to targets in a user-defined way. Ten patients with prostate cancer were included in this retrospective study. Rectum and bladder were considered as OARs. DLVCRO was compared with the conventional robust optimization (RO) method. Plan robustness was quantified using the worst-case analysis method. Besides the dose-volume histogram indices, the analogous LET-volume histogram, extrabiological dose (the product of per voxel dose and LET) volume histogram (xBDVH) indices characterizing the joint dose/LET distributions and DLVH indices were also used. The Wilcoxon signed-rank test was performed to measure statistical significance.

In the nominal scenario, DLVCRO significantly improved joint distribution of dose and LET to protect OARs compared with RO. The physical dose distributions in targets and OARs are comparable. In the worst-case scenario, DLVCRO markedly enhanced OAR protection (more robust) while maintaining almost the same plan robustness in target dose coverage and homogeneity.

DLVCRO upgrades 2D DVH-based to 3D DLVH-based treatment planning to adjust dose/LET distributions simultaneously and robustly. DLVCRO is potentially a powerful tool to improve patient outcomes in SSPT.

Advances in the treatment of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) include transoral robotic surgery (TORS) and proton beam therapy (PBT). This study aims to improve understanding of the treatment toxicities associated with adjuvant PBT following TORS for OPSCC.

A retrospective review.

An academic tertiary care center in Baltimore, Maryland.

Patients undergoing TORS followed by adjuvant PBT from 2017 to 2023 were reviewed.

Forty-seven patients with HPV-associated OPSCC underwent TORS followed by adjuvant PBT. Forty-one (87.2%) patients were male. The median age at first radiation fraction was 61.7 years. Forty-one (87.2%) identified as white and 6 (12.8%) as African American. Most patients had T1 (23 [48.9%]) or T2 (22 [46.8%]), N1 (41 [87.2%]) disease. The majority (98.3%) of acute toxicities were grade 1 or 2, with only 1 (2.1%) patient developing grade 3 toxicities. Three (6.4%) patients required a feeding tube for nutrition during adjuvant proton radiation treatment. The 3 patients who required feeding tubes during radiation also required postoperative nasogastric tubes for a median of 16 days, compared with 3 days for all other patients (Mann-Whitney U, P = .02). The most common chronic toxicities included xerostomia, dysphagia, dysgeusia, and lymphedema, which decreased over time.

HPV-associated OPSCC treated with TORS followed by adjuvant PBT demonstrated a favorable toxicity profile with mostly grade 1 or 2 acute toxicities. Feeding tube requirement during adjuvant PBT was low at 6.4%. Many chronic toxicities appeared to decrease in frequency with time from radiation, although further study is required.

In recent years, particle therapy has shown promise as a local treatment for salivary gland carcinoma (SGC); however, its efficacy and safety remain unclear. This study aimed to evaluate the clinical outcomes of intensity-modulated proton therapy (IMPT) for SGC.

We performed a single-institution retrospective analysis of patients with SGC who underwent IMPT.

IMPT was performed on 28 SGC patients, of which 18 were for definitive treatment and 10 were for postoperative treatment. The 2-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates for definitive treatment cases were 70.1%, 25.0%, and 82.5%, respectively. The 2-year OS, PFS, and LC rates for postoperative treatment cases were 100%, 80.0%, and 90.0%, respectively. Quality of life scores in the EORTC QLQ-C30 and QLQ-HN35 were preserved for 1 year after treatment.

Our study suggests the efficacy and safety of IMPT in SGC patients.

Rapid technological advances in radiation therapy have significantly improved dose delivery and tumor control for head and neck cancers. However, treatment-related toxicities caused by high-dose exposure to critical structures remain a significant clinical challenge, underscoring the need for accurate prediction of clinical outcomes-encompassing both tumor control and adverse events (AEs). This review critically evaluates the evolution of data-driven approaches in predicting patient outcomes in head and neck cancer patients treated with radiation therapy, from traditional dose-volume constraints to cutting-edge artificial intelligence (AI) and causal inference framework. The integration of linear energy transfer in patient outcomes study, which has uncovered critical mechanisms behind unexpected toxicity, was also introduced for proton therapy. Three transformative methodological advances are reviewed: radiomics, AI-based algorithms, and causal inference frameworks. While radiomics has enabled quantitative characterization of medical images, AI models have demonstrated superior capability than traditional models. However, the field faces significant challenges in translating statistical correlations from real-world data into interventional clinical insights. We highlight that how causal inference methods can bridge this gap by providing a rigorous framework for identifying treatment effects. Looking ahead, we envision that combining these complementary approaches, especially the interventional prediction models, will enable more personalized treatment strategies, ultimately improving both tumor control and quality of life for head and neck cancer patients treated with radiation therapy.

Proton therapy offers significant advantages due to its unique physical and biological properties, particularly the Bragg peak, enabling precise dose delivery to tumors while sparing healthy tissues. However, the clinical implementation is challenged by the oversimplification of the relative biological effectiveness (RBE) as a fixed value of 1.1, which does not account for the complex interplay between dose, linear energy transfer (LET), and biological endpoints. Lack of heterogeneity control or the understanding of the complex interplay may result in unexpected adverse events and suboptimal patient outcomes. On the other hand, expanding our knowledge of variable tumor RBE and LET optimization may provide a better management strategy for radioresistant tumors. This review examines recent advancements in LET calculation methods, including analytical models and Monte Carlo simulations. The integration of LET into plan evaluation is assessed to enhance plan quality control. LET-guided robust optimization demonstrates promise in minimizing high-LET exposure to organs at risk, thereby reducing the risk of adverse events. Dosimetric seed spot analysis is discussed to show its importance in revealing the true LET-related effect upon the adverse event initialization by finding the lesion origins and eliminating the confounding factors from the biological processes. Dose-LET volume histograms (DLVH) are discussed as effective tools for correlating physical dose and LET with clinical outcomes, enabling the derivation of clinically relevant dose-LET volume constraints without reliance on uncertain RBE models. Based on DLVH, the dose-LET volume constraints (DLVC)-guided robust optimization is introduced to upgrade conventional dose-volume constraints-based robust optimization, which optimizes the joint distribution of dose and LET simultaneously. In conclusion, translating the advances in LET-related research into clinical practice necessitates a better understanding of the LET-related biological mechanisms and the development of clinically relevant LET-related volume constraints directly derived from the clinical outcomes. Future research is needed to refine these models and conduct prospective trials to assess the clinical benefits of LET-guided optimization on patient outcomes.

Intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC) is associated with acute and late toxicities that impact patient quality of life. Proton radiotherapy (PRT) can reduce exposure to surrounding tissues, but the clinical magnitude of this advantage is unclear. A systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Included studies reported toxicity or oncologic outcomes from patients treated with PRT for OPC. Pooled outcomes were estimated using random-effects models. Comparisons between PRT and IMRT were performed using log odds ratios. Primary outcomes were the pooled rates of adverse events, overall survival (OS), and progression-free survival (PFS). A total of 18 studies (16 retrospective, two prospective) consisting of 956 patients were identified. Pooled rates of acute grade 3+ toxicities were as follows: dermatitis 19%, mucositis 32%, xerostomia 1.3%, dysphagia 13%, and weight loss 1.4%. The pooled rate of acute hospitalizations was 10%. Among studies reporting late toxicities, the rates of grade 3+ xerostomia and dysphagia were 1.1% and 1.6%, respectively. Compared to IMRT, PRT was associated with lower rates of acute feeding tube use (21% versus 31%; P = 0.0012), but not long-term feeding tube use (1.4% versus 2.7%; P = 0.24). After PRT, OS at two and three years were 98% and 96%, while PFS at two and three years were 93% and 86%. PRT for patients with OPC is associated with favorable toxicity and oncologic outcomes. While randomized clinical trials are ongoing, these data provide additional evidence regarding the efficacy of PRT in the upfront treatment of OPC.

Radiotherapy (RT) is an integral component in the multidisciplinary management of patients with head and neck squamous cell carcinoma (HNSCC). Significant advances have been made toward optimizing tumor control and toxicity profiles of RT for HNSCC in the past two decades. The development of intensity modulated radiotherapy (IMRT) and concurrent chemotherapy established the standard of care for most patients with locally advanced HNSCC around the turn of the century. More recently, selective dose escalation to the most radioresistant part of tumor and avoidance of the most critical substructures of organs at risk, often guided by functional imaging, allowed even further improvement in the therapeutic ratio of IMRT. Other highly conformal RT modalities, including intensity modulated proton therapy (IMPT) and stereotactic body radiotherapy (SBRT) are being increasingly utilized, although there are gaps in our understanding of the normal tissue complication probabilities and their relative biological effectiveness. There is renewed interest in spatially fractionated radiotherapy (SFRT), such as GRID and LATTICE radiotherapy, in both palliative and definitive settings. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with recurrent and metastatic HNSCC. Novel RT modalities, including IMPT, SBRT, and SFRT, have the potential to reduce lymphopenia and immune suppression, stimulate anti-tumor immunity, and synergize with ICIs. The next frontier in the treatment of HNSCC may lie in the exploration of combined modality treatment with new RT technologies and ICIs.

Head and neck cancers rank as the seventh most common cancer worldwide, nearly half of which result in death. The most common treatment methods for head and neck cancers include radiotherapy and surgery. Proton therapy has emerged in radiotherapy for cases where tumors are located near anatomically sensitive areas where the radiation dose must be strictly limited. The purpose of the work is to discuss the role of the proton therapy in the treatment in various types of cancer, and particularly head and neck tumors.

Proton therapy allows for the delivery of radiation doses to critical organs to be reduced, resulting in a decrease in the occurrence of late adverse effects on these organs. The occurrence of side effects caused by proton therapy depends on the relative and absolute volume of organs at risk receiving specific radiation doses. Proton therapy represents a promising alternative to conventional radiotherapy due to the reduced number of complications in healthy tissues by delivering a lower radiation dose outside the tumor area.

To comprehensively evaluate the therapeutic efficacy and safety when utilizing proton therapy (PT) versus intensity-modulated radiation therapy (IMRT) in head and neck cancer patients. Pubmed, ScienceDirect, Embase, Scopus, and Web of Science were systematically searched for studies on comparative PT and IMRT outcomes. We performed a random effect model meta-analysis to estimate the hazard ratio (HR) and odds ratio (OR) for efficacy and safety outcome variables between PT and IMRT. From 641 identified articles, 11 studies met the inclusion criteria, comprising 3087 patients (606 treated with PT and 2481 with IMRT). On toxicity analysis, PT is associated with decreased acute grade 1 nausea (OR = 0.34, 95% CI: 0.13-0.84, p = 0.02) compared to IMRT. In grade 2 toxicity, PT showed significant advantages over IMRT in mucositis (OR = 0.44, p < 0.0001), dysgeusia (OR = 0.35, p = 0.02), dysphagia (OR = 0.36, p < 0.0001), fatigue (OR = 0.29, p = 0.001), pain (OR = 0.34, p = 0.01), and weight loss (OR = 0.54, p = 0.02). Proton therapy also exhibited increased safety in grade 3 dysphagia incidence (OR = 0.44, p < 0.0001) compared to IMRT. PT demonstrated improved overall survival (OS) compared to IMRT across multiple time points: 1-year OS (HR = 0.43, p = 0.02), 2-year OS (HR = 0.44, p < 0.0001), and 5-year OS (HR = 0.78, p = 0.004). In terms of disease-free survival (DFS), PT also showed improved outcomes at 2-year DFS (HR = 0.65, p = 0.03) and 5-year DFS (HR = 0.81, p = 0.03). Proton therapy demonstrated superior overall survival (OS), disease-free survival (DFS), and better local control rate (LCR) compared to IMRT. The data also showed better safety outcomes in PT patients, particularly when involving grade 2 acute toxicity events.

As preparation for a national randomized study comparing proton radiotherapy to photon radiotherapy, DAHANCA 35, we performed a non-randomized pilot study to investigate patient selection, logistics, planning, and treatment delivery. With the present study, as a comprehensive safety analysis, we want to compare toxicity during and up to two months after therapy to a historically matched group of patients treated with photon radiotherapy.

62 patients treated with protons were matched to 124 patients who received photon treatment outside a protocol. Available data were retrieved from the DAHANCA database. Patients were matched on treatment centre, concurrent chemotherapy, tumour site, stage, p16 status for oropharynx cancers. Selection of patients for proton therapy was based on comparative treatment plans with a NTCP reduction for dysphagia and xerostomia at six months.

Baseline characteristics between groups were well balanced, except for the type of drug used concurrently; more photon patients received Carboplatin (21.2 % vs 5.8 %, p = 0.01). Proton therapy was associated with significantly less weight loss at the end of treatment, mean weight loss of 3 % for protons and 5 % for photons (p < 0.001). There were more grade 3 skin reactions and grade 3 mucositis after proton treatment compared with photons at the end of treatment, Risk Ratio (RR) 1.9 (95 % CI: 1.01-3.5, p = 0.04) and RR 1.5 (95 % CI: 1.3-1.7, p < 0.001), respectively. All differences resolved at follow up two months after treatment. There were no significant differences between groups on opioid use, use of feeding tubes, or hospitalization during the observation period.

Proton treatment resulted in excess objective mucositis and dermatitis, which was transient and did not seem to negatively influence weight or treatment compliance and intensity. Selection bias was likely especially since NTCP models were used for selection of proton treatment and photon treated patients were matched manually. We are currently including patients in a randomized controlled trial.

Xerostomia is a common radiation-associated toxicity in patients with head and neck cancer. Although several studies examined the decrease in saliva production due to radiotherapy (RT) and investigated the factors associated with this side effect, little is known about the change in radiation-associated saliva composition. This systematic review is the first to summarize existing data and give an overview of the change in pH/buffer capacity, electrolytes, proteins, enzymes, and mucins due to radiation to the salivary glands. Literature search was performed in PubMed and Embase with 47 articles finally eligible for the review, analyzing the saliva composition at several time points before, during and/or after RT, or comparing findings in irradiated patients to a healthy control group. Overall, RT leads to a substantial decrease in salivary pH and buffer capacity. For sodium, chloride and calcium ion, as well as amylase, an increased concentration or activity during RT was reported in most of the studies, followed by a subsequent decrease either already during RT or after the end of treatment. Different trends have been described for the total protein concentration during and after RT. Lactoferrin, however, increased considerably, especially in the first phase of RT. Mucin 5B (MUC5B) concentrations showed a slight increase during RT and concentrations around baseline values again six months post-radiotherapy.

Osteoradionecrosis (ORN) is a severe late complication of head and neck radiation therapy shown to have profound negative effect on the quality of life of cancer survivors. Over the past few decades, improvements in radiation delivery techniques have resulted in a decrease in the incidence of ORN. However, even with modern radiation therapy techniques, ORN remains an important clinical concern. In recent literature, there is a wide range of reported ORN rates from 0% to as high as 20%. With such a high level of variability in the reported incidence of ORN, oncologists often encounter difficulties estimating the risk of this serious radiation therapy toxicity.

In this review, the authors present a summary of the factors that contribute to the high level of variability in the reported incidence of ORN.

Variable definition, variable grading, and heterogeneity of both study inclusion criteria and treatment parameters can each significantly influence the reporting of ORN rates.

Given numerous factors can affect the reported incidence of ORN, a thorough understanding of the clinical context behind the reported ORN rates is needed to comprehend the true risk of this important radiation therapy toxicity.

Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution.

Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans.

IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03).

IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.

The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC.

Radiation therapy (RT) is a crucial treatment for head and neck squamous cell carcinoma (HNSCC); however, it can have adverse effects on patients' long-term function and quality of life. Biomarkers that can predict tumor response to RT are being explored to personalize treatment and improve outcomes. While tissue and blood biomarkers have limitations, imaging biomarkers derived from magnetic resonance imaging (MRI) offer detailed information. The integration of MRI and a linear accelerator in the MR-Linac system allows for MR-guided radiation therapy (MRgRT), offering precise visualization and treatment delivery. This data descriptor offers a valuable repository for weekly intra-treatment diffusion-weighted imaging (DWI) data obtained from head and neck cancer patients. By analyzing the sequential DWI changes and their correlation with treatment response, as well as oncological and survival outcomes, the study provides valuable insights into the clinical implications of DWI in HNSCC.

Focused Very-High Energy Electron (VHEE, 50-300 MeV) and Ultra-High Energy Electron (UHEE, > 300 MeV) beams can accurately target both large and deeply seated human tumors with high sparing properties, while avoiding the spatial requirements and cost of proton and heavy ion facilities. Advanced testing phases are underway at the CLEAR facilities at CERN (Switzerland), NLCTA at Stanford (USA), and SPARC at INFN (Italy), aiming to accelerate the transition to clinical application. Currently, Monte Carlo (MC) transport is the sole paradigm supporting preclinical trials and imminent clinical deployment. In this paper, we propose an alternative: the first extension of the nuclear-reactor deterministic chain NJOY-DRAGON for VHEE and UHEE applications. We have extended the Boltzmann-Fokker-Planck (BFP) multigroup formalism and validated it using standard radio-oncology benchmarks, complex assemblies with a wide range of atomic numbers, and comprehensive irradiation of the entire periodic table. We report that [Formula: see text] of water voxels exhibit a BFP-MC deviation below [Formula: see text] for electron energies under [Formula: see text]. Additionally, we demonstrate that at least [Formula: see text] of voxels of bone, lung, adipose tissue, muscle, soft tissue, tumor, steel, and aluminum meet the same criterion between [Formula: see text] and [Formula: see text]. For water, the thorax, and the breast intra-operative benchmark, typical average BFP-MC deviations of [Formula: see text] and [Formula: see text] were observed at [Formula: see text] and [Formula: see text], respectively. By irradiating the entire periodic table, we observed similar performance between lithium ([Formula: see text]) and cerium ([Formula: see text]). Deficiencies observed between praseodymium ([Formula: see text]) and einsteinium ([Formula: see text]) have been reported, analyzed, and quantified, offering critical insights for the ongoing development of the Evaluated Nuclear Data File mode in NJOY.

Proton radiotherapy offers a dosimetric advantage compared to photon therapy in sparing normal tissue, but the clinical evidence for toxicity reductions in the treatment of head and neck cancer is limited. The Danish Head and Neck Cancer Group (DAHANCA) has initiated the DAHANCA 35 randomised trial to clarify the value of proton therapy (NCT04607694). The DAHANCA 35 trial is performed in an enriched population of patients selected by an anticipated benefit of proton therapy to reduce the risk of late dysphagia or xerostomia based on normal tissue complication probability (NTCP) modelling. We present our considerations on the trial design and a test of the selection procedure conducted before initiating the randomised study.

Extracellular vesicles (EVs) are membrane-bound particles released from cells, and their cargo can alter the function of recipient cells. EVs from X-irradiated cells have been shown to play a likely role in non-targeted effects. However, EVs derived from proton irradiated cells have not yet been studied. We aimed to investigate the proteome of EVs and their cell of origin after proton or X-irradiation. The EVs were derived from a human oral squamous cell carcinoma (OSCC) cell line exposed to 0, 4, or 8 Gy from either protons or X-rays. The EVs and irradiated OSCC cells underwent liquid chromatography-mass spectrometry for protein identification. Interestingly, we found different protein profiles both in the EVs and in the OSCC cells after proton irradiation compared to X-irradiation. In the EVs, we found that protons cause a downregulation of proteins involved in cell growth and DNA damage response compared to X-rays. In the OSCC cells, proton and X-irradiation induced dissimilar cell death pathways and distinct DNA damage repair systems. These results are of potential importance for understanding how non-targeted effects in normal tissue can be limited and for future implementation of proton therapy in the clinic.

The purpose of this study was to investigate acute normal tissue responses in the head and neck region following proton- or X-irradiation of a murine model.

Female C57BL/6J mice were irradiated with protons (25 or 60 MeV) or X-rays (100 kV). The radiation field covered the oral cavity and the major salivary glands. For protons, two different treatment plans were used, either with the Bragg Peak in the middle of the mouse (BP) or outside the mouse (transmission mode; TM). Delivered physical doses were 41, 45, and 65 Gy given in 6, 7, and 10 fractions for BP, TM, and X-rays, respectively. Alanine dosimetry was used to assess delivered doses. Oral mucositis and dermatitis were scored using CTC v.2.0-based tables. Saliva was collected at baseline, right after end of irradiation, and at day 35.

The measured dose distribution for protons (TM) and X-rays was very similar. Oral mucositis appeared earlier, had a higher score and was found in a higher percentage of mice after proton irradiation compared to X-irradiation. Dermatitis, on the other hand, had a similar appearance after protons and X-rays. Compared to controls, saliva production was lower right after termination of proton- and X-irradiation. The BP group demonstrated saliva recovery compared to the TM and X-ray group at day 35.

With lower delivered doses, proton irradiation resulted in similar skin reactions and increased oral mucositis compared to X-irradiation. This indicates that the relative biological effectiveness of protons for acute tissue responses in the mouse head and neck is greater than the clinical standard of 1.1. Thus, there is a need for further investigations of the biological effect of protons in normal tissues.

To compare the oncologic outcomes between proton therapy and intensity-modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC) patients undergoing curative radiotherapy (RT).

We studied HNSCC patients who underwent curative-intent RT from 2015 to 2019, comparing the oncologic outcomes of proton therapy and IMRT. Our national retrospective HNSCC cohort study involved three institutes with proton therapy and 17 institutes (medical center levels) with IMRT in Taiwan. We utilized the Taiwan Cancer Registry Database to collect medical data for this study. We classified patients into two groups based on treatment method: Group 1 received IMRT, while Group 2 received proton therapy. 3:1 propensity score matching was performed to minimize the impact of potential confounders. Cox proportional hazards models were used to evaluate oncologic outcomes.

This study of 60,485 patients with HNSCC found that proton therapy was associated with better overall and cancer-specific survival and lower locoregional recurrence rates than IMRT. After matching, 982 patients were analyzed, with well-balanced factors. Proton therapy was a significant predictor of all-cause mortality, cancer-specific death, and locoregional recurrence (LRR). Patients who received proton therapy had significantly lower risks of all-cause mortality (adjusted hazard ratio, aHR=0.43), cancer-specific death (aHR=0.44), and LRR (aHR=0.61) than those who received IMRT.

Proton therapy is associated with superior outcomes in terms of overall survival, cancer-specific survival, and locoregional recurrence rates compared to IMRT in patients with HNSCC. These results provide valuable evidence for clinicians and patients in decision-making regarding the choice of radiation therapy for HNSCC.

Background: Multidisciplinary management is crucial in cancer diagnosis and treatment. Multidisciplinary teams include specialists in surgery, medical therapies, and radiation therapy (RT), each playing unique roles in oncology care. One significant aspect is RT, guided by radiation oncologists (ROs). This paper serves as a detailed primer for non-oncologists, medical students, or non-clinical investigators, educating them on contemporary RT practices. Methods: This report follows the process of RT planning and execution. Starting from the decision-making in multidisciplinary teams to the completion of RT and subsequent patient follow-up, it aims to offer non-oncologists an understanding of the RO's work in a comprehensive manner. Results: The first step in RT is a planning session that includes obtaining a CT scan of the area to be treated, known as the CT simulation. The patients are imaged in the exact position in which they will receive treatment. The second step, which is the primary source of uncertainty, involves the delineation of treatment targets and organs at risk (OAR). The objective is to ensure precise irradiation of the target volume while sparing the OARs as much as possible. Various radiation modalities, such as external beam therapy with electrons, photons, or particles (including protons and carbon ions), as well as brachytherapy, are utilized. Within these modalities, several techniques, such as three-dimensional conformal RT, intensity-modulated RT, volumetric modulated arc therapy, scattering beam proton therapy, and intensity-modulated proton therapy, are employed to achieve optimal treatment outcomes. The RT plan development is an iterative process involving medical physicists, dosimetrists, and ROs. The complexity and time required vary, ranging from an hour to a week. Once approved, RT begins, with image-guided RT being standard practice for patient alignment. The RO manages acute toxicities during treatment and prepares a summary upon completion. There is a considerable variance in practices, with some ROs offering lifelong follow-up and managing potential late effects of treatment. Conclusions: Comprehension of RT clinical effects by non-oncologists providers significantly elevates long-term patient care quality. Hence, educating non-oncologists enhances care for RT patients, underlining this report's importance.

Advances in proton therapy have garnered much attention and speculation in recent years as the indications for proton therapy have grown beyond pediatric, prostate, spine, and ocular tumors. To achieve and maintain consistent access to this cancer treatment and to ensure the future viability and availability of proton centers in the United States, a call for evidence has been heard and answered by proton radiation oncologists. Answers provided in this review include the evolution of proton therapy research, rationale for proton clinical trial design, challenges in and barriers to the conduct of proton therapy research, and other unique considerations for the study of proton therapy.

Given emerging data suggesting that uncertainty in the relative biologic effectiveness at the distal end of the Bragg peak results in increased mucosal injury in patients with oropharynx cancer receiving adjuvant proton therapy, we evaluated the results of post-treatment positron emission tomography-computed tomography (PET/CT) in patients with p16-positive oropharynx cancer (p16+OPC) treated with definitive intensity-modulated proton therapy (IMPT).

A retrospective cohort study of patients with p16+OPC treated with definitive IMPT between 2016 and 2022 was performed at a single institution. Patients with PET/CT scans within 6 months following completion of IMPT were included in the study. Positive post-treatment scans were defined by a maximum standard uptake values (SUVmax) >4.0 or a <65% reduction in SUVmax in either the primary tumor or lymph node. The Fisher's exact test was used to evaluate factors associated with positive post-treatment PET/ CT values.

Sixty-two patients were included for analysis. Median follow-up was 21 months (range: 3-71 months) with a median time to post-treatment PET/CT of 3 months (range: 2-6 months). Median post-treatment SUVmax of the primary disease and nodal disease was 0 (mean: 0.8, range: 0-7.7) and 0 (mean: 0.7, range: 0-9.5), respectively. Median post-treatment percent reduction in SUVmax for the primary site and lymph node was 100% (mean: 94%, range: 31.3-100%) and 100% (mean: 89%, range: 23-100%), respectively. Eleven patients had a positive post-treatment PET/CT with one biopsy-proven recurrence. Negative and positive predictive values (NPV and PPV) were 98% and 9.1%, respectively. There were no factors associated with positive post-treatment PET/CT.

Similar to patients treated with photon-based radiation therapy, post-treatment PET/CT has a high NPV for patients with p16+OPC treated with definitive proton therapy and should be used to guide patient management. Additional patients and more events are needed to confirm the PPV of a post-treatment PET/CT in this favorable patient cohort.

Adolescent and young adult cancer patients are at high risk of developing radiation-associated side effects after treatment. Proton beam radiation therapy might reduce the risk of these side effects for this population without compromising treatment efficacy.

We review the current literature describing the utility of proton beam radiation therapy in the treatment of central nervous system tumors, sarcomas, breast cancer and Hodgkin lymphoma for the adolescent and young adult cancer population.

Proton beam radiation therapy has utility for the treatment of certain cancers in the young adult population. Preliminary data suggest reduced radiation dose to normal tissues, which might reduce radiation-associated toxicities. Research is ongoing to further establish the role of proton therapy in this population.

This report highlights the potential utility of proton beam radiation for certain adolescent young adult cancers, especially with reducing radiation doses to organs at risk and thereby potentially lowering risks of certain treatment-associated toxicities.

Radiation therapy (RT) is a crucial treatment for head and neck squamous cell carcinoma (HNSCC), however it can have adverse effects on patients' long-term function and quality of life. Biomarkers that can predict tumor response to RT are being explored to personalize treatment and improve outcomes. While tissue and blood biomarkers have limitations, imaging biomarkers derived from magnetic resonance imaging (MRI) offer detailed information. The integration of MRI and a linear accelerator in the MR-Linac system allows for MR-guided radiation therapy (MRgRT), offering precise visualization and treatment delivery. This data descriptor offers a valuable repository for weekly intra-treatment diffusion-weighted imaging (DWI) data obtained from head and neck cancer patients. By analyzing the sequential DWI changes and their correlation with treatment response, as well as oncological and survival outcomes, the study provides valuable insights into the clinical implications of DWI in HNSCC. [Table: see text].

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90-100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, with surgery, radiotherapy, chemotherapy, and immunotherapy being the primary treatment modalities. The treatment for HNSCC has evolved over time, due to which the prognosis has improved drastically. Despite the varied treatment options, major challenges persist. HNSCC chemotherapeutic and immunotherapeutic drugs are usually administered systemically, which could affect the patient's quality of life due to the associated side effects. Moreover, the systemic administration of salivary stimulating agents for the treatment of radiation-induced xerostomia is associated with toxicities. Localized drug delivery systems (LDDS) are gaining importance, as they have the potential to provide non-invasive, patient-friendly alternatives to cancer therapy with reduced dose-limiting toxicities. LDDSs involve directly delivering a drug to the tissue or organ affected by the disease. Some of the common localized routes of administration include the transdermal and transmucosal drug delivery system (DDSs). This review will attempt to explore the different treatment options using LDDSs for the treatment of HNSCC and radiotherapy-induced damage and their potential to provide a better experience for patients, as well as the obstacles that need to be addressed to render them successful.

Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT).Approach.A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism.Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia (mean reductions of 8.25, 5.42 and 5.12 pp respectively). While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone.SignificanceOnline adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC.

To discuss the role of proton beam therapy (PBT) in the treatment of patients with oropharyngeal squamous cell carcinoma (OPSCC).

A review of the pertinent literature.

Proton beam therapy likely results in reduced acute and late toxicity as compared with intensity-modulated radiation therapy (IMRT). The extent of the reduced toxicity, which may be modest, depends on the endpoint and technical factors such as pencil beam versus passive scattered PBT and adaptive replanning. The disease control rates after PBT are likely similar to those after IMRT.

Proton beam therapy is an attractive option to treat patients with OPSCC. Whether it becomes widely available depends on access.

Intensity modulated proton beam therapy (IMPT) for head and neck cancer offers dosimetric benefits for the organs at risk when compared to photon-based volumetric modulated arch therapy (VMAT). However, limited data exists about the potential benefits of IMPT for tooth-bearing regions. The aim of this study was to compare the IMPT and VMAT radiation dosimetrics of the tooth-bearing regions in head and neck cancer patients. Also, we aimed to identify prognostic factors for a cumulative radiation dose of ≥40 Gy on the tooth-bearing areas, which is considered the threshold dose for prophylactic dental extractions.

A total of 121 head and neck cancer patients were included in this retrospective analysis of prospectively collected data. We compared the average Dmean values of IMPT versus VMAT of multiple tooth-bearing regions in the same patients. Multivariate logistic regression analysis was performed for receiving a cumulative radiation dose of ≥40 Gy to the tooth-bearing regions (primary endpoint) in both VMAT and IMPT.

A lower Dmean was seen after applying IMPT to the tooth-bearing tumour regions (p < 0.001). Regarding VMAT, oral cavity tumours, T3-T4 tumours, molar regions in the mandible, and regions ipsilateral to the tumour were risk factors for receiving a cumulative radiation dose of ≥40 Gy.

IMPT significantly reduces the radiation dose to the tooth-bearing regions.

Complex anatomy surrounding the oropharynx makes proton therapy (PT), especially intensity-modulated PT (IMPT), a potentially attractive option due to its ability to reduce the volume of irradiated healthy tissues. Dosimetric improvement may not translate to clinically relevant benefits. As outcome data are emerging, we aimed to evaluate the evidence of the quality of life (QOL) and patient-reported outcomes (PROs) following PT for oropharyngeal carcinoma (OC).

We searched PubMed and Scopus electronic databases (date: 15 February 2023) to identify original studies on QOL and PROs following PT for OC. We employed a fluid strategy in the search strategy by tracking citations of the initially selected studies. Reports were extracted for information on demographics, main results, and clinical and dose factor correlates. Quality assessment was performed using the NIH's Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The PRISMA guidelines were followed in the preparation of this report.

Seven reports were selected, including one from a recently published paper captured from citation tracking. Five compared PT and photon-based therapy, although none were randomized controlled trials. Most endpoints with significant differences favored PT, including xerostomia, cough, need for nutritional supplements, dysgeusia, food taste, appetite, and general symptoms. However, some endpoints favored photon-based therapy (sexual symptoms) or showed no significant difference (e.g., fatigue, pain, sleep, mouth sores). The PROs and QOL improve following PT but do not appear to return to baseline.

Evidence suggests that PT causes less QOL and PRO deterioration than photon-based therapy. Biases due to the non-randomized study design remain obstacles to a firm conclusion. Whether or not PT is cost-effective should be the subject of further investigation.

Proton therapy (PBRT) is a form of external beam radiotherapy with several dosimetric advantages compared with conventional photon (x-ray) radiotherapy. Unlike x-rays, protons deposit most of their dose over a finite range, with no exit dose, in a pattern known as the Bragg peak. Clinically, this can be exploited to optimize dose to tumors while delivering a lower integral dose to normal tissues. However, the optimal role of PBRT is not as well-defined as advanced x-ray-based techniques such as intensity-modulated radiotherapy.

This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes.

IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT.

Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D₉₈ degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands.

Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively.

Retrospective analysis of prospective cohort.

Tertiary care Veterans Health Administration (VHA) medical center.

Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who received definitive or adjuvant EBRT (2016-2020).

Most patients were dentate and 80 % underwent dental extractions prior to EBRT of which 16 (16 %) had complications. The rate of ORN was 3.7 % for oral cavity SCC patients and 8.1 % for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start.

ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication.

Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is a unique entity with increased responsiveness to treatment and excellent oncologic outcomes. The purpose of this narrative review is to highlight how an improved prognosis for HPV (+) tumors and an ever-increasing understanding of the risk factors, risk stratification, and areas of potential spread are shaping management options. Additionally, we aim to detail how advances in treatment technology on both the surgical and radiation fronts are facilitating the delivery of increasingly personalized and precise treatments. This review will describe key aspects of recent and currently-ongoing trials investigating the de-escalation and individualization of treatment in this patient cohort, and how they are building a foundation for distinct treatment paradigms for HPV (+) tumors. Further studies into the integration of biomarker-guided treatments combined with clinical trial enrollment will help ensure a future of personalized treatments and improved outcomes, both in terms of oncologic outcomes and toxicity, for patients with HPV (+) OPC.

To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT).

We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed.

Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%).

Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer.