International Journal of Radiation Oncology*Biology*Physics

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 Cardiovascular adverse events (CVAEs) after chemoradiotherapy (CRT) for lung cancer are major concerns in Appalachia due to high rates of smoking and pre-existing cardiovascular diseases (CVD). The objectives of this study were to characterize the incidence of CVAEs in this population and evaluate machine learning (ML) models for CVAEs risk stratification and mortality prediction. Methods A retrospective study was conducted among Appalachian patients with lung cancer treated with definitive CRT at a single institution between 2013 and 2025. Baseline clinical variables, including demographics, smoking status, pre-existing CVD, and post-CRT CVAEs were collected. Heart dosimetric parameters were also obtained. ML models [Random Forest (RF), Gradient Boosting (GBM), Support Vector Machine (SVM), Logistic Regression (LR)] were trained using 5 fold cross validation and evaluated using AUC, sensitivity, specificity, and F1 score. Feature importance was assessed using permutation analysis. Wilcoxon and Chi-squared tests were used for descriptive comparisons. Results Eighty-six patients (mean age 66 years, 47% male) were included. At diagnosis, 80% (n=69) had NSCLC and 20% (n=17) had LS-SCLC. CVAEs occurred in 51 patients (59%). The most frequent events were NSTEMI (n=15, 29.4%), pericardial disease (n=15, 29.4%), and arrhythmia (n=8, 15.7%). Mean heart dose was higher in the CVAE group (13.4 vs 9.4 Gy, p=0.27). For CVAE prediction, GBM achieved the highest AUC (0.55, 95% CI 0.44-0.69) and sensitivity (75%), while RF showed the highest sensitivity (80%, 95% CI 69-90%). Key predictors included age and cardiac dosimetrists (Heart V20, V40, V50, and mean heart dose). For mortality prediction, RF achieved the highest discrimination (AUC = 0.63, 95% CI 0.496-0.750). Age, cardiac dosimetry, disease stage, and cardiovascular comorbidity were the most influential predictors. Conclusion High incidence of CVAEs occurred among patients with lung cancer treated with CRT in this Appalachian cohort. While ML models demonstrated modest predictive performance, tree-based approaches demonstrated high sensitivity for identifying patients at risk for CVAEs and mortality. Age and cardiac radiation dose metrics consistently emerged as key predictors, highlighting the importance of cardiac dose optimization and ML-based risk stratification for cardio-oncology surveillance.

BackgroundIn a recent phase III randomized control trial (FLAME), delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve outcomes for prostate cancer patients without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice as well as physicians perceived barriers toward its implementation. MethodsAn online survey assessing the use of intraprostatic focal boost was conducted in December 2022 and February 2023. The survey link was distributed to radiation oncologists worldwide via email list, group text platform, and social media. ResultsThe survey initially collected 205 responses from various countries over a two-week period in December 2022. The survey was then reopened for one week in February 2023 to allow for more participation, leading to a total of 263 responses. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). 57% of participants reported not routinely using intraprostatic focal boost. Even among complete subspecialists, a substantial proportion (39%) do not routinely use focal boost. Less than half of participants in both high-income and low-to-middle-income countries were shown to routinely use focal boost. The most commonly cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%). ConclusionDespite level 1 evidence from the FLAME trial, most radiation oncologists surveyed are not routinely offering focal RT boost. Adoption of this technique might be accelerated by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.

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.

BackgroundAlthough escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT. MethodsPre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols. ResultsMultivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified [&ge;]33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier. ConclusionFollowing RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors.

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)

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 [&ge;] 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.

Abstract Purpose: To compare scalar circulating blood dose summaries, assess whether associations with grade 3 or higher lymphopenia and overall survival persisted after planning target volume (PTV) adjustment, and distinguish scalar from exploratory dynamic blood dose analyses. Methods and Materials: The assembled dataset included 133 patients from 2 retrospective thoracic radiation cohorts; 121 entered the dosimetric main analysis and 116 passed a post hoc dosimetric gate. Six scalar exposures were compared: an ICE3 (Immune Circulation radiation Exposure Estimator Engine) 10 compartment mean-dose metric, corrected effective dose to immune cells (EDIC), body remainder dose, a hematological dose (HEDOS) derived organ-mean approximation, mean lung dose, and mean heart dose. Logistic base models included baseline absolute lymphocyte count, concurrent chemotherapy, and cohort; PTV was then added. Overall survival used cohort-stratified Cox models on an endpoint-specific common set. Benjamini Hochberg correction was applied within prespecified 6exposure families and, separately, across 3 selected post hoc bootstrap contrasts. Results: The lymphopenia analysis included 94 patients and 69 events. After PTV adjustment, the HEDOS derived approximation remained nominally associated (odds ratio, 2.54; 95% confidence interval, 1.18-5.45; P=.017; q=.102), but no exposure survived false-discovery-rate control. The survival set contained 92 patients and 42 deaths; no PTV adjusted scalar exposure was associated with survival (all q>=.531). In post hoc analyses, the standardized association of mean heart dose with overall survival was more positive than that of ICE3 (difference in log hazard ratios, 0.44; 95% CI, 0.13 0.94; multiplicity-adjusted q=.024). The corresponding contrast with the HEDOS derived approximation did not meet the adjusted significance threshold (q=.053). These coefficient contrasts do not establish superior predictive performance or causality. Exported ICE3 kinetic summaries had no false-discovery-rate-significant residual associations. A 13 case HEDOS bDVH audit showed little change under one continuous versus 10 second gap perturbation. Conclusions: PTV adjustment attenuated scalar blood-dose associations with severe lymphopenia, and no scalar exposure retained a multiplicity-robust survival association. The selected mean heart dose coefficient contrast is hypothesis generating and does not establish superior prediction. The primary cohort comparison evaluated a HEDOS derived organ-mean approximation rather than the full dynamic HEDOS framework; therefore, these findings should not be interpreted as evidence against the potential value of particle level blood dose distributions or time-dependent blood-flow modeling.

IntroductionBrain metastases (BMs) affect an increasing number of cancer patients and are typically managed with stereotactic radiosurgery (SRS). Our institution advocates the use of Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR), where radiation is delivered in high-dose pulses at extended intervals allowing for treatment adaptation and easy concurrent systemic therapy integration. We explore the integration of PULSAR with central nervous system (CNS)-active drugs (CNS-aDs) compared to traditional fractionated stereotactic radiotherapy (FSRT). MethodsThis study involved a retrospective evaluation of patients treated with either PULSAR or FSRT using Gamma Knife from 2018-2024. We collected demographic, clinical, and specific treatment details, outcomes such as local failure (LF) and toxicity rates. Cumulative incidence analysis for local failure and toxicity, considering death a competing risk, and Kaplan-Meier survival analysis for overall survival (OS) were conducted. Multivariate (MV) Cox proportional hazard models assessed failure and toxicity rates. ResultsAnalysis included 166 lesions treated with FSRT and 109 with PULSAR, predominantly in patients with lung and breast cancer. The median follow-up and OS were 1.88 and 1.48 years. 1- and 2-year LF rates were similar; 5%/8.9% vs 8.2%/12.3% for PULSAR and FSRT and 3.4%/5.5% vs 10.1%/12.3% with concurrent CNS-aDs (cCNS-aDs). BMs > 2 cm LF rates were 9.4% and 17.3% at two years for PULSAR and FSRT (p=0.1). No LFs were observed in BMs > 2 cm treated with PULSAR+CNS-aDs at 2.5 years. The two-year grade 3+ toxicity rate for PULSAR (8.7%) and FSRT (11.7%), without an increase in toxicity when combined with cCNS-aDs. BMs treated with PULSAR+cCNS-aDs were less likely to fail (HR 0.15, p=0.048) on MV analysis (MVA). ConclusionThe integration of PULSAR with cCNS-aDs appears to offer excellent local control for larger brain metastases without increased toxicity. These promising results merit further prospective investigation to validate the findings and potentially establish new treatment protocols.

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.

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.

BackgroundDespite advances in cancer genomics, radiation therapy (RT) is still prescribed based on an empiric one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic adjusted radiation dose (GARD) to personalize RT prescription dose based on the biological effect of a given physical RT dose, calculated using individual tumor genomics. We hypothesize that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared to physical RT dose alone. To test this hypothesis, and the GARD-based RT dosing paradigm, we performed a pooled pan-cancer analysis in 11 separate clinical cohorts of 1,615 unique patients with 7 different cancer types that represent all available cohorts with the data required to calculate GARD, together with clinical outcome. MethodsUsing 11 previously-published datasets of cancers including breast, head and neck, non-small cell lung, pancreas, endometrium, melanoma and glioma, we defined two clinical endpoints: (i) time to first recurrence and (ii) overall survival, comprising 1,298 (982 +RT, 316 -RT) and 677 patients (424 +RT, 253 -RT), respectively. We used Cox regression stratified by cohort to test association between GARD and outcome with separate models using RT dose and sham-GARD for comparison. Interaction tests between GARD and treatment (+/- RT) were performed using the Wald statistic. ResultsPooled analysis of all available data reveal that GARD as a continuous variable is associated with recurrence (HR = 0.982, CI [0.970, 0.994], p = 0.002) and survival (HR = 0.970, CI [0.953, 0.988], p = 0.001). The interaction test revealed the effect of GARD on survival depends on whether or not that patient received RT (Wald statistic: p=0.011). Physical RT dose and sham-GARD were not significantly associated with either outcome. ConclusionsThe biologic effect of radiation therapy, as quantified by GARD, is significantly associated with recurrence and survival for those patients treated with radiation: it is predictive of RT benefit; and physical RT dose is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalizing RT prescription dose.

Surgery is the primary treatment for localized neuroendocrine tumors (NETs). Grade 1-2 NETs traditionally have been considered radioresistant due to their indolent nature but data regarding a role for radiation therapy (RT) are limited to old, small retrospective studies. We performed a retrospective review of patients with grade 1-2 NETs treated with RT at a large academic center to assess response and local failure rates. Radiographic response was evaluated with logistic regression. Local failure was assessed with cumulative incidence rates and competing risk regressions. We identified 35 patients with 78 treated lesions between 1974 and 2017. Most tumors originated from the pancreas (n=13) and bronchus/lung (n=11). Nine (26%) patients had grade 1 tumors, 16 (46%) had grade 2 tumors, and ten (29%) had grade 1-2 tumors. The median biologically effective dose (BED10) was 50.7 Gy (range, 20.0-106.5). The median follow-up was 13.5 months (range, 0.5 to 140.6 months). 20 of 21 (95%) patients had palliation of symptoms. Of 52 intact lesions, response was complete in 7 (13%), partial in 14 (27%), stable in 25 (48%), and progressive in 6 (12%) lesions. Higher BED10 was associated with a response (odds ratio/Gy 1.06; 95% CI, 1.02-1.11; p=0.008). Of 59 intact or resected lesions, the 2-year cumulative incidence of local failure was 26.4%. Grade 2 lesions were associated with local failure (hazard ratio 7.70; 95% CI, 1.22-48.8; p=0.03). We show that grade 1-2 NETs often respond radiographically and symptomatically to RT. RT should be considered in the management of grade 1-2 NETs.

BackgroundIn an attempt to reduce interruptions in radiation treatment, our department implemented universal SARS-CoV-2 PCR testing during the peak of the New York City COVID-19 epidemic. MethodsStarting 4/18/20, outpatients coming into the Department of Radiation Oncology for either simulation or brachytherapy were required to undergo PCR testing for SARS-CoV-2. Starting on 5/6/20, patients were offered simultaneous SARS CoV-2 IgG antibody testing. ResultsBetween 4/18/20-6/25/20, 1360 patients underwent 1,401 outpatient screening visits (Table 1). Of the patients screened, 411 were screened between 4/18/20 and 5/6/20 (Phase 1) with PCR testing: 13 (3.1%) patients were PCR positive. From 5/7/20 to 6/25/20, 990 patients were scheduled for both PCR and antibody testing (Phase 2), including 41 previously screened in Phase 1. Of those with known antibody status (n=952), 5.5% were seropositive. After 5/21/20, no screened patient (n=605) tested PCR positive. In the month prior to screening (3/17/20-4/19/20), 24 of 625 patients initiating external radiation had treatment interrupted due to COVID-19 infection (3.8%) vs 7 of 600 patients (1.1%) in the month post screening (4/20/20-5/24/20) (p=0.002). O_TBL View this table: org.highwire.dtl.DTLVardef@1fd270aorg.highwire.dtl.DTLVardef@10e1f44org.highwire.dtl.DTLVardef@26b73corg.highwire.dtl.DTLVardef@1c7e2feorg.highwire.dtl.DTLVardef@79ad0_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1:C_FLOATNO O_TABLECAPTIONDemographic and Disease Data C_TABLECAPTION C_TBL ConclusionsState-wide mitigation efforts, coupled with intensive departmental screening, helped prevent interruptions in radiation during the COVID-19 epidemic that could have compromised treatment efficacy.

BackgroundRadiation therapy is integral to the curative treatment of childhood brain tumors but contributes to late neurocognitive impairment in survivors. FLASH (ultra-high dose rate, >40Gy/s) reduces normal-tissue toxicity in preclinical models, and proton-FLASH is currently the only modality capable of delivering ultra-high dose rates to the deep targets, such as pediatric brain tumors. However, two questions remain unresolved before clinical translation: (1) whether the FLASH effect can be achieved on synchrotron-based proton systems, which deliver protons in discrete spills that may be insufficient to cover a clinical target within a single delivery, and (2) which dose-rate metric, among the multiple definitions currently used in the field, best predicts the biological FLASH effect. MethodsC57BL/6 mice (7-8 weeks) received 10 Gy whole-brain RT via a clinical Hitachi ProBEAT synchrotron with CBCT-guided delivery, using three transmission-beam techniques: single-spill pencil beam scanning (SS PBS), multi-spill PBS with [~]2-second inter-spot delay (MS PBS), and passive scatter (PS), compared to conventional (CONV) delivery and unirradiated controls (n=24-28/group, equal sex distribution). Dose rate was quantified using three frameworks: field dose rate (FDR), PBS dose rate (PBSDR), and dose-averaged dose rate (DADR). Recognition memory was assessed by novel object recognition (NOR) at 6 weeks post-RT, and cognitive flexibility was assessed via touchscreen visual discrimination and reversal learning at 14 weeks. Hippocampal neuroinflammation was evaluated by immunofluorescence and immunohistochemistry for Iba1, NeuN, and GFAP. ResultsFLASH conditions were met by SS PBS and PS under all three dose-rate definitions, but MS PBS qualified as FLASH only by DADR. Despite this, neuroprotection was preserved across all three FLASH techniques: discrimination index was significantly higher for SS PBS (P=0.021), MS PBS (P=0.008), and PS (P<0.001) versus CONV, with no significant difference between FLASH techniques. On touchscreen testing, FLASH-treated females demonstrated preserved cognitive flexibility (P=0.047 vs. CONV on reversal learning correct trials). Iba1+ microglia were reduced in FLASH compared to CONV mice, with morphology suggestive of preserved homeostatic state. ConclusionsSynchrotron-based proton FLASH preserves neurocognitive function across all delivery techniques, including under multi-spill delivery essential for treating clinical-scale pediatric brain tumors. Critically, this neuroprotection was observed even for deliveries that qualified as FLASH only by DADR, identifying DADR as the dose-rate metric most relevant to the biological FLASH effect with direct implications for clinical trial design and dose-rate reporting standards.

BackgroundWe hypothesized that the radiosensitivity index (RSI), would classify non-small cell lung cancer (NSCLC) patients into radioresistant (RR) or radiosensitive (RS). MethodsWe identified resected pathologic stage III NSCLC. For the radiation group (RT) group, at least 45 Gy of external beam radiation was required. mRNA was extracted from primary tumor. The predefined cut-point was the median RSI with a primary endpoint of local control. Similar criteria were then applied to two extramural datasets (E1; E2) with progression free survival as the primary endpoint. ResultsMedian follow-up from diagnosis was 23.5 months (range: 4.8-169.6 months). RSI was associated with time to local failure in the RT group with a two-year rate of local control of 80% and 56% between RS and RR groups, respectively p=0.02. RSI was the only variable found to be significant on Cox local control analysis (HR 2.9; 95% CI: 1.2-8.2; p=0.02). There was no significance of RSI in predicting local control in patients not receiving RT, p=0.48. A cox regression model between receipt of radiotherapy and RSI combining E1 and E2 showed that the interaction term was significant for PFS (3.7; 95% CI 1.4-10; p=0.009). A summary measure combining E1 and E2 showed statistical significance for PFS between RR and RS patients treated with radiotherapy (HR 2.7l; 95% CI 1.3-5.6; p=0.007) but not in patients not treated with radiotherapy (HR 0.94; 95% CI 0.5-1.78; p=0.86). ConclusionsRSI appears to be predictive for benefit from adjuvant radiation. Prospective validation is required.

PurposeTo develop a new patient consult program, where patients are invited to meet directly with a clinical medical physicist to learn and ask questions about the technical aspects of their care. MethodsPatients are invited to meet voluntarily with a clinical medical physicist directly after the treatment planning CT appointment, and then again after treatment starts. Each consult starts with an overview of the clinical medical physicists role in patient care. This is followed by a detailed explanation of the treatment planning CT, treatment planning, and treatment delivery processes. Data are collected after each patient encounter, including: age, gender, treatment intent, treatment site, consult duration, discussion points, overall impression, and a summary of the questions asked. Qualitative data analysis focused on understanding the number and types of questions asked during the physics consults. Additional analyses focused on evaluating the encounter notes for interesting insights regarding meeting tone, number of meeting attendees, and other non-clinical discussion points. ResultsSixty three patients were seen between August 2016 and December 2017, accounting for 29% of the total department patient load. The average physics consult duration was 24 minutes. When evaluating the patient encounter notes for overall tone, 55 patients (87%) had positive descriptors such as "pleasant conversation". Thirty three patients (52%) brought at least one other person into the consult, and 27 patients (43%) contributed personal stories or professional background information to the conversation. When the collection of patient questions was grouped into question types, the data show that the majority of the consult discussion addresses questions related to treatment delivery, treatment planning, and other technical questions. ConclusionsIncorporation of a medical physics patient consult program into clinical practice requires modest time commitment, and has the benefits of increasing medical physics engagement with patient care and improving patient satisfaction through better education.

PurposeConformal dose distributions in proton radiotherapy promise to reduce normal tissue toxicity such as radiation-induced pneumonitis, but this has not been fully realized in clinical trials. To further investigate dose and toxicity, we employ voxel-based normal tissue evaluation techniques such as ventilation maps throughout treatment. We hypothesize that ventilation change after 1 week of treatment (WK1) predicts for ventilation change at the end of treatment (EOT). MethodsFor 48 photon and 23 proton lung cancer patients, 4DCT-based ventilation maps were generated using stress-based methods at planning, WK1, and EOT. Voxel-wise ventilation change from planning to WK1 and EOT was calculated and binned by planned dose, and median ventilation change at WK1 and EOT was calculated across all patients in each dose bin. Patients were stratified into 6 groups based on modality and increased, decreased, or stable ventilation at WK1. Mann-Whitney U tests were performed to determine if median ventilation change at WK1 and EOT in each dose bin was significantly different from zero. Univariate analysis was performed to correlate ventilation change at EOT with change at WK1 and other clinical factors. A linear regression model was developed to predict ventilation at EOT using a variety of input features including ventilation at planning, ventilation at WK1, tumor response information, and tumor location. Accuracy of the model was assessed through R2. ResultsFor patients that decreased in ventilation at WK1, 90% of photon patients and 92% of proton patients were stratified similarly at EOT. Patients that were stratified as increased ventilation at WK1 were stratified similarly (72% for photon, 80% for proton) at EOT. These patients were more likely to develop Grade 2+ pneumonitis though the difference was not significant when computing a Fishers exact test. Univariate analysis indicated that only ventilation change at WK1 was correlated with ventilation change at EOT. The linear regression model achieved R2 of 0.65. ConclusionVentilation changes at EOT can be predicted using ventilation information from planning and WK1. Patients that increased in ventilation at WK1 were more likely to develop pneumonitis. Further work is needed to characterize the relationship between ventilation change with pneumonitis development.

Purpose: Elective nodal (EN) irradiation (ENI) during radiotherapy for locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) influences hematotoxicity, anti-tumor immunity, and synergy with immunotherapy. We evaluated whether EN-sparing upfront boosts affect DNA damage, systemic immune signaling in peripheral blood lymphocytes (PBLs), and radiation-induced lymphopenia (RIL). Methods and Materials: Twenty-eight patients with LA-HNSCC were randomized to either adjuvant or definitive chemoradiotherapy with standard ENI or EN-sparing upfront boost (adjuvant: 2x2 Gy; definitive: 5x2 Gy). Blood was collected pre-radiotherapy, 15 min, and 24 h after the first fraction, and before the sixth fraction. DNA damage in PBLs was assessed via {gamma}H2AX and 53BP1 foci and dicentric chromosome (DIC) assay. RNA sequencing was performed in two patients per group (definitive setting) at pre-CRT, before the sixth fraction, and at therapy end. Absolute lymphocyte counts (ALCs) were monitored weekly to assess RIL. Results: DNA damage in PBLs correlated with planning target volume and whole-body dose, both of which were reduced by EN-sparing by 9.9-fold and 4.4-fold, respectively (p < 0.001 each). Correspondingly, EN-sparing significantly reduced radiation-induced foci and DIC levels in PBLs (3-4-fold, p < 0.001) and lowered the fraction of radiation-damaged PBLs per fraction (11% vs. 23% with ENI, p < 0.001). EN-sparing preserved baseline ALCs during week 1 of chemoradiotherapy and delayed RIL, whereas ENI caused an immediate ALC decline and RIL. Lymphocyte counts after week 1 negatively correlated with planning target volume, whole-body dose, and DNA damage in PBLs (p < 0.01). Transcriptomics showed metabolic and interferon signaling associated with EN-sparing, versus sterile inflammatory and damage-associated patterns with ENI. Conclusions: EN-sparing by an upfront boost significantly reduced PBL damage and early RIL with distinct immune responses associated with lymphocyte viability and immune maturation. These findings support upfront EN-sparing strategies to mitigate RIL and improve radiotherapy-immunotherapy synergy in HNSCC.

Purpose/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.