International Journal of Radiation Oncology*Biology*Physics

BackgroundWhile chimeric antigen receptor (CAR) T cells have achieved significant success against hematological malignancies, efficacy against neuroblastoma has been limited. Virus-free CRISPR-edited GD2 TRAC-CAR T cells have been developed as a potential means of improving CAR T efficacy but are not curative. Radiopharmaceutical therapy (RPT) is a promising approach to enhance the effectiveness of immunotherapies, including immune checkpoint inhibitors. However, it remains unclear whether RPT can synergize with GD2 TRAC-CAR T cells to improve outcomes in neuroblastoma. MethodsDosimetry studies were conducted to measure the absorbed radiation dose delivered by lutetium-177 (177Lu) in both in vitro and in vivo models. Tumor-bearing mice were treated sequentially with low dose radiation by 177Lu-NM600, an alkylphosphocholine mimetic radiopharmaceutical agent, followed 9 days later by GD2 TRAC-CAR T cells generated in a virus-free manner by CRISPR/Cas9. Tumor burden was monitored through bioluminescence imaging and tumor size measurements. Mechanistic studies were performed using flow cytometry, multiplex assay and single-cell proteomic analysis. ResultsLow dose radiation delivered by 177Lu-NM600 synergized with GD2 TRAC-CAR T cells in a localized neuroblastoma model, resulting in complete tumor regression in all mice. The optimal combination was dependent on both the radiation dose and timing to minimize the negative impact of radiation on CAR T cell viability. Irradiation of neuroblastoma cells by low-dose RPT before GD2 TRAC-CAR T cells enhanced the release by CAR T cells of perforin, granzyme B and cytokines like TNF- and IL-7 while abrogating TGF-{beta}1 secretion. Additionally, low-dose RPT upregulated Fas on neuroblastoma cells, potentially enabling a CAR-independent killing. ConclusionsThis study demonstrates that low-dose RPT can enhance CAR T cell efficacy to treat a solid tumor. Findings suggest that optimization of radiation dose and timing may be needed for each patient and RPT to account for effects of varied tumor radiosensitivity and dosimetry. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/621668v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@153ff5dorg.highwire.dtl.DTLVardef@1a269b7org.highwire.dtl.DTLVardef@1ca9a53org.highwire.dtl.DTLVardef@59f461_HPS_FORMAT_FIGEXP M_FIG C_FIG

PURPOSEThe first long-term safety data with a 212Pb-labelled radiopharmaceutical reported significant renal adverse events after more than two years of follow-up. Understanding the pharmacokinetic drivers of dose delivery for alpha emitting radioligand therapy (RLT) will be critical to optimizing molecules. We aimed to model and compare the dosimetry and therapeutic index (TI) of a single pharmaceutical, rhPSMA-10.1, when labeled with either 225Ac or 212Pb, using human pharmacokinetic data. METHODSDosimetry data from a Phase 1 trial of 177Lu-rhPSMA-10.1 in 13 mCRPC patients was used to generate time-activity curves for tumors and select organs-at-risk. These curves were used to model the dosimetry of 225Ac-rhPSMA-10.1 and 212Pb-rhPSMA-10.1 by substituting the physical half-life and decay properties of 177Lu with those of the alpha-emitters. Absorbed doses and TIs were calculated. The potential impact of daughter radionuclide translocation on organ doses and TIs was also modeled. RESULTSTo deliver 5Gy(RBE5) absorbed dose to tumors, a [~]29-fold higher administered activity of 212Pb was required compared to 225Ac (131 MBq versus 4.6 MBq, respectively). At this tumor dose, the activity of 212Pb resulted in 2.5-fold and 2.2-fold higher absorbed doses to the kidneys and salivary glands, respectively, compared with 225Ac. Consequently, 225Ac demonstrated a substantially improved TI, with a [~]3-fold higher tumor:kidney dose ratio (9.85 versus 3.36) and a [~]2.2-fold higher tumor:salivary gland ratio (15.9 versus. 7.1). Even when modeling a worst-case scenario for daughter translocation, 225Ac maintained a superior TI. Importantly, based on the pharmacokinetics of this drug, to achieve 120Gy(RBE5) absorbed dose to tumors would require the delivery of 12.1Gy(RBE5) and 35.7Gy(RBE5) to the kidneys for 225Ac and 212Pb respectively. Modeling daughter translocation, these values become 39.1Gy(RBE5) and 114.3Gy(RBE5) respectively which may help to explain recently reported safety data from 212Pb-labelled RLT. CONCLUSIONSThe physical half-life of 225Ac is better suited to the pharmacokinetic profile of rhPSMA-10.1 than the shorter half-life of 212Pb. This results in substantially enhanced TI for 225Ac-rhPSMA-10.1, permitting the delivery of markedly lower absorbed doses to organs-at-risk for a fixed tumor dose. Importantly, labelling with 212Pb may lead to very high renal absorbed radiation doses driven predominantly by demetallation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/25333110v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@3b6dbdorg.highwire.dtl.DTLVardef@1a1a1c6org.highwire.dtl.DTLVardef@83cf00org.highwire.dtl.DTLVardef@18b1699_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background and purposeStereotactic body radiotherapy (SBRT) has become a standard treatment option for localized prostate cancer, with low rates of clinically relevant late toxicity. However, the identification of robust dosimetric predictors of toxicity remains challenging due to the high dimensionality and collinearity of dose-volume histogram (DVH) metrics. This study aimed to explore whether principal component analysis (PCA) of DVHs can identify dose regions associated with late gastrointestinal and genitourinary toxicity after prostate SBRT. Materials and methodsWe analysed a single-institution cohort of patients treated with prostate SBRT. Rectum, rectal wall, bladder and bladder wall DVHs were extracted with a dose bin resolution of 0.5 Gy. PCA was applied separately to each structure to identify dominant patterns of dose-volume variability. PCA-derived dose metrics were subsequently evaluated using Spearman correlation analyses, receiver operating characteristic (ROC) curves, and exploratory logistic regression models. Late toxicity was scored according to CTCAE version 5.0, with grade [≥] 2 events at 12 months as the primary endpoint. ResultsPCA demonstrated that a limited number of components accounted for most DVH variability, with the largest contributions arising from intermediate-dose regions. For the whole rectum, intermediate-dose metrics showed the strongest association with late rectal toxicity. Rectal V18.1 Gy yielded the highest discriminative performance (AUC = 0.87), followed by V29 Gy (AUC = 0.83), whereas low-dose (V1.5 Gy) and high-dose (V42.5 Gy) metrics showed limited or no discrimination. Rectal wall metrics demonstrated weaker and less robust associations, and no clinically meaningful discriminative performance was observed for bladder or bladder wall DVH metrics. Exploratory regression analyses supported the association between intermediate rectal dose exposure and late rectal toxicity. ConclusionIn prostate SBRT, PCA of DVHs highlights intermediate rectal dose exposure as the primary dosimetric determinant of late rectal toxicity. Whole-rectum intermediate-dose metrics outperform both low- and high-dose parameters, as well as rectal wall and bladder-derived metrics. These findings support a parsimonious, data-driven focus on intermediate-dose rectal volumes for toxicity risk assessment and hypothesis generation in prostate SBRT planning.

BackgroundDNA repair inhibitors may safely enhance targeted radiotherapy if they can be administered when radioisotope has cleared from critical normal tissues. We investigated whether the kinetics of [177Lu]Lu-PSMA-617 (Pluvicto) would be consistent with such a strategy in metastatic castrate resistant prostate cancer (mCRPC). Materials and MethodsPluvicto effective t1/2 was measured for organs-at-risk (kidneys, parotid and submandibular glands) and lesions from 60 mCRPC patients. Based on this, a safe strategy for DDR inhibition was defined, and its potential benefit to the lesion was calculated, using published in vitro radiosensitivity data. ResultsPluvicto clearance is almost 3x faster in normal organs-at-risk compared to lesions. Using pre-clinical estimates of DDRi sensitization, a meaningful increase in lesion effective treatment dose could be achieved with minor additional risk to normal organs.

PurposeRadiation therapy planning for locally-advanced non-small cell lung cancer (NSCLC) is challenging due to the balancing of target coverage and organs-at-risk (OAR) sparing. Using the Varian Ethos Treatment Planning System (TPS), we developed a methodology to automatically generate efficient, high-quality treatment plans for locally-advanced lung cancer patients. Methods and MaterialsFifty patients previously treated with Eclipse-generated plans for inoperable Stage IIIA-IIIC NSCLC were included in this Institutional Review Board (IRB)-approved retrospective study. Fifteen patients were used to iteratively optimize an Ethos TPS planning template, and the remaining thirty-five patients had plans automatically generated without manual intervention using the created template. Ethos and Eclipse plan quality was then assessed using 1) standard dose volume histogram (DVH) metrics, 2) adherence to clinical trial objectives, and 3) radiation oncologist qualitative review. ResultsEthos-generated plans showed improved primary and nodal planning target volume (PTVp and PTVn, respectively) V100% and V95% coverage (p<0.001) and reduced PTVp Dmax values (p=0.023). Furthermore, the Ethos template-generated plans had lower spinal cord Dmax, lungs V5Gy, and heart V25Gy, V30Gy, and V45Gy values (p[&le;]0.021). However, Ethos esophagus metrics (mean, V35Gy, V50Gy, Dmax) and brachial plexus metrics (Dmax) were greater than Eclipse (p[&le;]0.008), but were still clinically acceptable. A large majority (80%) of automatically generated plans had entirely "per protocol" or "variation acceptable" metrics. Three radiation oncologists qualitatively scored the Ethos plans; 78% of plans were scored as clinically acceptable during physician evaluation, with zero plans receiving scores requiring major changes. ConclusionsA standard Ethos template generated lung cancer radiotherapy plans with greater target coverage, increased spinal cord, heart, and lung V5Gy sparing, but increased esophagus and brachial plexus dose, compared to manually generated Eclipse plans. This template elucidates an efficient approach for generating automated, high quality lung radiation therapy treatment plans.

PurposeRadiation Therapy (RT) can modulate the immune system and generate anti-tumor T cells. However, this anti-tumor-activity is countered by radiation-induced immunosuppression (RIIS). Clinical advantages of proactively sparing RT dose to immune rich organs have not previously been evaluated. MethodsWe conducted a phase II randomized trial from 2020 to 2023, enrolling 51 early-stage lung cancer patients treated with SBRT, to evaluate the effect of dose reduction to immune rich organs on RIIS. Two groups were: RIIS-optimized-treatment (lowering the dose to blood, bone-marrow and lymph-node-stations) and standard-treatment. All treatments followed national protocol guidelines. Peripheral blood was collected at baseline, immediately, 4-weeks and 6-months post-treatment. ResultsALC changes from baseline immediately, 4-weeks and 6-months post-SBRT are: optimized-arm: -16%, -22%, -16%, standard-arm: -31%, -34%, -26%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 13.4 (5.3) % (95% CI, 2.8 to 24.0; p = 0.01). Central tumors had the largest improvement in ALC from baseline: optimized-arm: - 8%, -18%, -14%, standard-arm: -39%, -43%, -47%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 29.5 (9.6) % (95% CI, 10.1 to 48.9; p = 0.004). Grade 3 lymphopenia occurred in 15.4% of standard arm patients but was absent in the optimized arm. Additionally, 2.8 times more patients in the optimized arm experienced an ALC increase post-SBRT. Dose to organs such as the heart, great vessels, thoracic spine, and lymph nodes significantly correlated with RIIS. A trend towards increased Event-Free-Survival (two-year: 75.0% (SE = 10.8%) versus 59.8% (SE = 11.2%), p=0{middle dot}10) and Overall Survival (two-year: 93.4% (SE=6.1%) versus 69.4% (SE=10.5%), p=0{middle dot}14) was observed with optimized-planning compared to standard-planning in treatment naive patients. ConclusionReducing RT dose to immune rich organs significantly reduces RIIS compared to standard-of-care. This has implications in enhancing immune system mediated anti-tumor-activity. (Funded by National Cancer Institute and others. ClinicalTrials.gov number, NCT04273893)

1.PurposeRadiotherapy treatment planning is a resource-intensive process characterized by multiple manual steps and clinical hand-offs that contribute to treatment delays and inter-observer variability. The Radiation Planning Assistant (RPA) is a web-based platform designed to deliver automated contouring and planning approaches tailored to low-resource settings. This work expands the RPA to develop and clinically validate end-to-end, AI-driven workflows for prostate and cervical cancers, designed to improve efficiency, consistency, and accessibility in low- and middle-income countries (LMICs). MethodsWe developed deep learning-based auto-contouring models using nnU-Net and integrated them with knowledge-based planning (KBP) models trained on curated datasets from over 1,000 prostate and 110 cervical cancer treatment plans. For prostate cancer, models were developed to accommodate prostate directed, prostate bed, and nodal treatment scenarios. Cervical cancer planning followed EMBRACE II guidelines and included pelvic and para-aortic nodal volumes. These tools were integrated into the RPA. Clinical acceptability of the auto-contours and plans was assessed retrospectively by radiation oncologists using a five-point Likert scale. ResultsIn total, 50 test patients (40 prostate, 10 cervical) were evaluated. For prostate cancer, 70% of target auto-contours and 73% of treatment plans were clinically acceptable without edits; for cervical cancer, these rates were 80% and 80%, respectively. For prostate cancer planning, 77% of target and 98% of organ-at-risk structures met all per-protocol compliance criteria. For cervical cancer planning, all EMBRACE II protocol hard constraint criteria were met. Bowel and vaginal contours demonstrated lower performance, but these did not compromise plan quality. ConclusionWe present validated, end-to-end radiotherapy planning workflows for prostate and cervical cancers that leverage the RPAs infrastructure to streamline treatment planning in a globally accessible platform and demonstrate high clinical acceptability. By reducing reliance on specialist input, this work addresses key barriers to equitable radiotherapy access in resource-limited settings and responds to global calls from the IAEA and WHO to expand radiotherapy capacity. FundingNational Institute of Health, National Science Foundation, Rising Tide Foundation, University of Texas MD Anderson Cancer Center

In a phase III randomized trial, adding a radiation boost to visible tumor(s) on MRI improved prostate cancer disease-free and metastasis-free survival without additional toxicity. However, radiation oncologists ability to identify prostate tumors is critical and represents a major barrier to widely adopting intraprostatic tumor radiotherapy boost for patients. We previously developed a quantitative diffusion MRI biomarker for prostate cancer, called the Restriction Spectrum Imaging restriction score (RSIrs), that has been shown to improve radiologist identification of clinically significant prostate cancer. 42 radiation oncologists (participants) from multiple, international institutions contoured prostate tumors on 40 patient cases using standard MRI with or without RSIrs map, producing 1646 target volumes. Use of RSIrs maps significantly improved all evaluated accuracy metrics, including participants percent overlap with consensus expert target volume (73% vs. 42%, p<0.001). A mixed effects model confirmed that RSIrs maps were the main variable driving the improvement in all metrics. System Usability Scores indicated RSIrs maps significantly improved the contouring experience (72 vs. 58, p<0.002). The expert-defined tumor was completely missed 158 times on standard MRI alone and only 19 times with RSIrs maps. RSIrs maps improve the accuracy of target delineation for prostate tumor boost. Patient SummaryAdding an extra boost of radiation to tumor(s) visible on MRI has been shown to prevent cancer recurrence and cancer spread beyond the prostate without adding additional side effects; however, drawing the prostate tumor on MRI is difficult, and most radiation oncologists have not been trained to do this. We have developed an advanced MRI technique (RSIrs maps) that increases tumor visibility. We found that RSIrs maps improve radiation oncologists accuracy in targeting prostate tumors.

Background and PurposeTo derive and validate the proton variable relative biological effectiveness (RBE) from CT imaging changes in patients with locally advanced non-small-cell lung cancer. Materials and MethodsWe retrospectively analyzed data for patients previously treated on a prospective randomized trial with standard fractionated intensity-modulated photon therapy (IMPT) or passive scattering proton therapy (PSPT). CT image density change (IDC) was calculated in the normal ipsilateral lung between the planning and follow-up CT. Using IDC as the clinical evidence of response, we correlated dose-IDC relationships by fitting a modified Lyman-Kutcher-Burman NTCP model for each treatment modality. RBE was calculated with corresponding planned dose for the IMRT patients and planned physical dose for PSPT patients from the fitted NTCP model. To validate the measured clinical radiographic-based RBE values, we benchmarked the measured RBE values with those calculated from the McNamara, Wedenberg, Mairani, and Flint empirical models. In addition, we also fitted the McNamara and Wedenberg models using the measured RBE, LETd, and IDC values. ResultsThe IDC-based RBE values ranged from 1.3-2.3. Linear regression comparing the radiographic-based RBE value with the empirical models, returned R2 values of 0.025-0.72. The fitted McNamara and Wedenberg models returned pseudo-R2 values of 0.95 and 0.85, respectively. ConclusionRBE values can be computed from CT image density changes as the clinical endpoint and validated using published empirical models. This is the first study to demonstrate the potential of using a clinical radiographic-based endpoint to improve our understanding of the biological effects of proton therapy.

IntroductionProstate cancer is one of the most commonly diagnosed cancers among men worldwide. Advances in radiotherapy, particularly Stereotactic Body Radiotherapy (SBRT), have enabled ultra-hypofractionated treatment schedules that enhance tumor control while reducing treatment time. This study focuses on evaluating the dosimetric accuracy and plan quality of prostate SBRT using RapidArc technology on a Varian Millennium Multileaf Collimator (MLC) system. Materials and MethodsA total of 24 patients with localized prostate adenocarcinoma received SBRT with a prescribed dose of 36.25 Gy in five fractions. Treatment planning was performed using Eclipse v15.6 with Acuros XB algorithm, utilizing three 6 MV flattening filter-free (FFF) arcs. Planning Target Volume (PTV) coverage, OAR doses, Paddick Conformity Index (PCI), Gradient Index (GI), and Monitor Units (MU) were analyzed. Multileaf collimator motion was evaluated through log files, including leaf speed and position dynamics. Quality assurance was performed using electronic portal imaging devices (EPID) and gamma pass rate evaluation. ResultsThe mean PTV D95 was 35.80 {+/-} 0.46 Gy, with mean Dmax and Dmean being 39.80 {+/-} 1.05 Gy and 37.10 {+/-} 0.40 Gy, respectively. V95% averaged 99.13 {+/-} 1.14%, confirming adequate coverage. Slight violations of rectum and bladder Dmax constraints were observed but remained clinically acceptable. The mean PCI and GI were 0.905 {+/-} 0.18 and 3.08 {+/-} 0.16, respectively. Gamma pass rates exceeded 99.6% for 2%/2 mm criteria. MLC leaf speed remained below the 2.5 cm/s threshold, ensuring mechanical safety and dose delivery accuracy. ConclusionProstate SBRT delivered via RapidArc on a Varian Millennium MLC system demonstrated high plan conformity, efficient delivery, and acceptable OAR sparing. The integration of intra-fraction CBCT improved setup accuracy, while MLC analysis confirmed mechanical precision. This approach supports the clinical adoption of RapidArc-based SBRT as a feasible and effective option for localized prostate cancer treatment.

BackgroundPrecision radiation strategies that expand the therapeutic window by selectively sensitizing tumors and sparing normal tissues are needed. We developed a matched tumoroid-organoid preclinical platform to identify and characterize personalized radiosensitization strategies. MethodsWe established 15 rectal cancer-derived tumoroids and 3 matched normal rectal epithelial organoids. Whole exome sequencing characterized mutation profiles and phylogenetic relationships. Tumoroids were treated with one of four DNA damage repair inhibitors (DDRi; ATMi, DNA-PKi, PARPi, or ATRi), 5-fluorouracil, or a DMSO control, followed by escalating doses of radiation. Cell viability was measured, and intrinsic radiosensitivity as well as radiosensitizer efficacy were characterized using linear regression models. Four tumoroids were derived from one patient at distinct stages and disease sites, including pre-progression tumoroids (primary tumor, splenic metastasis) and post-progression tumoroids (rectal recurrence and vaginal recurrence). ResultsTumoroid radiosensitivity demonstrated variability, paralleling the spectrum of clinical responses seen in rectal cancer. Genomic analyses revealed two distinct mutational signatures (SBS14 and SBS17b) associated with radioresistance. Radiation sensitization by DDRis was highly heterogeneous, depending on both specific tumoroid and inhibitor choice. In the subset of four tumoroids derived pre- and post-progression, post-progression tumoroids demonstrated greater radioresistance and diminished DDRi-induced radiosensitization. Phylogenetic analysis revealed increased clonal and subclonal complexity in these radiation and DDRi-resistant tumoroids. Lastly, comparing matched patient-derived tumoroids and normal organoids established that tumoroids were generally more radiosensitive and exhibited enhanced DDRi-mediated radiosensitization compared to normal organoids. However, the optimal DDRi for maximizing therapeutic index varied among tumoroids. ConclusionTo our knowledge, this is the first ex vivo study to systematically quantify intrinsic radiation sensitivity and DDRi sensitization in a comprehensive, patient-specific tumoroid platform. Our findings underscore the utility of a patient-matched tumoroid-organoid model as a platform to quantify and predict personalized responses to radiation and DDR inhibitors. Moreover, by comparing tumoroids from a single patient across different disease stages, our model reveals how tumors adapt to therapeutic pressure and develop increased radioresistance, offering a valuable potential framework for guiding precision radiotherapy. Moreover, the data show that DDRi efficacy is largely tumor-selective and not solely predicted by mutational profiles, highlighting opportunities to refine treatment for radioresistant tumors, minimize injury to normal tissues, and adapt therapy over disease progression.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackground and purposeC_ST_ABSMandibular osteoradionecrosis (ORN) is a severe side effect affecting patients undergoing radiation therapy for head and neck cancer. Variations in the bones vascularization and composition across the mandible may influence the susceptibility to ORN. Recently, deep learning-based models have been introduced for predicting mandibular ORN using radiation dose distribution maps to incorporate spatial information. These studies, however, only feature internal validation on a holdout subset of the data used for training. Materials and methodsThis study externally validated a 3D DenseNet-40 (DN40) ORN prediction model on an independent dataset. Model performance was evaluated in terms of discrimination and calibration, with Platt scaling applied for improved external calibration. The DN40 models discriminative ability on the external dataset was compared to a Random Forest model on corresponding dose-volume histogram (DVH) data. ResultsThe overall model performance was worse at external validation than at internal validation, with Platt scaling improving balance between recall and specificity but not significantly improving the overall calibration. Although the discrimination ability of the DN40 model was slightly lower at external validation (AUROC 0.63 vs. 0.69), this was statistically comparable to that of a DVH-based RF model for the same dataset (p-value 0.667). ConclusionsOur results suggest that, in addition to potential model overfitting issues, dosimetric data distribution differences between the two datasets could explain the low generalisability of the DN40 ORN prediction model. Future work will involve a larger and more diverse cohort.

PurposeTemporally feathered radiation therapy (TFRT) for head-and-neck cancer (HNC) radiotherapy combines variable-dose daily subplans to increase the rest time of organs-at-risk (OARs) as sought in intensity modulated radiation therapy (IMRT). While the standard TFRT recommends uniform rest time for each OAR, improved toxicity outcomes may be achieved through variable rest time for OARs by incorporating the OARs variable radiosensitivity profiles. Methods and MaterialsA decision-making model was constructed to maximize the combined recovery of OARs by determining OARs optimal rest times. Two main components were incorporated: the cumulative biologically effective dose based on the linear-quadratic model; and a dynamical model capturing the adjusted recovery of OARs as a function of delivered dose. Further, variable radiosensitivity profiles were allowed across the OARs to capture their variable recovery time. Individual recoveries of each OAR under IMRT and the standard TFRT (sTFRT) was compared against optimized TFRT (oTFRT). ResultsFive OARs (larynx, esophagus, parotid, spinal cord, brainstem) were considered. When the cumulative dose delivered under TFRT and IMRT remains the same, three OARs exhibited higher recovery under oTFRT compared to the second-best approach (larynx (81.8% vs. 74.1%), esophagus (95.9% vs. 93.9%), parotid (85.6% vs. 83.5%), while the recovery of spinal cord (90.5% vs. 90.8%) and brainstem (96.2% vs. 96.6%) remained comparable under TFRT and IMRT approaches. With different cumulative dose under TFRT and IMRT, oTFRT achieved significantly higher recovery for larynx (95.5% vs. 81.8%) and parotid (92.9% vs. 85.6%), while it is slightly outperformed by IMRT for esophagus (93.4% vs. 95.9%), spinal cord (87.1% vs. 90.5%), and brainstem (90.2% vs. 96.6%). When considering the minimum end-of-treatment recovery, oTFRT always achieved higher recovery among the other two approaches. ConclusionsBy considering non-identical radiosensitivity profiles of OARs in HNC radiotherapy, TFRT can optimize their rest time to enhance recovery at the end of treatment, potentially reducing patient toxicities.

PurposeEquivalent dose in 2 Gy fractions (EQD2), based on the original biological effective dose (BED) equation, is frequently used to guide treatment in the clinic. This work addresses the limitations of EQD2 in the context of voxelized dosimetry, clarifies potential sources of confusion, and provides an alternative formulation for improved precision. Methods and MaterialsThe EQD2 formula was evaluated by a simple insertion of the EQD2 dose into the BED equation. The mathematically exact form of EQD2, referred to here as equivalent physical dose (EPD), was provided by solving the linear-quadratic model BED equation for dose using the quadratic formula. The EPD derivation was compared in terms of absolute error to the EQD2 derivation, which separates the Relative Effect term from the BED equation. ResultsThe EQD2 expression implicitly assumed a homogenous dose, demonstrating that its use in voxelized dosimetry can mislead. As an alternative formulation, EPD was shown to adhere more closely to the first principles of radiobiological modeling. An error analysis identified absolute errors from EQD2 sometimes in excess of 10%. ConclusionsAssumptions in the standard EQD2 equation are inappropriate in the context of voxelized dosimetry, where voxels within a structure, such as a target volume, may receive a dose that differs from the prescribed dose. Using EPD (or BED) instead of EQD2 would address these areas of confusion. Optimizing therapy according to biological properties in this way could provide enhanced and more reliable radiobiological input to radiotherapy treatment planning.

BackgroundAccurate delineation of orodental structures on radiotherapy CT images is essential for dosimetric assessments and dental decisions. We propose a deep-learning auto-segmentation framework for individual teeth and mandible/maxilla sub-volumes aligned with the ClinRad ORN staging system. MethodsMandible and maxilla sub-volumes were manually defined, differentiating between alveolar and basal regions, and teeth were labelled individually. For each task, a DL segmentation model was independently trained. A Swin UNETR-based model was used for the mandible sub-volumes. For the smaller structures (e.g., teeth and maxilla sub-volumes) a two-stage segmentation model first used the ResUNet to segment the entire teeth and maxilla regions as a single ROI that was then used to crop the image input of the Swin UNETR. In addition to segmentation accuracy and geometric precision, a dosimetric comparison was made between manual and model-predicted segmentations. ResultsSegmentation performance varied across sub-volumes - mean Dice values of 0.85 (mandible basal), 0.82 (mandible alveolar), 0.78 (maxilla alveolar), 0.80 (upper central teeth), 0.69 (upper premolars), 0.76 (upper molars), 0.76 (lower central teeth), 0.70 (lower premolars), 0.71 (lower molars) - and exhibited limited applicability in segmenting teeth and sub-volumes often absent in the data. Only the maxilla alveolar central sub-volume showed a statistically significant dosimetric difference (Bonferroni-adjusted p-value = 0.02). ConclusionWe present a novel DL-based auto-segmentation framework of orodental structures, enabling spatial localization of dose-related differences in the jaw. This tool enhances image-based bone injury detection, including ORN, and improves clinical decision-making in radiation oncology and dental care for head and neck cancer patients.

PurposeIn order to improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T MR-Linac, 3D fat-suppressed T2-weighted MRI sequences were developed and optimized. MethodsAfter initial testing of fat suppression techniques, SPectral Attenuated Inversion Recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a non-suppressed T2-weighted sequence were acquired on five HNC patients on the Unity MR-Linac. The primary tumor, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated by five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences based on a combination of qualitative and quantitative metrics. ResultsSequences were analyzed for signal-to-noise (SNR), contrast-to-noise (CNR) compared to fat and muscle, conspicuity, pairwise distance metrics, segmentor assessment, and MR physicist assessment. From this analysis, the non-suppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but was superior for the pterygoid muscles. Two SPAIR sequences consistently received the highest scores among the analysis categories and are recommended for use to Unity MR-Linac users for HNC radiotherapy treatment planning. ConclusionsTwo deliverables resulted from this study. First, an optimized 3D fat-suppressed T2-weighted sequence was developed that can be disseminated to Unity MR-Linac users. Second, a robust image quality analysis process pathway, used to objectively score the various SPAIR sequences, was developed and can be customized and generalized to any image quality optimization. Improved segmentation accuracy with the proposed SPAIR sequence can potentially lead to improved treatment outcomes and reduced toxicity by maximizing target coverage and minimizing organ-at-risk exposure.

PurposeThis study evaluated the safety and effectiveness of an intraoral light-emitting diode (LED)-based photobiomodulation (PBM) device to reduce the incidence and severity of oral mucositis (OM) from intensity modulated radiation therapy (IMRT) for head and neck cancer (HNC). MethodsThis randomized, double-blind, sham-controlled trial enrolled patients with HNC undergoing high-dose IMRT over 6-8 weeks, with or without concurrent chemotherapy. Participants received daily 10-minute PBM or sham treatments immediately before IMRT sessions. Assessments were conducted at baseline, daily and weekly during IMRT, and two weeks post-IMRT. ResultsEighty-five participants (42 PBM; 43 sham) were enrolled across 12 US sites. No device-related adverse events were observed, and 99.5% of initiated sessions were completed. In the intent-to-treat population, severe OM (WHO Grade [&ge;]3) incidence was significantly lower with PBM across six weeks of IMRT (36.8% vs 57.1%; p = 0.046) and at two weeks post-treatment (10.8% vs 36.4%; p = 0.042). In the per-protocol population, the PBM arm reported significantly greater taste preservation (p = 0.034), lower increases in mouth/throat soreness (p = 0.029) and throat pain (p = 0.028) and needed fewer feeding tube placements (p = 0.073) than the control arm. ConclusionDaily intraoral PBM therapy using an LED-based device was safe, well tolerated, and significantly reduced the incidence of severe OM and associated complications in HNC patients undergoing IMRT with or without concurrent chemotherapy. These findings align with guidelines recommending daily intraoral PBM therapy for preventing cancer therapy-related OM, a dose-limiting toxicity for which effective preventive interventions are needed. Trial RegistrationClinicalTrials.gov Registration Number NCT03972527. Registered on June 3, 2019. Concise SummaryDaily intraoral PBM therapy using an LED-based device was safe, well tolerated, and significantly reduced the incidence of severe OM and associated complications in HNC patients undergoing IMRT with or without concurrent chemotherapy. These findings align with guidelines recommending daily intraoral PBM therapy for preventing cancer therapy-related OM, a dose-limiting toxicity for which effective preventive interventions are needed.

PurposeTo investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, and to evaluate potential departures from the linear-quadratic (LQ) response. To obtain best-fitting parameters for low (LR), intermediate (IR), and high risk (HR) prostate cancer. Methods and MaterialsWe have constructed a dataset of dose-response containing 87 entries (35 LR, 32 IR, 20 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fitted to tumor control probability models based on the LQ model, linear-quadratic-linear (LQL), and a modification of the LQ (LQmod) accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike-Information-Criterion (AIC) was used to compare models. ResultsThe AIC shows that the LQ model is superior to the LQL and LQmod for all risks, except for IR where the LQL outperforms the other models. The analysis shows a low /{beta} for all risks: 2.01 Gy for LR (95% confidence interval 1.74-2.26), 3.44 Gy for IR (2.99-4.02), and 2.78 Gy for HR (1.43-4.18). Best-fits do not show proliferation for LR, and only moderate proliferation for IR/HR. ConclusionsIn general, the LQ model describes the response of prostate cancer better than the alternative models. Only for IR the LQL outperforms the LQ. This study confirms a low /{beta} for all risks, with doses per fraction ranging from <2 Gy up to 10 Gy.

Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy - which accounts for the vast majority - is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. In this study we aimed to explore the exact nature of the differential impact of the two radiation modalities upon the immune system. We used multiparametric flow cytometry and deep sequencing of rearranged TCRb loci to investigate a cohort of 20 patients with gastrointestinal tumors who received either therapy. Proton-treated patients remained relatively stable throughout treatment for most metrics considered, whereas those who received photons saw a profound depletion in naive T cells, increase in effector/memory populations, and loss of TCR diversity. The repertoires of photon-treated patients underwent oligoclonal expansion after their lymphocyte count nadirs, particularly of CD8+ Temra cells, driving this reduction in diversity. Across the entire cohort, this reduction in post-nadir diversity inversely correlated with the overall survival time of those patients who died. This raises the possibility that increased adoption of proton-based or other lymphocyte sparing radiotherapy regimes may lead to better survival in cancer patients.

BackgroundQuantitative mapping of the longitudinal relaxation rate (R1=1/T1) is a major building block for several multiparametric MRI protocols intended for adaptive radiation therapy planning. The implementation of these protocols is challenging in anatomical sites that experience large physiological motion. PurposeTo implement and validate a motion-resolved quantitative T1 mapping method on a 1.5T MR-Linac that combines non-Cartesian k-space sampling trajectories with compressed sensing (CS) reconstruction techniques. MethodsFour 3D non-Cartesian k-space trajectories were evaluated: radial and stack-of-stars sampling using half- and full-spoke coverage. A variable flip angle acquisition was performed using the spoiled gradient-echo sequence, and T1 mapping was validated using two standard phantoms. Gradient delay timing was optimized empirically to minimize trajectory-induced artifacts. Eight compressed sensing reconstruction strategies were tested using spatial and spatiotemporal regularization operators. Reconstructions were evaluated across multiple implementation parameters and ranked based on spatial resolution, bias, and variability. In vivo studies included one healthy volunteer and one patient undergoing radiotherapy to a target in the kidney. Motion-resolved imaging was performed using respiratory self-gating and phase-sorted reconstruction. ResultsAll non-Cartesian trajectories demonstrated high repeatability and low longitudinal bias in phantom studies, with coefficients of variation below 3.3%. Radial half-spoke sampling achieved the shortest scan times and highest agreement with Cartesian benchmarks. Reconstruction methods incorporating spatiotemporal regularization maintained spatial resolution and quantitative accuracy across undersampling factors up to 20-fold. In human subjects, non-Cartesian T1 mapping provided improved accuracy and reduced variability in mobile abdominal tissues compared to Cartesian acquisitions, particularly in the kidney cortex and medulla, where motion artifacts led to overestimation and higher variance in the reference method. ConclusionsT1 mapping using non-Cartesian trajectories and compressed sensing reconstruction is feasible on a 1.5T MR-Linac. The proposed approach enables accurate, motion-resolved quantitative imaging within clinically practical acquisition times. These results support integration of quantitative T1 mapping into adaptive MR-guided radiotherapy workflows and establish a foundation for future development of multiparametric imaging and response-adaptive treatment strategies.