BACKGROUND AND PURPOSE:SABR-5 was a provincially coordinated, single-arm phase II trial of SABR for patients with up to five extracranial metastases across all six BC Cancer centres. The primary objective was to prospectively quantify treatment-related toxicity in a population-based setting. This analysis reports extended follow-up and long-term toxicity outcomes. MATERIALS AND METHODS:Adults with oligometastatic or oligoprogressive disease (≤5 extracranial metastases) were enrolled between 2016 and 2020, when SABR for these indications in BC was available only through this trial. All grade ≥ 3 events underwent central review by a provincial toxicity committee. Toxicity was evaluated using crude per-patient rates, cumulative incidence methods, annual landmark analyses to year 5, and assessment of toxicity duration. Median follow-up for this update was 54.2 months. RESULTS:A total of 380 patients were treated (median age 69 years; 32% female). Most patients (91%) had one or two lesions treated. Crude per-patient rates of treatment-related toxicity were 18.9% for grade 2, 5.8% for grade 3, 0.0% for grade 4, and 0.3% for grade 5. There were no additional treatment-related deaths beyond the single previously reported case. The most frequent grade ≥ 3 toxicities were fracture (2.9%) and pain (1.8%). The cumulative incidence of grade 2 and grade ≥ 3 toxicity at 5 years was 24% and 7%, respectively. Annual landmark analyses demonstrated that most evaluable patients remained grade 0-1 at each timepoint. Analysis of toxicity duration demonstrated that most grade 3 events resolved within a year (median durations typically < 12 months), and persistent long-term toxicity was uncommon and predominantly low-grade. CONCLUSION:SABR delivered within a population-based, quality-assured program is associated with a low incidence of late high-grade toxicity and no new treatment-related deaths. These findings provide durable reassurance regarding the long-term safety of SABR for patients with limited extracranial metastatic disease. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02933242.

Background: Online adaptive radiotherapy is an emerging technology. Purpose: It is hypothesized that deformable polymer gel dosimetry is a feasible method to provide volumetric information for the assessment of spatial and dosimetry accuracy of adaptive radiotherapy on Ethos. Methods: In this work, HyperSight cone-beam CT (CBCT) imaging on Ethos was benchmarked to the TrueBeam CBCT for stationary polymer gel dosimeter (PGD) using gamma pass rate (GPR), signal-to-noise ratio (SNR), and dose profiles. A deformation phantom was fabricated and tested on Ethos and assessed with GPR. A deformed PGD was irradiated with adapted radiotherapy. The deformed and undeformed states were compared to the adapted and scheduled treatment plans using GPR and dose maps.Results: Experiments with stationary PGDs found that image SNR on Ethos was up to 40% lower compared to TrueBeam. For a 3-field plan, Ethos had a GPR of 83.1%, compared to a GPR of 94.1% on TrueBeam with a 3%/3 mm criteria. The GPR in the new deformation phantom was 88.1% with a 3%/3 mm criteria when the scheduled (unadapted) plan was delivered. Finally, a deformed PGD was irradiated with adaptive radiotherapy. When compared to the adapted plan, the deformed gel had a GPR of 85.8%, demonstrating improved agreement, but not meeting the conventional 90% pass rate. Conclusions: Although Ethos produced lower SNR and GPRs compared to TrueBeam, this work has demonstrated the feasibility of deformable PGD on Ethos.

PURPOSE:This study evaluates the dosimetric and geometric precision of a virtual cone technique using CBCT-based polymer gel dosimetry, enabling radiation delivery, and imaging readout within an identical spatial coordinate system. METHODS:We created a C# script for a virtual cone technique that generates a treatment plan with 10 gantry arcs at 0°, 36°, 72°, 288°, and 324° couch angles, with 2 arcs per couch angle using 45° and 135° collimator angles. Two verification plans using Eclipse v15.6 (AcurosXB) were created with 20 Gy at the maximum dose for: (1) a cylindrical gel, with an additional calibration region; (2) a 3D printed anthropomorphic skull phantom with a gel insert. The 50% isodose (10 Gy) width through the central axis of the axial and sagittal planes (SPs) were measured for the gel experiment. The distance between the centers-of-masses of the 10 Gy isodose region of the plan and the gel (skull phantom) were calculated for an end-to-end spatial accuracy test. RESULTS:The maximum point dose measured with gel was within 1% of the plan, though the gel measured 50% isodose widths of 5.56 ± $\; \pm \;$ 0.02 mm, 5.65  ± $ \pm \;$ 0.04 mm, 4.23  ± $ \pm \;$ 0.01 mm for axial (anterior-posterior), axial (left-right), sagittal (superior-inferior) respectively, which were slightly narrower than Eclipse (1.29 mm maximum difference in the SP due to CBCT slice thickness). The center-of-mass distance was 0.66 mm for the gel experiment, and 0.94 mm for complete end-to-end testing with the anthropomorphic phantom, including CBCT setup (kV-MV isocenter uncertainty). CONCLUSION:The 50% isodose width of the gel measurement was 5.15 mm (mean), which was tighter than our Eclipse v15.6 beam model. The end-to-end spatial accuracy test, only achievable with gel dosimetry using CBCT readout, resulted in sub-millimeter accuracy. This study demonstrates the value of gel dosimetry in verifying the dosimetric and spatial accuracy of this high precision, stereotactic technique.

Susceptibility to radiation-induced lung disease differs among people and among inbred strains of mice; C3H/HeJ mice develop early onset distress from pneumonitis and C57BL/6J mice present later onset pneumonitis with fibrosis. Previous studies revealed C3H/HeJ alleles at a 28 Mb locus on chromosome 2 to be linked to early onset distress and at an 18 Mb locus on chromosome 17 (called Radpf1 for radiation-induced pulmonary fibrosis-1) to decrease fibrosis in whole-thorax irradiated mice. To potentially reduce these genomic intervals, parental chr17-subcongenic mice with 0.71 Mb of C3H/HeJ alleles, and chr 2-congenic mice with region-spanning C3H/HeJ alleles from 95 to 123 Mb, and four lines of subcongenic mice received 16 Gy whole thorax irradiation and were assessed for onset of respiratory distress and histological lung disease at distress. One hundred percent of irradiated C3H/HeJ and C57BL/6J mice exhibited respiratory distress from pneumonitis and pneumonitis with fibrosis (6.8% of lung), respectively, while 18/19 chr17-subcongenic mice survived to 25 weeks post-treatment without symptoms of distress and with significantly decreased radiation-induced pulmonary fibrosis (0.3% of lung, P = 0.002). Of the chr2-subcongenics, mice of one line, which we refer to as Pneum1 (pneumonitis one), succumbed at an average of 20.2 ± 1.1 weeks postirradiation in females and 26.3 ± 1.2 weeks in males (P > 0.22 vs. congenic mice), reducing this locus to 5.6 Mb. Bioinformatic analyses revealed 114 candidate genes within these reduced intervals, with effects on pathways including on immune pathways. Mapping refined genetic susceptibility to radiation-induced lung disease in mice.

Purpose Although stereotactic ablative radiation therapy (SABR) is known for low toxicity and safety, its combined use with specific systemic therapies requires further investigation. This study aims to evaluate the toxicity of SABR in combination with various systemic therapies. Materials and Methods A secondary analysis of the SABR-5 trial evaluated grade 2+ and 3+ toxicities post-SABR in patients who had received high-risk or non-high-risk systemic therapies before SABR at 4 predefined intervals: concurrent with SABR, 1 day to 1 week prior, 1 to 2 weeks prior, or 2 to 12 weeks prior. High-risk systemic therapy was a priori defined as drugs that may increase treatment toxicity when delivered in close proximity to SABR. This category encompasses cytotoxic chemotherapy, multitargeted tyrosine kinase inhibitors, CDK 4/6 inhibitors, EGFR inhibitors, anti-VEGF agents, and anti-CTLA-4 agents. Results Among 380 patients, grade 2+ toxicity rates were 17.3% (35/202) off systemic therapy, 19.2% (19/99) on non-high-risk therapy, and 42.9% (3/7) on high-risk therapy concurrent with SABR. Grade 3+ rates were 3.5% (7/202), 4.0% (4/99), and 28.6% (2/7), respectively. On multivariable analysis, concurrent use of high-risk systemic therapy was associated with a higher risk of grade 3+ toxic effects (OR, 14.88; P = .009). No significant risk was noted when high-risk drugs were used within 1 week, 2 weeks, or 2 to 12 weeks of SABR or with any non-high-risk drugs. Grade 2+ toxic effects associated with concurrent high-risk systemic therapy were primarily bone/pain related. Increased tumor diameter also elevated grade 2+ toxicity risk (per 1 cm increment; G2+ OR, 1.19; P < .001). Conclusion Concurrent use of high-risk drugs has demonstrated a potential of increased SABR-related toxicity, warranting caution in their concurrent use with SABR. In contrast, combining non-high-risk drugs (eg, hormonal therapy) with SABR did not increase risk. Further research is essential to identify risks associated with this therapeutic combination.

Linac-based stereotactic radiosurgery (SRS) with planning target volume (PTV) margins <1 mm has become increasingly common in recent years. Optical surface imaging for surface-guided radiation therapy (SGRT) is often used for intra-fraction motion monitoring during these treatments to facilitate the use of a smaller PTV margin by providing real-time quantitative patient positioning information. However, rotating the couch introduces errors to SGRT-reported translations and rotations that can be problematic for SRS treatments with non-coplanar arcs and very small PTV margins. This work presents a novel approach for decreasing the magnitude of these errors by performing a pre-treatment dry run and capturing reference surfaces with the SGRT system at each couch angle included in the treatment plan. Time from cone beam computed tomography (CBCT) to treatment initiation and total treatment session time were reviewed for 30 single-fraction brain SRS cases treated using this technique to determine the effect of including the dry run on treatment session times. Out of the 30 cases treated between April 2023 and January 2024, 23 treatments required only a single CBCT prior to treatment, with no additional mid-treatment imaging required to verify patient positioning after motion. The median time between CBCT and treatment initiation was 7.98 minutes (interquartile range (IQR) = 7.28 to 8.93 minutes). The median time from CBCT to treatment completion was 15.43 minutes (IQR = 13.67 to 21.97 minutes). In the six patients that required one additional CBCT, the treatment session times ranged from 24.32 to 32.83 minutes. There was one patient who required three mid-treatment CBCTs, and the treatment session time was 67.87 minutes. Incorporating the pre-treatment dry run with the acquisition of reference surfaces at each treatment angle decreased errors in SGRT-reported translations and rotations associated with couch rotation without significantly increasing treatment session times.

Purpose: To evaluate the feasibility of an open-source, semi-automated, and reproducible vertex placement tool to improve the efficiency of lattice radiotherapy (LRT) planning. We used polymer gel dosimetry with a Cone Beam CT (CBCT) readout to commission this LRT technique. Material and methods: We generated a volumetric modulated arc therapy (VMAT)-based LRT plan on a 2 L NIPAM polymer gel dosimeter using our Eclipse Acuros version 15.6 AcurosXB beam model, and also recalculated the plan with a pre-clinical Acuros v18.0 dose calculation algorithm with the enhanced leaf modelling (ELM). With the assistance of the MAAS-SFRThelper software, a lattice vertex diameter of 1.5 cm and center-to-center spacing of 3 cm were used to place the spheres in a hexagonal, closed packed structure. The verification plan included four gantry arcs with 15 degrees, 345 degrees, 75 degrees, 105 degrees collimator angles. The spheres were prescribed 20 Gy to 50% of their combined volume. The 6 MV Flattening Filter Free beam energy was used to deliver the verification plan. The dosimetric accuracy of the LRT delivery was evaluated with 1D dose profiles, 2D isodose maps, and a 3D global gamma analysis. Results: Qualitative comparisons between the 1D dose profiles of the Eclipse plan and measured gel showed good consistency at the prescription dose mark. The average diameter measured 13.3 +/- 0.2 mm (gel for v15.6), 12.6 mm (v15.6 plan), 13.1 +/- 0.2 mm (gel for v18.0), and 12.3 mm (v18.0 plan). 3D gamma analysis showed that all gamma pass percent were > 95% except at 1% and 2% at the 1 mm distance to agreement criteria. Conclusion: This study presents a novel application of gel dosimetry in verifying the dosimetric accuracy of LRT, achieving excellent 3D gamma results. The treatment planning was facilitated by publicly available software that automatically placed the vertices for consistency and efficiency.

PURPOSE:The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS:The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS:A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS:Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Aims: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. Materials and methods: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9,12,15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. Results: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P 1 / 4 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P 1 / 4 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P 1 / 4 0.064) and grade 2 or higher SABRassociated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P 1 / 4 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. Conclusions: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis- directed therapies. Crown Copyright (c) 2024 Published by Elsevier Ltd on behalf of The Royal College of Radiologists. All rights reserved.

A 74-year-old woman with pathologic T4a N1 M0 adenocarcinoma of the cecum, initially treated with right hemicolectomy, developed rising serum carcinoembryonic antigen levels while receiving adjuvant chemotherapy. Re-staging investigations demonstrated two soft tissue metastases in the right abdomen comprised of a retrocolic lesion immediately posterior to the colon and a retroperitoneal lesion with no other sites of metastases. The patient was treated with stereotactic ablative radiotherapy (SABR) to a dose of 40 Gy in five daily fractions to both pericolonic soft tissue metastases simultaneously. A standard volumetric modulated arc therapy (VMAT) plan had suboptimal dose coverage of the retrocolic metastasis adjacent to the colon, so cone-beam computed tomography (CBCT)-guided online adaptive radiotherapy (ART) was employed to maximize radiation dose to the tumors due to the radioresistant histology. An intensity-modulated radiotherapy (IMRT) plan was created using artificial intelligence tools integrated with the treatment unit. Median contouring and plan creation for each fraction was 21.5 minutes (range 14.9-28.1). For the retrocolic metastasis, compared to the standard VMAT plan, the CBCT-guided online ART plan improved coverage of the gross target volume by the prescription dose from 80.0% to 99.7%. SABR to pericolonic soft tissue metastases was feasible using CBCT-guided online ART and can significantly improve target volume coverage when targets are adjacent to mobile normal organs, which may be particularly important for radioresistant histologies for local control.

PURPOSE:Deep learning-based auto-segmentation algorithms can improve clinical workflow by defining accurate regions of interest while reducing manual labor. Over the past decade, convolutional neural networks (CNNs) have become prominent in medical image segmentation applications. However, CNNs have limitations in learning long-range spatial dependencies due to the locality of the convolutional layers. Transformers were introduced to address this challenge. In transformers with self-attention mechanism, even the first layer of information processing makes connections between distant image locations. Our paper presents a novel framework that bridges these two unique techniques, CNNs and transformers, to segment the gross tumor volume (GTV) accurately and efficiently in computed tomography (CT) images of non-small cell-lung cancer (NSCLC) patients.METHODS:Under this framework, input of multiple resolution images was used with multi-depth backbones to retain the benefits of high-resolution and low-resolution images in the deep learning architecture. Furthermore, a deformable transformer was utilized to learn the long-range dependency on the extracted features. To reduce computational complexity and to efficiently process multi-scale, multi-depth, high-resolution 3D images, this transformer pays attention to small key positions, which were identified by a self-attention mechanism. We evaluated the performance of the proposed framework on a NSCLC dataset which contains 563 training images and 113 test images. Our novel deep learning algorithm was benchmarked against five other similar deep learning models.RESULTS:The experimental results indicate that our proposed framework outperforms other CNN-based, transformer-based, and hybrid methods in terms of Dice score (0.92) and Hausdorff Distance (1.33). Therefore, our proposed model could potentially improve the efficiency of auto-segmentation of early-stage NSCLC during the clinical workflow. This type of framework may potentially facilitate online adaptive radiotherapy, where an efficient auto-segmentation workflow is required.CONCLUSIONS:Our deep learning framework, based on CNN and transformer, performs auto-segmentation efficiently and could potentially assist clinical radiotherapy workflow.

Objective. To develop and benchmark a novel 3D dose verification technique consisting of polymer gel dosimetry (PGD) with cone-beam-CT (CBCT) readout through a two-institution study. The technique has potential for wide and robust applicability through reliance on CBCT readout. Approach. Three treatment plans (3-field, TG119-C-shape spine, 4-target SRS) were created by two independent institutions (Institutions A and B). A Varian Truebeam linear accelerator was used to deliver the plans to NIPAM polymer gel dosimeters produced at both institutions using an identical approach. For readout, a slow CBCT scan mode was used to acquire pre- and post-irradiation images of the gel (1 mm slice thickness). Independent gel analysis tools were used to process the PGD images (A: VistaAce software, B: in-house MATLAB code). Comparing planned and measured doses, the analysis involved a combination of 1D line profiles, 2D contour plots, and 3D global gamma maps (criteria ranging between 2%1 mm and 5%2 mm, with a 10% dose threshold). Main results. For all gamma criteria tested, the 3D gamma pass rates were all above 90% for 3-field and 88% for the SRS plan. For the C-shape spine plan, we benchmarked our 2% 2 mm result against previously published work using film analysis (93.4%). For 2%2 mm, 99.4% (Institution A data), and 89.7% (Institution B data) were obtained based on VistaAce software analysis, 83.7% (Institution A data), and 82.9% (Institution B data) based on MATLAB. Significance. The benchmark data demonstrate that when two institutions follow the same rigorous procedures gamma passing rates up to 99%, for 2%2 mm criteria can be achieved for substantively different treatment plans. The use of different software and calibration techniques may have contributed to the variation in the 3D gamma results. By sharing the data across institutions, we observe the gamma passing rate is more consistent within each pipeline, indicating the need for standardized analysis methods.

Background and Purpose: Stereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). Methods: This single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. The protocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. Results: 549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86-0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93-0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69-0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and 'other' (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. Conclusion: PTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning. (c) 2023 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 183 (2023) 1-8

•There are limited studies on the long-term quality of life (QoL) impact of SABR treatment to oligometastatic sites.•This was an analysis of longitudinal patient-reported QoL of the phase II SABR-5 trial using treatment site-specific tools.•Transient declines in QoL were observed, but most patients reported stable QoL on long-term follow-up.•Future clinical trials may incorporate treatment site-specific QoL measures to assess QoL in this patient population.•Further studies are needed to determine the predictors of QoL decline in the oligometastatic setting.

3D polymer gel dosimetry is a promising means to verify complex radiation treatments such as stereotactic radiosurgery (SRS), as it provides both 3D dosimetric and spatial information. The purpose of the study is to use a polymer gel read-out with cone-beam computed tomography (CBCT) to commission Varian’s HyperArc ® -treatment planning and delivery. Three targets (3 cm, 2 cm, 1 cm diameter respectively) were defined on a treatment plan with a maximum dose of 25 Gy, resembling a single isocentre, multiple-lesion SRS plan. Pre- and post-irradiation CBCT images of the gel were obtained for dosimetry analysis. One slice containing two large targets was used to self-calibrate the entire gel volume for dose comparison. We were able to achieve sub-millimeter spatial accuracy and all evaluated gamma criterion (5% 1mm, 3% 1mm, 2% 1 mm were > 95%). In summary, in this study we have demonstrated that CBCT polymer gel dosimetry can be a highly valuable tool for commissioning complex radiation treatment techniques such as SRS.