Background Treatment options for prostate cancer are limited for patients that have had prior colorectal anastomosis and pelvic radiation. Prior surgery and radiation increase the risk of toxicity from a subsequent course of either modality. Case Presentation A 68-year-old male presented with a cT1cN0M0, Gleason 4+4=8 (ISUP grade group 4) adenocarcinoma of the prostate. He had a prior history of a cT3N1M0 adenocarcinoma of the rectum treated 7 years prior with neoadjuvant chemoradiation with concurrent Xeloda and a laparoscopic low anterior resection (LAR) with a stapled side-to-end descending colon-to-rectal anastomosis and loop ileostomy (ypT3 ypN0). After consideration of this past medical history, he was treated with MRI-guided stereotactic body radiation therapy to the prostate to a dose of 3625 cGy in 5 fractions, with neoadjuvant, concurrent and adjuvant androgen deprivation therapy. Conclusions Re-irradiation using an MRI-guided approach allowed for definitive prostate radiation to be delivered safely and adequately while limiting toxicity. Long term disease control continues to be assessed as the patient continues on hormonal therapy.

PURPOSE:Thoracic stereotactic ablative radiation therapy (SABR) is an effective treatment for lung tumors. We evaluated the association between tumor control and (a) tumor respiratory motion and motion management approach and (b) single-fraction dose metrics in patients treated on a prospective clinical trial. METHODS AND MATERIALS:We evaluated 235 patients with 277 thoracic tumors treated on the iSABR trial. Motion management approaches included motion inclusive (MI, 41%), MI with extreme breaths excluded (13%), expiratory gating (Exp Gating, 24%), and inspiratory breath hold (IBH, 22%). The association between tumor motion, motion management technique, and local recurrence (LR) was evaluated using Fine-Gray Analysis. Among the cohort of patients treated in a single fraction (150 tumors), we performed a tumor control probability analysis for dose to the gross tumor (GTV) and planning treatment volumes. RESULTS:There was no significant difference in LR by tumor motion when dichotomized to <1 cm or ≥1 cm (3-year LR of 5.8% vs 6.3%, P = .98). Similarly, there was no difference in LR between patients treated with MI, MI with extreme breaths excluded, Exp Gating, and IBH with 24-month estimates of 5.5%, 5.9%, 4.7%, and 3.7%, respectively (P = .75). For tumors treated with single-fraction SABR, GTV D68.3% and planning treatment volume D65.3% had the strongest correlation with local control (LC). Tumor control probability analysis demonstrated a statistically significant association with GTV D99.7%, D95%, and D68.3%. Rates of LC at 3 years were greater than 90% with a GTV D68.3% > 29.4 Gy and a GTV D95% > 28.1 Gy. CONCLUSIONS:These findings suggest that motion management techniques including Exp Gating and IBH can adequately control respiratory motion. Furthermore, single-fraction SABR with 25 Gy resulted in high rates of LC for small tumors when using heterogeneous dosimetry, including 29.4 Gy to 68.3% of the GTV and 28.1 Gy to 95% of the GTV.

The first clinical biology-guided radiation therapy system, RefleXion X1, was commissioned for clinical use at our institution. This study evaluates the X1 treatment planning feasibility of complex craniospinal targets for pediatric medulloblastoma patients and compares plan quality to multi-isocenter linac-based Volumetric Modulated Arc Therapy (VMAT) plans. Five pediatric patients treated with multi-isocenter VMAT craniospinal irradiation (CSI) were selected for this retrospective study. All planning target volumes (PTVs) had a craniocaudal length < 50 cm and received 36 Gy in 20 fractions. The target volumes and organs-at-risk (OARs) used for VMAT plans were utilized to generate plans using RefleXion X1. PTV D2%, OARs Dmean and Dmax, and treatment times were collected for analysis. A paired-sample t-test was performed to detect significance at P < 0.05. All 5 X1 CSI plans were successfully generated and deemed clinically acceptable for treatment. PTV D2% was found to be greater for X1 compared with VMAT plans (P = .08). For the X1 plans, the Dmean to the bowel, cochleas, heart, kidneys, lungs, and oral cavity was not found to be statistically significant (P > .05) compared with VMAT plans. The average treatment beam-on time for X1 plans was 16.7 minutes vs 3.6 minutes for VMAT plans (P < .01). However, the RefleXion X1 platform enables one isocenter treatment and 90-cm-long kilovoltage CT scan, which has the potential to reduce the setup/imaging time, and thus the total treatment time compared with multi-isocenter linac-based VMAT, where the total treatment time of up to 43.5 minutes was observed. Apart from a greater maximum dose to PTV, X1 plans showed comparable dosimetry to multi-isocenter VMAT plans. Although the average beam-on time with X1 was longer, there is a potential for a more streamlined setup and IGRT using a single isocenter plan.

Background/Objectives: The aim of this study was to establish the relationship between target size and the required diagnostic PET maximum standard uptake value (SUVmax) thresholds needed for successful Biology-guided Radiotherapy (BgRT) delivery on RefleXion X1 PET-linac. The current clinical eligibility recommendation is an SUVmax ≥ 6 at simulation, but the RefleXion system subsequently evaluates Activity Concentration (AC), which must exceed 5 kBq/mL for successful BgRT planning. Methods: A custom 3D-printed phantom containing six spherical targets (8 to 20 mm diameter) was used with varying target-to-background ratios (5:1 to 20:1) of 18F-FDG to systematically achieve a range of SUVmax values for each target size. Images were acquired on Siemens Biograph mCT for SUVmax quantification and RefleXion X1 for AC measurements. Twenty-four BgRT plans were evaluated, and delivery accuracy was validated using ArcCHECK. Additionally, retrospective data from 18 patients across four institutions were analyzed to validate the phantom-derived findings. Results: The PET-linac successfully planned treatments for 13/24 experiments, all achieving an AC > 5 kBq/mL. SUVmax requirements varied by target size: 16–20 mm targets required an SUVmax > 6, consistent with current recommendations, while smaller targets required higher thresholds (e.g., 13 mm: SUVmax > 10, and 11 mm: SUVmax > 15). 8 and 9 mm targets failed to meet AC requirements even at SUVmax 14. Successful deliveries maintained acceptable accuracy, with gamma passing rates of 92.4% ± 5.0% (3%/2 mm) and 97.6% ± 1.9% (3%/3 mm). Analysis revealed that Volume (cc) × SUVmax > 11 consistently predicted successful BgRT planning across all target sizes. This threshold was validated using multi-institutional PET-CT patient data (mean: 11.36, 95% CI: 9.1–12.9), correctly predicting treatment eligibility in 15 of 18 cases. Conclusions: Target size significantly influences BgRT eligibility. We derived a new criterion, Volume(cc) × SUVmax > 11 (95% CI: 9.1–12).

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide (VIP) neuropeptide family and plays a role in the regulation of several releasing hormones and tropic hormones. The hypothalamic-pituitary-gonadal (HPG) axis governs the synthesis and the release of sex hormones and the gametogenesis in all mammals. While the effects of PACAP on fertility is well-documented in females, much less data are available in males. The aim of our study was to examine potential structural and expressional changes in the hypothalamus that might underlie the fertility deficits observed in male PACAP knockout (KO) mice. To this end, we performed immunofluorescent, immunohistochemical and RNAscope in situ hybridization stainings to detect the protein and/or mRNA expression of gonadotropin-releasing hormone (GnRH), kisspeptin, estrogen receptor alpha (ERα) and androgen receptor (AR) in the hypothalamus. Our results revealed that the number and immunoreactivity of GnRH neurons were lower in the medial preoptic area (MPOA) in PACAP KO mice. In contrast, the number of kisspeptin neurons was higher in the rostral periventricular region of the third ventricle (RP3V) and the mid arcuate nucleus (ARC). Furthermore, higher number of Esr1-positive cells was found in the kisspeptin-rich RP3V and the ARC. Notably, less AR-positive cells, and more ERα-positive cells were detected in the MPOA demonstrating a possible misbalance between estrogenic and androgenic signaling. Our results suggest that neuroendocrine changes induced by PACAP deficiency in the hypothalamus might contribute to the development of reproductive dysfunction in PACAP-deficient males by disrupting normal HPG axis function.

BACKGROUND AND PURPOSE:Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk. MATERIALS AND METHODS:This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting. RESULTS:There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall. CONCLUSION:For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

BACKGROUND:Biology-guided radiotherapy (BgRT) is a novel radiotherapy delivery technique that utilizes the tumor itself to guide dynamic delivery of treatment dose to the tumor. The RefleXion X1 system is the first radiotherapy system developed to deliver SCINTIX® BgRT. The X1 is characterized by its split arc design, employing two 90-degree positron emission tomography (PET) arcs to guide therapeutic radiation beams in real time, currently cleared by FDA to treat bone and lung tumors.PURPOSE:This study aims to comprehensively evaluate the capabilities of the SCINTIX radiotherapy delivery system by evaluating its sensitivity to changes in PET contrast, its adaptability in the context of patient motion, and its performance across a spectrum of prescription doses.METHODS:A series of experimental scenarios, both static and dynamic, were designed to assess the SCINTIX BgRT system's performance, including an end-to-end test. These experiments involved a range of factors, including changes in PET contrast, motion, and prescription doses. Measurements were performed using a custom-made ArcCHECK insert which included a 2.2 cm spherical target and a c-shape structure that can be filled with a PET tracer with varying concentrations. Sinusoidal and cosine4 motion patterns, simulating patient breathing, was used to test the SCINTIX system's ability to deliver BgRT during motion-induced challenges. Each experiment was evaluated against specific metrics, including Activity Concentration (AC), Normalized Target Signal (NTS), and Biology Tracking Zone (BTZ) bounded dose-volume histogram (bDVH) pass rates. The accuracy of the delivered BgRT doses on ArcCHECK and EBT-XD film were evaluated using gamma 3%/2 mm and 3%/3 mm analysis.RESULTS:In static scenarios, the X1 system consistently demonstrated precision and robustness in SCINTIX dose delivery. The end-to-end delivery to the spherical target yielded good results, with AC and NTS values surpassing the critical thresholds of 5 kBq/mL and 2, respectively. Furthermore, bDVH analysis consistently confirmed 100% pass rates. These results were reaffirmed in scenarios involving changes in PET contrast, emphasizing the system's ability to adapt to varying PET avidities. Gamma analysis with 3%/2 mm (10% dose threshold) criteria consistently achieved pass rates > 91.5% for the static tests. In dynamic SCINTIX delivery scenarios, the X1 system exhibited adaptability under conditions of motion. Sinusoidal and cosine4 motion patterns resulted in 3%/3 mm gamma pass rates > 87%. Moreover, the comparison with gated stereotactic body radiotherapy (SBRT) delivery on a conventional c-arm Linac resulted in 93.9% gamma pass rates and used as comparison to evaluate the interplay effect. The 1 cm step shift tests showed low overall gamma pass rates of 60.3% in ArcCHECK measurements, while the doses in the PTV agreed with the plan with 99.9% for 3%/3 mm measured with film.CONCLUSIONS:The comprehensive evaluation of the X1 radiotherapy delivery system for SCINTIX BgRT demonstrated good agreement for the static tests. The system consistently achieved critical metrics and delivered the BgRT doses per plan. The motion tests demonstrated its ability to co-localize the dose where the PET signal is and deliver acceptable BgRT dose distributions.

Purpose: The aim of this study was to present the first -year experience of treating patients using intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) with a biology -guided radiation therapy machine, the RefleXion X1 system, installed in a clinical setting. Methods and Materials: A total of 78 patients were treated on the X1 system using IMRT and SBRT from May 2021 to May 2022. Clinical and technical data including treatment sites, number of pretreatment kilovoltage computed tomography (kVCT) scans, beamon time, patient setup time, and imaging time were collected and analyzed. Machine quality assurance (QA) results, machine performance, and user satisfactory survey were also collected and reported. Results: The most commonly treated site was the head and neck (63%), followed by the pelvis (23%), abdomen (8%), and thorax (6%). Except for 5 patients (6%) who received SBRT treatments for bony metastases in the pelvis, all treatments were conventionally fractionated IMRT. The number of kVCT scans per fraction was 1.2 +/- 0.5 (mean +/- standard deviation). The beam -on time was 9.2 +/- 3.5 minutes. The patient setup time and imaging time per kVCT was 4.8 +/- 2.6 minutes and 4.6 +/- 1.5 minutes, respectively. The daily machine output deviation was 0.4 +/- 1.2% from the baseline. The patient QA had a passing rate of 97.4 +/- 2.8% at 3%/2 mm gamma criteria. The machine uptime was 92% of the total treatment time. The daily QA and kVCT image quality received the highest level of satisfaction. The treatment workflow for therapists received the lowest level of satisfaction. Conclusions: One year after the installation, 78 patients were successfully treated with the X1 system using IMRT and/or SBRT. With the recent Food and Drug Administration clearance of biology -guided radiation therapy, our department is preparing to treat patients using positron emission tomography -guidance via a new product release, which will address deficiencies in the current image -guided radiation therapy workflow. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose/Objective(s) BgRT was approved for clinical use and a medical technology company was commissioned for SCINTIX BgRT at our institution. These abstract aims to evaluate the congruence of the measured PET signal during BgRT and the delivered doses for the first two patients treated with BgRT to their lung tumors. Materials/Methods Biology-guided Radiotherapy (BgRT) uses PET emissions from the patient to guide the radiotherapy beam to tumor. During delivery of BgRT, while the PET emissions are collected, they are converted into beamlets and delivered to the patient. At the end of this process, a PET image is reconstructed and the delivered dose is calculated for that fraction. Two patients were treated with SCINTIX™ BgRT at our institution, each receiving 50 Gy/4 fractions to their lung tumors. The GTV is contoured in end-expiration phase of the simulation 4DCT and a 5 mm margin was added to generate PTV. The tumor motion extent was captured using the ITV and a 10 mm margin was added to ITV to generate Biological Tracking Zone (BTZ). For each fraction, the mean PET intensity in GTV was measured and used to threshold the signal to find the centroid of PET biodistribution. The 80% isodose line, corresponding to 10 Gy, was converted to a volume and used to estimate the centroid of the delivered doses. The distance between the PET and 80% dose centroids were used to estimate the congruence of the PET signal and delivered BgRT doses for each fraction. For comparison, the BgRT plans were calculated with a grid size of 2.1 mm, and the PET image acquired had a grid size of 4 mm. Results Both patients were able to complete their course of treatment successfully. For Patient 1, the PET modeling mean PET signal in GTV was 19.5 kBq/ml and it was 22.0, 21.1 18.7 and 18.6 for the 4 fractions. Patient 2 had a PET modeling mean intensity of 18.8 kBq/ml and during the treatments it was 21.0, 14.3, 17.9 and 12.4. A total of eight post-treatment delivered dose volumes were calculated using the fluence patterns delivered by the X1. The mean congruence of the PET and delivered doses for patient 1 was 0.5, 2.0, 0.6 and 1.8 mm whereas the Patient 2 had the delivered doses agree with 1.3, 0.8, 2.7 and 1.4 mm for 4 fractions. From 8 fractions analyzed, the maximum disagreement was 1.0, 2.4 and 1.7 mm in the L/R, A/P and S/I directions. Conclusion The BgRT doses agreed well with the isocenter of the PET, confirming that the medical technology company system delivered doses for both patients where the PET signal was emanating from. Given the pixel size of the dose calculation (2.1 mm) and the PET pixel size (4.0 mm), the measured agreement provide assurance for the geometric accuracy of BgRT delivery in patients.

Purpose/Objective(s) Stereotactic ablative radiation therapy (SABR) leads to excellent local control in patients with primary or metastatic lung tumors. While there are multiple strategies for motion management in thoracic SABR, there is limited data to compare the efficacy of different approaches. We compared local tumor control by the extent of tumor motion and the motion management strategy for patients treated on the iSABR clinical trial. Materials/Methods This is a secondary analysis of patients treated on the multicenter phase II iSABR clinical trial that utilized an individualized dosing strategy for patients with primary or metastatic lung tumors. We evaluated the extent of tumor motion on 4D CT and the motion management approach used during treatment (free breathing, breath hold [BH], or expiratory gating [EG]). For patients treated with free breathing or EG approaches, an internal target volume (ITV) was contoured based on tumor movement on the 4D CT. Patients were treated on a linear accelerator using Real-time Position Management (RPM) triggering. In-field local control rates were compared using the Kaplan-Meier method. Results In total, 62 patients with 63 tumors had available data on motion management. Fifteen patients (24.2%) underwent SABR with free breathing, 22 (35.5%) had BH (20 inspiratory, and 2 expiratory), and 26 (41.9%) had EG (24 amplitude based, and 2 phase based). 1-, and 2-year local control rates were 100% and 100% with free breathing, 94.7% and 83.2% with BH, and 90.7% and 78.6% with EG (p = 0.2), respectively. Overall, median maximal tumor motion was 10mm (3.5mm for tumors treated with free breathing vs 14.5mm for tumors treated with BH or EG). There was no association between local control and maximum extent of motion on 4D CT (HR = 1.01, p = 0.75). 1- and 2-year local control rates were 92.9% and 89.1% for tumors with maximal motion <10mm, and 96.3% and 82.5% for tumors with maximal motion >10mm (HR = 0.6, p = 0.53), respectively. Conclusion Patients on the iSABR trial were treated with a range of motion management strategies including motion inclusive free breathing, BH and EG with no observed association between local control by treatment approach. The similar local control rates between mobile and non-mobile tumors suggests that the RPM approach used on the iSABR trial was effective. Our results will be further analyzed pending motion management data collection for the entire iSABR cohort.

SABR for lung tumors using the individualized protocol on this trial showed excellent LR rates. We identified dosimetric parameters that were associated with LR, including V110% and V115% within the multi-fraction cohort, as well as the 50 Gy in 4 fraction cohort the D1cc, D0.03cc, and proportions of the PTV receiving 110%, 115%, and 120% of the prescription dose in the 50 Gy in 4 fraction cohort. Optimal thresholds for these parameters will be identified in further analyses. There did not appear to be an association with LR and BED10, D99%, or comparing single- vs multi-fraction regimens.

Accounting for LAD dose in treatment planning may help reduce future MACE risks. LAD dose can be significantly reduced without compromising PTV coverage or having significant effects on other OAR dose sparing.