8034 Background: Adjuvant osimertinib (osi) improves survival outcomes in patients (pts) with early-stage EGFR -mutated NSCLC harboring the classical EGFR exon 19 deletions (ex19del) or L858R mutation after surgery or chemoradiotherapy. Pts with early-stage NSCLC harboring atypical EGFR mutations were excluded from the respective clinical trials. Outcomes in this pt population remain unknown. Methods: We conducted a multi-institutional retrospective analysis of pts with stage IA-IIIC EGFR -mutated NSCLC (2010-2024) who were classified into two groups: those with tumors harboring classical EGFR mutations (c- EGFR : ex19del or L858R) or atypical EGFR mutations (a- EGFR : non-ex19del or L858R). Kaplan-Meier analyses compared disease-free survival (DFS), central nervous system (CNS) DFS, and overall survival (OS). Multivariable Cox regression adjusted for disease stage, definitive therapy, and adjuvant therapy. Results: Among 417 pts, 293 had tumors harboring c- EGFR and 124 had a- EGFR mutations. Baseline characteristics were similar between groups (Table). Median follow-up was 4 years. Among pts not treated with adjuvant osi (n = 346), a- EGFR was associated with a significantly lower 3-year DFS compared to c- EGFR (52.5% vs 71.2%; HR 1.71, 95% CI 1.21-2.42; P = 0.003). Compared to c- EGFR , a- EGFR had higher rates of recurrence to the ipsilateral lung (24% vs 14%) and bone (12% vs 6%). A- EGFR was associated with a significantly lower 3-year CNS DFS (81.3% vs 87.1%; P = 0.002) and 5-year OS (77.7% vs 85.6%; P = 0.007) compared to c- EGFR . Among pts with a- EGFR mutations, EGFR exon 20 insertions (ex20ins) were associated with a significantly reduced 3-year DFS compared to other alterations (35.9% vs 68.2%; HR 2.04, 95% CI 1.10-3.77; P = 0.013), and with a lower 3-year CNS DFS (70.9% vs 92.2%; P = 0.028) and trend towards lower 5-year OS (71.3% vs 84.4%; P = 0.141). Among pts who underwent surgery for stage IB-IIIA NSCLC (n = 209), adjuvant osi improved 3-year DFS among c- EGFR (84.2% with osi vs 63.4% without osi) whereas a- EGFR had a lower 3-year DFS (36.4%; P < 0.001), which was driven by EGFR ex20ins compared to other alterations (19.9% vs 59.2%; P = 0.003). Conclusions: Atypical EGFR mutations are associated with inferior survival outcomes compared to classical EGFR mutations in early-stage NSCLC. EGFR ex20ins appear to drive poor outcomes among the atypical EGFR mutations. Novel adjuvant therapy strategies are warranted to improve definitive treatment of early-stage atypical EGFR -mutated NSCLC. Classical EGFR , N=293 (%) Atypical EGFR , N=124 (%) Ex19del / L858R 46 / 54 - Ex20ins / G719X / L861Q / Other - 49 / 26 / 17 / 8 Stage IA / IB / II / III 35 / 23 / 17 / 25 38 / 14 / 23 / 25 Surgery / XRT / CRT 81 / 8 / 8 82 / 8 / 7 Neoadjuvant Chemo / EGFR TKI 4 / 3 7 / 2 Adjuvant Chemo / EGFR TKI / Osi 26 / 25 / 23 26 / 8 / 4 3-year DFS* 71.2 52.5 3-year CNS DFS* 87.1 81.3 5-year OS* 85.6 77.7 *In non-adjuvant osi cohort (n=346). Statistically significant difference.

Background:Clinical linear accelerators are an accessible platform for preclinical research on the biological effects of ultra-rapid electron irradiation (FLASH). However, they are not inherently designed for the accurate pulse control required for experiments using a small number of relatively high-dose pulses, and available methods for beam control such as respiratory gating can be error-prone owing to system latency. Purpose:Here we experimentally characterize the temporal latency of the respiratory gating system for controlling beam-on and beam-off at the individual linac pulse level. We use this information to develop accurate pulse delivery methods for preclinical FLASH research. Methods and Materials:We used programmable controller boards and a relay circuit to monitor and control delivery of specific numbers of pulses through the built-in monitor chamber and respiratory gating system of a Varian Trilogy linac. We modeled system response latency as a normally distributed random variable and experimentally recorded the probability of successful pulse delivery and inhibition relative to the time of beam-on and beam-off request signals to derive the mean and standard deviation of latency times at different pulse repetition frequencies. We implemented two methods - an adaptive method using only the delivered-pulse signal, and a synchronization method additionally using the linac's internal pulse-timing signal - and characterized their performance for standard and customized pulse sequences. Results:The mean and standard deviation values of the respiratory gating latency at 60, 90 and 180 Hz pulse repetition frequency were respectively 2.0±0.8 ms, 2.1±2.8 ms, and 2.4±1.9 ms for beam-on and 1.3±0.9 ms, 1.9±2.9 ms, and 1.8±2.1 ms for beam-off. Beam-on and beam-off latencies were similar to each other, and similar across pulse repetition frequencies. Characterizing the latency parameters permitted choosing optimal timing parameters that maximized the rate of successfully delivering the desired number of pulses using both adaptive and synchronization methods, exceeding 99% at 90 Hz for both methods, and reaching 95% (adaptive) and 80% (synchronization) at 180 Hz. This also enabled successful implementation of custom pulse sequences not natively available on the system. Conclusions:We demonstrated that accounting for latency and/or using the ability to read the prior information on expected pulse timing can provide high accuracy in delivering specified numbers of pulses. This reliability is critical for accurate dose delivery in preclinical FLASH research of single fraction and especially fractionated dosing regimens. The ability to generate custom pulse sequences enables more detailed exploration of the temporal dependence of biological FLASH effects.

The integration of FLASH radiotherapy with stereotactic techniques presents a promising avenue for improving therapeutic outcomes through normal tissue sparing while maintaining tumor control. However, significant technical challenges must be addressed for successful clinical implementation. This review evaluates emerging platforms and technical requirements for combining FLASH delivery with stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). While electrons have enabled extensive preclinical FLASH research, their limited penetration depth makes them unsuitable for most stereotactic applications. Photon-based systems face significant engineering challenges in achieving both FLASH dose rates (>40 Gy/s) and the beam characteristics necessary for stereotactic delivery, particularly regarding heat management and multi-angle treatment capabilities. Proton and heavy ion systems offer advantages through the Bragg peak but require substantial development to overcome technical limitations in beam delivery and scanning speeds. We evaluate emerging platforms including novel accelerator designs, beam monitoring systems, and delivery techniques aimed at clinical translation. Critical technical requirements are discussed, including specialized dosimetry systems capable of ultra-high dose rate measurements, quality assurance protocols, treatment planning systems that optimize both spatial and temporal aspects of delivery, and novel image guidance strategies.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

Configuring clinical linear accelerators (linacs) for ultra-high dose rate (UHDR) electron experiments typically requires invasive hardware manipulation and/or irreversible manufacturer modifications, limiting broader implementation. We present an independently developed UHDR electron configuration of a clinical TrueBeam linac that allows reversible switching between preclinical UHDR and conventional (CONV) modes using only non-invasive software settings. UHDR mode was achieved via service mode software with RF and beam current settings typical of a photon beam, the photon target and monitor chamber retracted, and a clinically unused low-energy scattering foil inserted. An external AC current transformer (ACCT) for beam monitoring, anatomy-specific collimator, and sample holder were mounted on the accessory tray, with external ion chamber in solid water for exit dose monitoring. Percent depth dose (PDD) was measured for UHDR and CONV beams. Dose-per-pulse (DPP) was varied by adjusting gun voltage and quantified with radiochromic film at different source-to-surface distances (SSD). Beam profiles assessed dose uniformity and usable field size. Dose calibration was established between film, ACCT, and ion chamber, and day-to-day reproducibility was tested. PDD confirmed similar energies for UHDR (12.8MeV) and CONV (11.9MeV) beams with matching profiles through mouse thickness. Maximum DPP exceeded 0.5Gy, reaching ~1.5Gy for collimated in vivo setups and ~0.7Gy at extended SSD for tissue culture. Field flatness and symmetry were maintained, supporting organ-specific irradiations and up to 5cm fields for culture. Calibration showed strong linearity across detectors, and output variation was <4%. We demonstrated accurate, reproducible UHDR delivery on a widely available clinical linac with no invasive hardware manipulation, enabling preclinical FLASH research on a clinical treatment machine.

Objective A significant proportion of patients with stage I non–small cell lung cancer (NSCLC) are considered at high risk for complications or mortality after lobectomy. The American Association for Thoracic Surgery (AATS) previously published important considerations in determining which patients are considered high risk. The current objective was to evaluate treatment options and important factors to consider during treatment selection for these high-risk patients. Methods The AATS Clinical Practice Standards Committee assembled an expert panel to review treatment options for high-risk patients with stage I NSCLC. After a systematic search of the literature identification of lung-nodule-related factors to consider in treatment selection, the panel developed expert consensus statements and vignettes using a modified Delphi method. A 75% consensus was required for approval. Results The expert panel identified sublobar resection, image-guided thermal ablation (IGTA), and stereotactic ablative radiotherapy (SABR), which is also known as stereotactic body radiation therapy (SBRT) or stereotactic radiosurgery (SRS), as modalities applicable in the treatment of high-risk patients with stage I NSCLC. Fourteen statements and 5 vignettes illustrating clinical scenarios were formulated, revised, and ultimately approved. Conclusions The choice of which modality (sublobar resection, SABR, or IGTA) is optimal in high-risk patients with stage I NSCLC is complex, but a surgical approach is generally favored when deemed safe. SABR and IGTA are reasonable options in select patients, with SABR being the likely next choice in nonsurgical patients. If possible, obtaining a biopsy is very important prior non-surgical treatment. A multi-disciplinary review of patient and tumor characteristics is essential for achieving an optimal decision. The clinical treatment decision should also take patient perspectives, preferences, and quality of life into consideration.

BACKGROUND:FLASH radiotherapy has emerged as a promising advancement in radiation oncology, demonstrating the potential to minimize normal tissue toxicity while preserving tumoricidal efficacy. However, the precise beam parameters required for clinical translation remain to be fully defined. METHODS:To optimize beam parameters for clinical application, we employed Very High Energy Electrons (VHEE) at the CLEAR facility, capable of targeting deep-seated tumors. These were used alongside a FLASH-validated Intermediate Energy Electron (IIE) beam and a 160-225 keV X-ray beam, collectively delivering dose rates from 1 Gy/min to 1011 Gy/s. High-throughput chemical assays investigated the radiochemical effects across this dose rate range, while zebrafish embryos provided an in vivo model to evaluate biological responses and developmental outcomes. This study offers the first comprehensive analysis of FLASH effects across a wide spectrum of dose rates and temporal parameters, from early physico-chemical interactions to complex biological systems. RESULTS:Data from CLEAR demonstrated that beam intensity, particularly bunch charge, is a critical determinant of the FLASH effect, and uncovered an unforeseen biological response when electrons are delivered over the picosecond timescale. CONCLUSION:Our findings suggest that scanning strategies employing high intensity beamlets may be optimal for the clinical implementation of FLASH radiotherapy. These insights are pivotal for guiding the development of future FLASH protocols in radiation oncology.

INTRODUCTION:The aim of this study was to investigate the clinical significance of inter-fraction volume changes during stereotactic ablative body radiotherapy (SABR) for early-stage NSCLC. The prevalence and impact on disease control remain poorly studied. This is the largest study examining the association between inter-fraction volume changes during lung SABR and clinical outcomes. PATIENTS AND METHODS:121 NSCLC patients treated between April 2009 and July 2019 were included. Gross tumor volume (GTV) was calculated from planning-CT, and inter-fraction volumes from cone-beam CT images taken before treatment. Univariable and multivariable linear regression analyzed relationships between volumetric changes and baseline characteristics. Fine-Gray models assessed volume change associations with local, regional, and distant recurrence, considering death as a competing risk. RESULTS:61.9% and 11.1% of tumors demonstrated a > 10% increase and decrease, respectively, in volume from the start to end of treatment. There was a negative correlation between initial tumor volume and inter-fraction volume increase on univariable analysis. Fine-Gray models showed no significant correlation between volume increase and local recurrence but found a negative association between volume increase and regional as well as distant recurrence. CONCLUSIONS:Notable radiographic volume changes occurred in over half of lung SABR patients. This phenomenon did not appear to adversely affect local control. Increased radiographic volume correlated with reduced regional and distant recurrence, possibly representing an immune effect. Our findings suggest volume changes are likely a consequence of acute inflammatory reactions rather than tumor growth, and modest PTV expansions may be sufficient for tumor coverage.

BACKGROUND:Hyperfractionated reirradiation (re-RT) has been shown to mitigate late toxicity for some cancers, but data on safety and efficacy for thoracic tumors are limited. METHODS:We evaluated a cohort of 28 consecutive cases among 25 patients treated with re-RT to either primary or metastatic thoracic tumors, using 60 Gy in 50 fractions delivered twice daily. Incidence rates of toxicity, local recurrence (LR), and any disease progression were evaluated using competing risk analysis. Cumulative dose to organs at risk (OARs) was calculated (EQD2 [alpha/beta = 3]), correlated with toxicity outcomes, and compared to published constraints for re-RT. RESULTS:There was direct overlap of 100 % isodose lines between treatment courses in 90.5 % of cases. Most patients had tumors abutting the proximal bronchial tree (PBT, 89 %). The median re-RT PTV volume was 67 cm3. The overall rate of ≥G2 toxicity was 46 % and the rate of ≥ G3 toxicity was 15 %. The rate of local recurrence and overall survival at 12 months was 33 % and 80 %, respectively. The lung volume receiving a cumulative dose of 20 Gy was kept under 40 % (V20 Gy < 40 %) for nearly all patients (91 %). Lung V5Gy ≥ 60 % was associated with higher rates of ≥ G2 pulmonary toxicity (69 vs. 18 %, p < 0.01). Cumulative Dmax exceeded previously published constraints in most cases for the PBT (110 Gy, 57 % of cases) and great vessels (120 Gy, 52 % of cases) without observed cases of ≥G2 pulmonary hemorrhage, stenosis, fistula, or great vessel toxicity. CONCLUSIONS:Hyperfractionated re-RT for thoracic tumors resulted in favorable rates of local control and toxicity in a high-risk cohort and is worthy of prospective evaluation. Putative dose constraints were not able to be met for many cases of definitive re-RT, particularly for the great vessels and PBT, without excessive observed toxicity.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Background Detection and segmentation of lung tumors on CT scans are critical for monitoring cancer progression, evaluating treatment responses, and planning radiation therapy; however, manual delineation is labor-intensive and subject to physician variability. Purpose To develop and evaluate an ensemble deep learning model for automating identification and segmentation of lung tumors on CT scans. Materials and Methods A retrospective study was conducted between July 2019 and November 2024 using a large dataset of CT simulation scans and clinical lung tumor segmentations from radiotherapy plans. This dataset was used to train a 3D U-Net-based, image-multiresolution ensemble model to detect and segment lung tumors on CT scans. Model performance was evaluated on internal and external test sets composed of CT simulation scans and lung tumor segmentations from two affiliated medical centers, including single primary and metastatic lung tumors. Performance metrics included sensitivity, specificity, false positive rate, and Dice similarity coefficient (DSC). Model-predicted tumor volumes were compared with physician-delineated volumes. Group comparisons were made with Wilcoxon signed-rank test or one-way ANOVA. P < 0.05 indicated statistical significance. Results The model, trained on 1,504 CT scans with clinical lung tumor segmentations, achieved 92% sensitivity (92/100) and 82% specificity (41/50) in detecting lung tumors on the combined 150-CT scan test set. For a subset of 100 CT scans with a single lung tumor each, the model achieved a median model-physician DSC of 0.77 (IQR: 0.65-0.83) and an interphysician DSC of 0.80 (IQR: 0.72-0.86). Segmentation time was shorter for the model than for physicians (mean 76.6 vs. 166.1-187.7 seconds; p<0.001). Conclusion Routinely collected radiotherapy data were useful for model training. The key strengths of the model include a 3D U-Net ensemble approach for balancing volumetric context with resolution, robust tumor detection and segmentation performance, and the ability to generalize to an external site.

Introduction: Radiotherapy is effective for breast cancer treatment but often causes undesirable side effects that impair quality of life. Ultra-high dose rate radiotherapy (FLASH) has shown reduced normal tissue toxicity while achieving comparable tumor growth delay compared to conventional dose rate radiotherapy (CONV). This study evaluated whether FLASH could achieve similar tumor control as CONV with tumor eradication as the primary endpoint, in an orthotopic breast cancer model. Methods: Non-metastatic, orthotopic tumors were generated in the left fourth mammary fat pad using the Py117 mammary tumor cell line in syngeneic C57BL/6J mice. Two sequential irradiation studies were performed using FLASH (93-200 Gy/s) and CONV (0.08 Gy/s) electron beams. Single fractions of 20, 25, or 30 Gy were applied to tumors with varying abdominal wall treatment fields (~3.75 or 2.5 mm treatment margin to tumor). Results: Both FLASH and CONV demonstrated comparable efficacy. Small tumors treated with 30 Gy and larger abdominal wall treatment fields appeared to have complete eradication at 30 days but also exhibited the highest skin toxicity, limiting follow-up and preventing confirmation of eradication. Smaller abdominal wall treatment fields reduced skin toxicity and allowed for extended follow-up, which resulted in 75% tumor-free survival at 48 days. Larger tumors showed growth delay but no eradication. Conclusions: In this preclinical, non-metastatic orthotopic breast cancer model, FLASH and CONV demonstrated equivalent tumor control with single-fraction doses of 20, 25, or 30 Gy. Overall, 30 Gy achieved the highest eradication rate but also resulted in the most pronounced skin toxicity.

Proton therapy provides superior dose conformity compared with photon radiotherapy, concentrating radiation within the tumor while sparing adjacent healthy tissue. This advantage has been most effectively realized for static tumors in anatomically stable regions, such as the head and neck. For thoracic and abdominal sites, however, physiological motion remains a critical challenge: because the proton dose distribution is highly sensitive to density variations, long delivery times relative to respiratory motion can compromise accuracy. Existing strategies to accelerate delivery often require substantial hardware modifications or are difficult to translate into routine practice. Here we report an optimization that enables high-speed proton delivery (5 to 10 sec per field) on a commercial synchrocyclotron platform without hardware changes. The method combines high-energy shoot-through beams with Bragg-peak delivery, an optimized nearest-neighbor scanning sequence, and a two-pulse dose regulation scheme. Applied to eight lung cancer cases (target volumes 100 to 1000 cc), the approach achieved full field delivery in under 10 sec compatible with a short breath hold while preserving conformity, dose accuracy, and sparing of organs at risk. This framework provides a practical route to motion robust proton therapy, improving precision, efficiency and patient tolerance. More broadly, it opens a pathway toward widespread clinical adoption of high-speed proton delivery for moving tumors.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Blood products, including apheresis platelets and plasma, are essential for medical use but pose risks of bacterial contamination and viral transmission. Platelets are prone to bacterial growth due to their storage conditions, while plasma requires extensive screening. This study explores rapid irradiation as an innovative pathogen reduction method. A clinical linear accelerator was configured to deliver ultra-high dose rate (6 kGy/min) irradiation to platelet and plasma components. Platelets spiked with Escherichia coli (E. coli; 10⁵ colony-forming units) were irradiated at 0.1–20 kGy, followed by bacterial growth and platelet count analysis. COVID-19 convalescent plasma (CCP) was irradiated at 25 kGy, and receptor-binding domain (RBD)-specific immunoglobulins (Ig) were assessed. Irradiation at 1 kGy reduced E. coli growth by 2.7-log without significant platelet loss, while 5 kGy achieved complete suppression. The estimated 6-log bacterial reduction dose (2.3 kGy) led to a 31% platelet count drop. Administering a 25 kGy virus-sterilizing dose to CCP resulted in a 9.2% decrease in RBD-specific IgG binding. This study demonstrates the proof-of-concept for rapid blood sterilization using a clinical linear accelerator. The method maintains platelet counts and CCP antibody binding at sterilizing doses, highlighting its potential as a point-of-care blood product sterilization solution.

Purpose: Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates. Methods and Materials: We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s). Results: The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups). Conclusions: Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. SIGNIFICANCE:This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534.

Purpose/Objective(s) Stereotactic ablative radiotherapy (SABR) effectively treats early-stage lung cancer, but tumor motion poses accuracy challenges. Inspiratory breath hold is an established strategy to mitigate lung motion, but its practicality is limited, especially in patients with reduced lung capacity. Percussive ventilation breath hold (PVB) is an innovative, non-invasive respiratory technique designed to maintain breathing function with minimal chest motion, thus eliminating motion uncertainty and improving treatment safety. This pilot study marks the first attempt to apply the novel physiology of PVB to lung SABR treatments. The primary objectives include determining the success rate of administering PVB for 5 minutes in healthy volunteers (Arm 1) and evaluating the success rate of PVB-SABR in lung cancer patients (Arm 2). Secondary objectives involve examining time-related endpoints for breath hold duration and assessing dosimetric benefits of PVB. Materials/Methods This interim analysis includes 10 healthy volunteers and 1 patient enrolled between 1/2023 - 7/2023 (IRB 63842). Any person age 18 or older who would be deemed clinically eligible to undergo lung SABR treatment qualified to participate. Patients in Arm 2 require a diagnosis of primary lung cancer or lung metastasis. PVB is administered with Percussionaire IPV-2C. Participants either underwent mock simulation with PVB (Arm 1) or PVB-SABR treatment (Arm 2). CO2 levels were monitored transcutaneously (Sentec), and adverse effects were recorded according to CTCAE v5. Results Arm 1, involving healthy volunteers, has been completed. 9 of 10 volunteers (90%) tolerated PVB for at least 5 minutes, with 3 of 10 (30%) maintaining a 10-minute breath hold. The average PVB duration was 7.32 minutes (range: 2.5 – 14.17 mins). CO2 levels increased significantly after 5 minutes of PVB (p = 0.002), indicating a correlation between PVB duration and CO2 levels. Minimal adverse events were documented, with dry mouth being the most notable (40%). All adverse events resolved within 24 hours. In addition, subjects demonstrated the ability to repeat multiple, sequential breath holds using the PVB technique. The first patient in Arm 2 has successfully been treated with PVB-SABR. They were able to maintain PVB for 10 minutes. There were no long-term adverse events. Conclusion This interim analysis on the first study evaluating use of PVB-SABR indicates a high tolerance for PVB with minimal adverse effects. Duration of successful PVB correlated with CO2 levels. These findings underscore PVB’s potential as a safe, effective approach to lung SABR motion management. Treatment arm completion is expected by mid-2024. Future dosimetric analysis may demonstrate potential target sparing benefits with use of PVB. Notably, we’ve acquired the Monsoon III, a new ventilator device with improved patient tolerability and gas exchange. To this end, we have included an additional 5 healthy volunteers and will utilize Monsoon III for future PVB-SABR treatments.