Intrafractional motion detection for spine SBRT via X-ray imaging using ExacTrac Dynamic.

Purpose: Due to its close vicinity to critical structures, especially the spinal cord, standards for safety for spine stereotactic body radiotherapy (SBRT) should be high. This study was conducted, to evaluate intrafractional motion during spine SBRT for patients without individualized immobilization (e.g., vacuum cushions) using high accuracy patient monitoring via orthogonal X-ray imaging. Methods: Intrafractional X-ray data were collected from 29 patients receiving 79 fractions of spine SBRT. No individualized immobilization devices were used during the treatment. Intrafractional motion was monitored using the ExacTrac Dynamic (ETD) System (Brainlab AG, Munich, Germany). Deviations were detected in six degrees of freedom (6 DOF). Tolerances for repositioning were 0.7 mm for translational and 0.5° for rotational deviations. Patients were repositioned when the tolerance levels were exceeded. Results: Out of the 925 pairs of stereoscopic X-ray images examined, 138 (15 %) showed at least one deviation exceeding the predefined tolerance values. In all 6 DOF together, a total of 191 deviations out of tolerance were recorded. The frequency of deviations exceeding the tolerance levels varied among patients but occurred in all but one patient. Deviations out of tolerance could be seen in all 6 DOF. Maximum translational deviations were 2.6 mm, 2.3 mm and 2.8 mm in the lateral, longitudinal and vertical direction. Maximum rotational deviations were 1.8°, 2.6° and 1.6° for pitch, roll and yaw, respectively. Translational deviations were more frequent than rotational ones, and frequency and magnitude of deviations showed an inverse correlation. Conclusion: Intrafractional motion detection and patient repositioning during spine SBRT using X-ray imaging via the ETD System can lead to improved safety during the application of high BED in critical locations. When using intrafractional imaging with low thresholds for re-positioning individualized immobilization devices (e.g. vacuum cushions) may be omitted.

Impact of daily plan adaptation on accumulated doses in ultra-hypofractionated magnetic resonance-guided radiation therapy of prostate cancer.

Background and purpose: Ultra-hypofractionated online adaptive magnetic resonance-guided radiotherapy (MRgRT) is promising for prostate cancer. However, the impact of online adaptation on target coverage and organ-at-risk (OAR) sparing at the level of accumulated dose has not yet been reported. Using deformable image registration (DIR)-based accumulation, we compared the delivered adapted dose with the simulated non-adapted dose. Materials and methods: Twenty-three prostate cancer patients treated at two clinics with 0.35 T magnetic resonance-guided linear accelerator (MR-linac) following the same treatment protocol (5 × 7.5 Gy with urethral sparing and daily adaptation) were included. The fraction MR images were deformably registered to the planning MR image. Both non-adapted and adapted fraction doses were accumulated with the corresponding vector fields. Two DIR approaches were implemented. PTV* (planning target volume minus urethra+2mm) D95%, CTV* (clinical target volume minus urethra) D98%, and OARs (urethra+2mm, bladder, and rectum) D0.2cc, were evaluated. Statistical significance was inferred from a two-tailed Wilcoxon signed-rank test (p < 0.05). Results: Normalized to the baseline, the accumulated PTV* D95% increased significantly by 2.7 % ([1.5, 4.3]%) through adaptation, and the CTV* D98% by 1.2 % ([0.1, 1.7]%). For the OARs after adaptation, accumulated bladder D0.2cc decreased by 0.4 % ([-1.2, 0.4]%), urethra+2mmD0.2cc by 0.8 % ([-1.6, -0.1]%), while rectum D0.2cc increased by 2.6 % ([1.2, 4.9]%). For all patients, rectum D0.2cc was still below the clinical constraint. Results of both DIR approaches differed on average by less than 0.2 %. Conclusions: Online adaptation in MRgRT improved target coverage and OARs sparing at the level of accumulated dose.

The role of online MR-guided multi-fraction stereotactic ablative radiotherapy in lung tumours.

Background: The aim of this prospective observational study was to evaluate the dosimetry benefits, changes in pulmonary function, and clinical outcome of online adaptive MR-guided SBRT. Methods: From 11/2020-07/2022, 45 consecutive patients with 59 lesions underwent multi-fraction SBRT (3-8 fractions) at our institution. Patients were eligible if they had biopsy-proven NSCLC or lung cancer/metastases diagnosed via clinical imaging. Endpoints were local control (LC) and overall survival (OS). We evaluated PTV/GTV dose coverage, organs at risk exposure, and changes in pulmonary function (PF). Acute toxicity was classified per the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: The median PTV was 14.4 cm3 (range: 3.4 - 96.5 cm3). In total 195/215 (91%) plans were reoptimised. In the reoptimised vs. predicted plans, PTV coverage by the prescribed dose increased in 94.6% of all fractions with a median increase in PTV VPD of 5.6% (range: -1.8 - 44.6%, p < 0.001), increasing the number of fractions with PTV VPD ≥ 95% from 33% to 98%. The PTV D95% and D98% (BED10) increased in 93% and 95% of all fractions with a median increase of 7.7% (p < 0.001) and 10.6% (p < 0.001). The PTV D95% (BED10) increased by a mean of 9.6 Gy (SD: 10.3 Gy, p < 0.001). At a median follow-up of 21.4 months (95% CI: 12.3-27.0 months), 1- and 2-year LC rates were 94.8% (95% CI: 87.6 - 100.0%) and 91.1% (95% CI: 81.3 - 100%); 1- and 2-year OS rates were 85.6% (95% CI: 75.0 - 96.3%) and 67.1 % (95% CI: 50.3 - 83.8%). One grade ≥ 3 toxicity and no significant reduction in short-term PF parameters were recorded. Conclusions: Online adaptive MR-guided SBRT is an effective, safe and generally well tolerated treatment option for lung tumours achieving encouraging local control rates with significantly improved target volume coverage.

Repeatability quantification of brain diffusion-weighted imaging for future clinical implementation at a low-field MR-linac.

BACKGROUND: Longitudinal assessments of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) during intracranial radiotherapy at magnetic resonance imaging-guided linear accelerators (MR-linacs) could enable early response assessment by tracking tumor diffusivity changes. However, DWI pulse sequences are currently unavailable in clinical practice at low-field MR-linacs. Quantifying the in vivo repeatability of ADC measurements is a crucial step towards clinical implementation of DWI sequences but has not yet been reported on for low-field MR-linacs. This study assessed ADC measurement repeatability in a phantom and in vivo at a 0.35 T MR-linac. METHODS: Eleven volunteers and a diffusion phantom were imaged on a 0.35 T MR-linac. Two echo-planar imaging DWI sequence variants, emphasizing high spatial resolution ("highRes") and signal-to-noise ratio ("highSNR"), were investigated. A test-retest study with an intermediate outside-scanner-break was performed to assess repeatability in the phantom and volunteers' brains. Mean ADCs within phantom vials, cerebrospinal fluid (CSF), and four brain tissue regions were compared to literature values. Absolute relative differences of mean ADCs in pre- and post-break scans were calculated for the diffusion phantom, and repeatability coefficients (RC) and relative RC (relRC) with 95% confidence intervals were determined for each region-of-interest (ROI) in volunteers. RESULTS: Both DWI sequence variants demonstrated high repeatability, with absolute relative deviations below 1% for water, dimethyl sulfoxide, and polyethylene glycol in the diffusion phantom. RelRCs were 7% [5%, 12%] (CSF; highRes), 12% [9%, 22%] (CSF; highSNR), 9% [8%, 12%] (brain tissue ROIs; highRes), and 6% [5%, 7%] (brain tissue ROIs; highSNR), respectively. ADCs measured with the highSNR variant were consistent with literature values for volunteers, while smaller mean values were measured for the diffusion phantom. Conversely, the highRes variant underestimated ADCs compared to literature values, indicating systematic deviations. CONCLUSIONS: High repeatability of ADC measurements in a diffusion phantom and volunteers' brains were measured at a low-field MR-linac. The highSNR variant outperformed the highRes variant in accuracy and repeatability, at the expense of an approximately doubled voxel volume. The observed high in vivo repeatability confirms the potential utility of DWI at low-field MR-linacs for early treatment response assessment.

Factors influencing local control after MR-guided stereotactic body radiotherapy (MRgSBRT) for adrenal metastases.

Purpose: Stereotactic body radiotherapy (SBRT) is an effective treatment for adrenal gland metastases, but it is technically challenging and there are concerns about toxicity. We performed a multi-institutional pooled retrospective analysis to study clinical outcomes and toxicities after MR-guided SBRT (MRgSBRT) using for adrenal gland metastases. Methods and Materials: Clinical and dosimetric data of patients treated with MRgSBRT on a 0.35 T MR-Linac at 11 institutions between 2016 and 2022 were analyzed. Local control (LC), local progression-free survival (LPFS), distant progression-free survival (DPFS) and overall survival (OS) were estimated using Kaplan-Meier method and log-rank test. Results: A total of 255 patients (269 adrenal metastases) were included. Metastatic pattern was solitary in 25.9 % and oligometastatic in 58.0 % of patients. Median total dose was 45 Gy (range, 16-60 Gy) in a median of 5 fractions, and the median BED10 was 100 Gy (range, 37.5-132.0 Gy). Adaptation was done in 87.4 % of delivered fractions based on the individual clinicians' judgement. The 1- and 2- year LPFS rates were 94.0 % (95 % CI: 90.7-97.3 %) and 88.3 % (95 % CI: 82.4-94.2 %), respectively and only 2 patients (0.8 %) experienced grade 3 + toxicity. No local recurrences were observed after treatment to a total dose of BED10 > 100 Gy, with single fraction or fractional dose of > 10 Gy. Conclusions: This is a large retrospective multi-institutional study to evaluate the treatment outcomes and toxicities with MRgSBRT in over 250 patients, demonstrating the need for frequent adaptation in 87.4 % of delivered fractions to achieve a 1- year LPFS rate of 94 % and less than 1 % rate of grade 3 + toxicity. Outcomes analysis in 269 adrenal lesions revealed improved outcomes with delivery of a BED10 > 100 Gy, use of single fraction SBRT and with fraction doses > 10 Gy, providing benchmarks for future clinical trials.

DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.

PURPOSE: The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. MATERIALS AND METHODS: For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). CONCLUSION AND RECOMMENDATIONS: Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

CT-guided high dose rate brachytherapy can induce multiple systemic proteins of proliferation and angiogenesis predicting outcome in HCC.

BACKGROUND AND PURPOSE: To determine the potential prognostic value of proliferation and angiogenesis plasma proteins following CT-guided high dose rate brachytherapy (HDR-BT) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: For this prospective study, HDR-BT (1 × 15 Gy) was administered to 24 HCC patients. Plasma was obtained and analyzed using an Olink proteomics Target-96 immuno-oncology-panel that included multiple markers of angiogenesis and proliferation. Fold-change (FC) ratios were calculated by comparing baseline and 48 h post HDR-BT paired samples. Patients were classified as responders (n = 12) if they had no local progression within 6 months or systemic progression within 2 years. Non-responders (n = 12) had recurrence within 6 months and/or tumor progression or extrahepatic disease within 2 years. RESULTS: Proliferation marker EGF was significantly elevated in non-responders compared to responders (p = 0.0410) while FGF-2, HGF, and PlGF showed no significant differences. Angiogenesis markers Angiopoietin-1 and PDGF-B were likewise significantly elevated in non-responders compared to responders (p = 0.0171, p = 0.0462, respectively) while Angiopoietin-2, VEGF-A, and VEGFR-2 did not differ significantly. Kaplan-Meier analyses demonstrated significantly shorter time to systemic progression in patients with increased EGF and Angiopoietin-1 (p = 0.0185, both), but not in patients with one of the remaining proteins elevated (all p > 0.1). Pooled analysis for these 9 proteins showed significantly shorter time to systemic progression for FC ≥1.3 and ≥1.5 for at least 3 proteins elevated (p = 0.0415, p = 0.0193, respectively). CONCLUSION: Increased plasma levels of EGF and Angiopoietin-1 after HDR-BT for HCC are associated with poor response and may therefore function as predictive biomarkers of outcome.

Auto-segmentation of pelvic organs at risk on 0.35T MRI using 2D and 3D Generative Adversarial Network models.

PURPOSE: Manual recontouring of targets and Organs At Risk (OARs) is a time-consuming and operator-dependent task. We explored the potential of Generative Adversarial Networks (GAN) to auto-segment the rectum, bladder and femoral heads on 0.35T MRIs to accelerate the online MRI-guided-Radiotherapy (MRIgRT) workflow. METHODS: 3D planning MRIs from 60 prostate cancer patients treated with 0.35T MR-Linac were collected. A 3D GAN architecture and its equivalent 2D version were trained, validated and tested on 40, 10 and 10 patients respectively. The volumetric Dice Similarity Coefficient (DSC) and 95th percentile Hausdorff Distance (HD95th) were computed against expert drawn ground-truth delineations. The networks were also validated on an independent external dataset of 16 patients. RESULTS: In the internal test set, the 3D and 2D GANs showed DSC/HD95th of 0.83/9.72 mm and 0.81/10.65 mm for the rectum, 0.92/5.91 mm and 0.85/15.72 mm for the bladder, and 0.94/3.62 mm and 0.90/9.49 mm for the femoral heads. In the external test set, the performance was 0.74/31.13 mm and 0.72/25.07 mm for the rectum, 0.92/9.46 mm and 0.88/11.28 mm for the bladder, and 0.89/7.00 mm and 0.88/10.06 mm for the femoral heads. The 3D and 2D GANs required on average 1.44 s and 6.59 s respectively to generate the OARs' volumetric segmentation for a single patient. CONCLUSIONS: The proposed 3D GAN auto-segments pelvic OARs with high accuracy on 0.35T, in both the internal and the external test sets, outperforming its 2D equivalent in both segmentation robustness and volume generation time.

Stereotactic body radiotherapy for pancreatic cancer - A systematic review of prospective data.

Purpose: This systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT). Methods: Following PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies. Results and conclusion: 31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.

Reduction of cone-beam CT artifacts in a robotic CBCT device using saddle trajectories with integrated infrared tracking.

BACKGROUND: Cone beam computed tomography (CBCT) is widely used in many medical fields. However, conventional CBCT circular scans suffer from cone beam (CB) artifacts that limit the quality and reliability of the reconstructed images due to incomplete data. PURPOSE: Saddle trajectories in theory might be able to improve the CBCT image quality by providing a larger region with complete data. Therefore, we investigated the feasibility and performance of saddle trajectory CBCT scans and compared them to circular trajectory scans. METHODS: We performed circular and saddle trajectory scans using a novel robotic CBCT scanner (Mobile ImagingRing (IRm); medPhoton, Salzburg, Austria). For the saddle trajectory, the gantry executed yaw motion up to ± 10 ∘ $\pm 10^{\circ }$ using motorized wheels driving on the floor. An infrared (IR) tracking device with reflective markers was used for online geometric calibration correction (mainly floor unevenness). All images were reconstructed using penalized least-squares minimization with the conjugate gradient algorithm from RTK with 0.5 × 0.5 × 0.5 mm 3 $0.5 \times 0.5\times 0.5 \text{ mm}^3$ voxel size. A disk phantom and an Alderson phantom were scanned to assess the image quality. Results were correlated with the local incompleteness value represented by tan ( ψ ) $\tan (\psi)$ , which was calculated at each voxel as a function of the source trajectory and the voxel's 3D coordinates. We assessed the magnitude of CB artifacts using the full width half maximum (FWHM) of each disk profile in the axial center of the reconstructed images. Spatial resolution was also quantified by the modulation transfer function at 10% (MTF10). RESULTS: When using the saddle trajectory, the region without CB artifacts was increased from 43 to 190 mm in the SI direction compared to the circular trajectory. This region coincided with low values for tan ( ψ ) $\tan (\psi)$ . When tan ( ψ ) $\tan (\psi)$ was larger than 0.02, we found there was a linear relationship between the FWHM and tan ( ψ ) $\tan (\psi)$ . For the saddle, IR tracking allowed the increase of MTF10 from 0.37 to 0.98 lp/mm. CONCLUSIONS: We achieved saddle trajectory CBCT scans with a novel CBCT system combined with IR tracking. The results show that the saddle trajectory provides a larger region with reliable reconstruction compared to the circular trajectory. The proposed method can be used to evaluate other non-circular trajectories.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12).

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCPex was a median of 1.77 (range 1.60-1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Comparison of adverse events in partial- or whole breast radiotherapy: investigation of cosmesis, toxicities and quality of life in a meta-analysis of randomized trials.

PURPOSE/OBJECTIVE: Adjuvant whole breast radiotherapy and systemic therapy are part of the current evidence-based treatment protocols for early breast cancer, after breast-conserving surgery. Numerous randomized trials have investigated the therapeutic effects of partial breast irradiation (PBI) compared to whole breast irradiation (WBI), limiting the treated breast tissue. These trials were designed to achieve equal control of the disease with possible reduction in adverse events, improvements in cosmesis and quality of life (QoL). In this meta-analysis, we aimed to investigate the differences between PBI and WBI in side effects and QoL. MATERIAL/METHODS: We performed a systematic literature review searching for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was performed using the published event rates and the effect-sizes for available acute and late adverse events. Additionally, we evaluated cosmetic outcomes as well as general and breast-specific QoL using the EORTC QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: Sixteen studies were identified (n = 19,085 patients). PBI was associated with a lower prevalence in any grade 1 + acute toxicity and grade 2 + skin toxicity (OR = 0.12; 95% CI 0.09-0.18; p < 0.001); (OR = 0.16; 95% CI 0.07-0.41; p < 0.001). There was neither a significant difference in late adverse events between the two treatments, nor in any unfavorable cosmetic outcomes, rated by either medical professionals or patients. PBI-technique using EBRT with twice-daily fractionation schedules resulted in worse cosmesis rated by patients (n = 3215; OR = 2.08; 95% CI 1.22-3.54; p = 0.007) compared to WBI. Maximum once-daily EBRT schedules (n = 2071; OR = 0.60; 95% CI 0.45-0.79; p < 0.001) and IORT (p = 0.042) resulted in better cosmetic results grade by medical professionals. Functional- and symptom-based QoL in the C30-scale was not different between PBI and WBI. Breast-specific QoL was superior after PBI in the subdomains of "systemic therapy side effects" as well as "breast-" and "arm symptoms". CONCLUSION: The analysis of multiple randomized trials demonstrate a superiority of PBI in acute toxicity as well breast-specific quality of life, when compared with WBI. Overall, late toxicities and cosmetic results were similar. PBI-technique with a fractionation of twice-daily schedules resulted in worse cosmesis rated by patients.

Prior knowledge based deep learning auto-segmentation in magnetic resonance imaging-guided radiotherapy of prostate cancer.

Background and purpose: Automation is desirable for organ segmentation in radiotherapy. This study compared deep learning methods for auto-segmentation of organs-at-risk (OARs) and clinical target volume (CTV) in prostate cancer patients undergoing fractionated magnetic resonance (MR)-guided adaptive radiation therapy. Models predicting dense displacement fields (DDFMs) between planning and fraction images were compared to patient-specific (PSM) and baseline (BM) segmentation models. Materials and methods: A dataset of 92 patients with planning and fraction MR images (MRIs) from two institutions were used. DDFMs were trained to predict dense displacement fields (DDFs) between the planning and fraction images, which were subsequently used to propagate the planning contours of the bladder, rectum, and CTV to the daily MRI. The training was performed either with true planning-fraction image pairs or with planning images and their counterparts deformed by known DDFs. The BMs were trained on 53 planning images, while to generate PSMs, the BMs were fine-tuned using the planning image of a given single patient. The evaluation included Dice similarity coefficient (DSC), the average (HDavg) and the 95th percentile (HD95) Hausdorff distance (HD). Results: The DDFMs with DSCs for bladder/rectum of 0.76/0.76 performed worse than PSMs (0.91/0.90) and BMs (0.89/0.88). The same trend was observed for HDs. For CTV, DDFM and PSM performed similarly yielding DSCs of 0.87 and 0.84, respectively. Conclusions: DDFMs were found suitable for CTV delineation after rigid alignment. However, for OARs they were outperformed by PSMs, as they predicted only limited deformations even in the presence of substantial anatomical changes.

Experimental comparison of linear regression and LSTM motion prediction models for MLC-tracking on an MRI-linac.

BACKGROUND: Magnetic resonance imaging (MRI)-guided radiotherapy with multileaf collimator (MLC)-tracking is a promising technique for intra-fractional motion management, achieving high dose conformality without prolonging treatment times. To improve beam-target alignment, the geometric error due to system latency should be reduced by using temporal prediction. PURPOSE: To experimentally compare linear regression (LR) and long-short-term memory (LSTM) motion prediction models for MLC-tracking on an MRI-linac using multiple patient-derived traces with different complexities. METHODS: Experiments were performed on a prototype 1.0 T MRI-linac capable of MLC-tracking. A motion phantom was programmed to move a target in superior-inferior (SI) direction according to eight lung cancer patient respiratory motion traces. Target centroid positions were localized from sagittal 2D cine MRIs acquired at 4 Hz using a template matching algorithm. The centroid positions were input to one of four motion prediction models. We used (1) a LSTM network which had been optimized in a previous study on patient data from another cohort (offline LSTM). We also used (2) the same LSTM model as a starting point for continuous re-optimization of its weights during the experiment based on recent motion (offline+online LSTM). Furthermore, we implemented (3) a continuously updated LR model, which was solely based on recent motion (online LR). Finally, we used (4) the last available target centroid without any changes as a baseline (no-predictor). The predictions of the models were used to shift the MLC aperture in real-time. An electronic portal imaging device (EPID) was used to visualize the target and MLC aperture during the experiments. Based on the EPID frames, the root-mean-square error (RMSE) between the target and the MLC aperture positions was used to assess the performance of the different motion predictors. Each combination of motion trace and prediction model was repeated twice to test stability, for a total of 64 experiments. RESULTS: The end-to-end latency of the system was measured to be (389 ± 15) ms and was successfully mitigated by both LR and LSTM models. The offline+online LSTM was found to outperform the other models for all investigated motion traces. It obtained a median RMSE over all traces of (2.8 ± 1.3) mm, compared to the (3.2 ± 1.9) mm of the offline LSTM, the (3.3 ± 1.4) mm of the online LR and the (4.4 ± 2.4) mm when using the no-predictor. According to statistical tests, differences were significant (p-value <0.05) among all models in a pair-wise comparison, but for the offline LSTM and online LR pair. The offline+online LSTM was found to be more reproducible than the offline LSTM and the online LR with a maximum deviation in RMSE between two measurements of 10%. CONCLUSIONS: This study represents the first experimental comparison of different prediction models for MRI-guided MLC-tracking using several patient-derived respiratory motion traces. We have shown that among the investigated models, continuously re-optimized LSTM networks are the most promising to account for the end-to-end system latency in MRI-guided radiotherapy with MLC-tracking.

Concomitant Irradiation to Checkpoint Inhibitor Therapy of Hepatocellular Carcinoma Patients: A Systematic Retrospective, Single-Center Analysis.

INTRODUCTION: Immunotherapy has been established as the standard treatment option for patients with advanced hepatocellular carcinoma (aHCC). Despite the increased efficacy, disease progression occurs in a relevant proportion of patients even after an objective response. Combination concepts with locoregional therapy are currently under investigation for hepatic disease but are also in discussion for the control of distant metastasis. Radiotherapy is a highly effective treatment modality for local tumor control. It is also thought to increase the efficacy of checkpoint inhibition and sensitize distant lesions to the effects of immunotherapy, but may potentially increase adverse effects. In our center, few patients with aHCC treated with immune checkpoint inhibitors (ICIs) received concomitant radiotherapy for symptom or disease control. The aim of this study was to retrospectively analyze adverse effects and efficacy of concomitant radiotherapy in patients with aHCC treated with checkpoint inhibition. METHODS: To this aim, patients who received a combination of ICI and radiotherapy in our institution were retrospectively considered for analysis. The predefined inclusion criterion was radiotherapy after initiated checkpoint inhibition and continuation of ICI therapy for at least 8 weeks. Adverse effects and efficacy measurements were performed according to local standards. RESULTS: The database search of 2016-2021 revealed six consecutive patients fulfilling the predefined criteria for concomitant ICI and radiotherapy. Three patients received high-dose-rate brachytherapy (15 Gy) to treat progredient hepatic lesions. Two patients received stereotactic body radiotherapy (SBRT) (25-30 Gy) for symptom control, and 1 patient received brachytherapy and SBRT to treat metastases. No severe adverse events were reported in the period (<6 months) after concomitant radiotherapy. In 5 out of 6 cases, long-term tumor control could be achieved by this therapeutic combination. CONCLUSION: A good efficacy of concomitant radiotherapy and checkpoint inhibition has been achieved with no safety concerns. Further investigations should evaluate the safety, appropriate clinical context, and efficacy of this promising approach.

Whole Breast Irradiation in Comparison to Endocrine Therapy in Early Stage Breast Cancer-A Direct and Network Meta-Analysis of Published Randomized Trials.

BACKGROUND: Multiple randomized trials have established adjuvant endocrine therapy (ET) and whole breast irradiation (WBI) as the standard approach after breast-conserving surgery (BCS) in early-stage breast cancer. The omission of WBI has been studied in multiple trials and resulted in reduced local control with maintained survival rates and has therefore been adapted as a treatment option in selected patients in several guidelines. Omitting ET instead of WBI might also be a valuable option as both treatments have distinctly different side effect profiles. However, the clinical outcomes of BCS + ET vs. BCS + WBI have not been formally analyzed. METHODS: We performed a systematic literature review searching for randomized trials comparing BCS + ET vs. BCS + WBI in low-risk breast cancer patients with publication dates after 2000. We excluded trials using any form of chemotherapy, regional nodal radiation and mastectomy. The meta-analysis was performed using a two-step process. First, we extracted all available published event rates and the effect sizes for overall and breast-cancer-specific survival (OS, BCSS), local (LR) and regional recurrence, disease-free survival, distant metastases-free interval, contralateral breast cancer, second cancer other than breast cancer and mastectomy-free interval as investigated endpoints and compared them in a network meta-analysis. Second, the published individual patient data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) publications were used to allow a comparison of OS and BCSS. RESULTS: We identified three studies, including a direct comparison of BCS + ET vs. BCS + WBI (n = 1059) and nine studies randomizing overall 7207 patients additionally to BCS only and BCS + WBI + ET resulting in a four-arm comparison. In the network analysis, LR was significantly lower in the BCS + WBI group in comparison with the BCS + ET group (HR = 0.62; CI-95%: 0.42-0.92; p = 0.019). We did not find any differences in OS (HR = 0.93; CI-95%: 0.53-1.62; p = 0.785) and BCSS (OR = 1.04; CI-95%: 0.45-2.41; p = 0.928). Further, we found a lower distant metastasis-free interval, a higher rate of contralateral breast cancer and a reduced mastectomy-free interval in the BCS + WBI-arm. Using the EBCTCG data, OS and BCSS were not significantly different between BCS + ET and BCS + WBI after 10 years (OS: OR = 0.85; CI-95%: 0.59-1.22; p = 0.369) (BCSS: OR = 0.72; CI-95%: 0.38-1.36; p = 0.305). CONCLUSION: Evidence from direct and indirect comparison suggests that BCS + WBI might be an equivalent de-escalation strategy to BCS + ET in low-risk breast cancer. Adverse events and quality of life measures have to be further compared between these approaches.

Simultaneous object detection and segmentation for patient-specific markerless lung tumor tracking in simulated radiographs with deep learning.

BACKGROUND: Real-time tumor tracking is one motion management method to address motion-induced uncertainty. To date, fiducial markers are often required to reliably track lung tumors with X-ray imaging, which carries risks of complications and leads to prolonged treatment time. A markerless tracking approach is thus desirable. Deep learning-based approaches have shown promise for markerless tracking, but systematic evaluation and procedures to investigate applicability in individual cases are missing. Moreover, few efforts have been made to provide bounding box prediction and mask segmentation simultaneously, which could allow either rigid or deformable multi-leaf collimator tracking. PURPOSE: The purpose of this study was to implement a deep learning-based markerless lung tumor tracking model exploiting patient-specific training which outputs both a bounding box and a mask segmentation simultaneously. We also aimed to compare the two kinds of predictions and to implement a specific procedure to understand the feasibility of markerless tracking on individual cases. METHODS: We first trained a Retina U-Net baseline model on digitally reconstructed radiographs (DRRs) generated from a public dataset containing 875 CT scans and corresponding lung nodule annotations. Afterwards, we used an independent cohort of 97 lung patients to develop a patient-specific refinement procedure. In order to determine the optimal hyperparameters for automatic patient-specific training, we selected 13 patients for validation where the baseline model predicted a bounding box on planning CT (PCT)-DRR with intersection over union (IoU) with the ground-truth higher than 0.7. The final test set contained the remaining 84 patients with varying PCT-DRR IoU. For each testing patient, the baseline model was refined on the PCT-DRR to generate a patient-specific model, which was then tested on a separate 10-phase 4DCT-DRR to mimic the intrafraction motion during treatment. A template matching algorithm served as benchmark model. The testing results were evaluated by four metrics: the center of mass (COM) error and the Dice similarity coefficient (DSC) for segmentation masks, and the center of box (COB) error and the DSC for bounding box detections. Performance was compared to the benchmark model including statistical testing for significance. RESULTS: A PCT-DRR IoU value of 0.2 was shown to be the threshold dividing inconsistent (68%) and consistent (100%) success (defined as mean bounding box DSC > 0.6) of PS models on 4DCT-DRRs. Thirty-seven out of the eighty-four testing cases had a PCT-DRR IoU above 0.2. For these 37 cases, the mean COM error was 2.6 mm, the mean segmentation DSC was 0.78, the mean COB error was 2.7 mm, and the mean box DSC was 0.83. Including the validation cases, the model was applicable to 50 out of 97 patients when using the PCT-DRR IoU threshold of 0.2. The inference time per frame was 170 ms. The model outperformed the benchmark model on all metrics, and the comparison was significant (p < 0.001) over the 37 PCT-DRR IoU > 0.2 cases, but not over the undifferentiated 84 testing cases. CONCLUSIONS: The implemented patient-specific refinement approach based on a pre-trained baseline model was shown to be applicable to markerless tumor tracking in simulated radiographs for lung cases.

Principles of oncology taught in a one-week course.

BACKGROUND: Growing challenges in oncology require evolving educational methods and content. International efforts to reform oncology education are underway. Hands-on, interdisciplinary, and compact course formats have shown great effectiveness in the education of medical students. Our aim was to establish a new interdisciplinary one-week course on the principles of oncology using state-of-the-art teaching methods. METHODS: In an initial survey, medical students of LMU Munich were questioned about their current level of knowledge on the principles of oncology. In a second two-stage survey, the increase in knowledge resulting from our recently established interdisciplinary one-week course was determined. RESULTS: The medical students' knowledge of clinically important oncological topics, such as the diagnostic workup and interdisciplinary treatment options, showed a need for improvement. Knowledge of the major oncological entities was also in an expandable state. By attending the one-week course on the principles of oncology, students improved their expertise in all areas of the clinical workup in oncology and had the opportunity to close previous knowledge gaps. In addition, students were able to gain more in-depth clinical knowledge on the most common oncological entities. CONCLUSION: The interdisciplinary one-week course on the principles of oncology proved to be an effective teaching method to expand the knowledge of the future physicians to an appropriate level. With its innovative and interdisciplinary approach, the one-week course could be used as a showcase project for the ongoing development of medical education in Germany.

Deep learning based automatic segmentation of organs-at-risk for 0.35 T MRgRT of lung tumors.

BACKGROUND AND PURPOSE: Magnetic resonance imaging guided radiotherapy (MRgRT) offers treatment plan adaptation to the anatomy of the day. In the current MRgRT workflow, this requires the time consuming and repetitive task of manual delineation of organs-at-risk (OARs), which is also prone to inter- and intra-observer variability. Therefore, deep learning autosegmentation (DLAS) is becoming increasingly attractive. No investigation of its application to OARs in thoracic magnetic resonance images (MRIs) from MRgRT has been done so far. This study aimed to fill this gap. MATERIALS AND METHODS: 122 planning MRIs from patients treated at a 0.35 T MR-Linac were retrospectively collected. Using an 80/19/23 (training/validation/test) split, individual 3D U-Nets for segmentation of the left lung, right lung, heart, aorta, spinal canal and esophagus were trained. These were compared to the clinically used contours based on Dice similarity coefficient (DSC) and Hausdorff distance (HD). They were also graded on their clinical usability by a radiation oncologist. RESULTS: Median DSC was 0.96, 0.96, 0.94, 0.90, 0.88 and 0.78 for left lung, right lung, heart, aorta, spinal canal and esophagus, respectively. Median 95th percentile values of the HD were 3.9, 5.3, 5.8, 3.0, 2.6 and 3.5 mm, respectively. The physician preferred the network generated contours over the clinical contours, deeming 85 out of 129 to not require any correction, 25 immediately usable for treatment planning, 15 requiring minor and 4 requiring major corrections. CONCLUSIONS: We trained 3D U-Nets on clinical MRI planning data which produced accurate delineations in the thoracic region. DLAS contours were preferred over the clinical contours.