PURPOSE:This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disease control in a very high-risk (VHR) population inadequately represented in prior trials. PATIENTS AND METHODS:This multi-institutional, single-arm, phase 2 trial enrolled patients with VHR localized prostate cancer, defined according to the National Comprehensive Cancer Network as histologically confirmed adenocarcinoma with ≥2 high-risk features: Gleason score 8 to 10, prostate-specific antigen (PSA) ≥20, clinical or radiographic ≥T3, or >4 cores containing Gleason score 8 disease. Patients received 6 months of apalutamide, abiraterone acetate, and leuprolide plus prostate/seminal vesicle-directed ultra-fractionated SBRT. The primary endpoint was 3-year biochemical recurrence (BCR) rate by Phoenix criteria, with a prespecified superiority threshold of <10%. Secondary endpoints included PSA ≥0.2 ng/mL, metastasis-free survival (MFS), and time to testosterone recovery >150 ng/dL. RESULTS:Between August 2016 and December 2022, 63 patients were treated. At 3 years, the Phoenix-defined BCR rate was 19%. BCR-free survival was 84.2% [95% confidence interval (CI), 75.6-93.7] with a median follow-up of 41 months (34-43). The 3-year MFS was 93.6% (95% CI, 87.8%-99.8%), with no deaths observed. The median time to testosterone recovery >150 ng/dL was 6 months (range, 3-24 months). No new safety signals emerged, and the only significant quality-of-life (QOL) decline was in the EPIC sexual subdomain at 12 months. CONCLUSIONS:Treatment intensification with apalutamide, AAP, androgen deprivation therapy, and SBRT was well-tolerated with limited impact on QOL. Although BCR rates exceed the superiority threshold, outcomes aligned with historic benchmarks, supporting further evaluation of the regimen in prospective trials.

Representativeness of Study Participants

PURPOSE:Diffusing alpha-emitters Radiation Therapy ("Alpha DaRT") is a new cancer treatment modality that employs radium-224-loaded metal sources implanted in solid tumors to disperse alpha-emitting atoms within a therapeutic "kill-zone" of a few millimeters around each source. Preclinical studies have demonstrated tumor growth delay in various cancer types, including glioblastoma multiforme, and the method is used in clinical trials for patients with skin and head and neck cancer. This study aims to assess the safety and feasibility of implementing Alpha DaRT for brain tumor treatment in a large animal model. METHODS:Alpha-DaRT sources were delivered via image-guided stereotactic implantation into both hemispheres of eight swine. 1-3 layers of radial deployment of 7 sources were delivered through a single penetration point into each hemisphere. A 90-day follow-up period included clinical evaluation, brain MRI, head CT, blood, CSF, urine, and feces sampling, and an analysis of source location over time. Brain tissue pathology was performed on termination. RESULTS:Alpha-DaRT sources were reproducibly and efficiently delivered to the brain cortex and subcortex. No unexpected abnormalities were detected in blood or CSF samples. MRI and CT scans revealed no evidence of major bleeding or infection. Measurements of 212Pb in blood and CSF exhibited the expected exponential decay from day 7 to day 14 post-source implantation. Minimal spatial and temporal movements of the sources were noted. Histopathological analysis demonstrated locally confined findings in brain parenchyma in a very close proximity to the sources. CONCLUSION:Alpha-DaRT sources can be safely delivered into a large animal brain using image-guided stereotactic implantation. These findings support further exploration of Alpha DaRT as a potential treatment modality for brain tumors.

BACKGROUND AND OBJECTIVE:NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response. METHODS:Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from NRG/RTOG 0521. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS). Treatment effects in luminal proliferating (LP) and non-LP cell subtypes were examined in relation to MFS, OS, and distant metastasis (DM). KEY FINDINGS AND LIMITATIONS:Samples were obtained from 283 patients and yielded 183 GC scores. Over median follow-up of 9.9 yr, 67 metastasis events were observed, including 34 DM events. Multivariable analysis revealed that GC was independently associated with DM (subdistribution hazard ratio 1.45) and MFS (hazard ratio 1.20). No biomarker-by-treatment interaction with GC and docetaxel was detected. The 10-yr restricted mean survival time difference in OS with CT was 13.7 mo for LP (p = 0.053) and 2.5 mo for non-LP (p = 0.63) tumors. CONCLUSIONS AND CLINICAL IMPLICATIONS:The Decipher GC score was independently associated with DM and MFS, and LP tumors may benefit from addition of CT. Validation of these findings may allow more effective use of CT in men with localized PC. The original NRG/RTOG 0521 trial is registered on ClinicalTrials.gov as NCT00288080.

Purpose/Objective(s) The dose to healthy tissue surrounding the tumor in diffusing alpha-emitters radiation therapy (DaRT) was shown in previous works to amount to negligible levels (< 3 Gy) already at a distance of ~4 mm from the outermost sources, where it is dominated by beta and gamma contributions. The aim of this work was to confirm these predictions using thermoluminescent dosimetry (TLD) detectors in the tumor margins. Materials/Methods Twelve subjects from an ongoing clinical trial had a TLD taped to a position approximately 5 mm from a DaRT source following implantation. The TLD was made from crystalline LiF: Mg, Ti, with a 10 uGy detection threshold and a linear dose response to 5 Gy. Following the 15–21-day duration of DaRT treatment, the TLD was removed and sent for dosimetric evaluation. In addition, subjects had a CT performed immediately following the DaRT source implantation, with the location of the TLD indicated with a radiopaque marker. The beta and gamma dose at the marker position was calculated as a superposition of contributions from all sources, based on their coordinates as inferred from the CT. Results The actual distance of TLD from the nearest DaRT source varied between 3.5 to 8.75 mm. In all cases where the TLD was placed greater than 5.5 mm from the nearest source (10 of 12 subjects), the measured dose was less than 0.18 Gy. TLDs placed 5.5 mm and 3.5 mm from the nearest source measured a dose of 0.5 Gy and 2.3 Gy, respectively. In all cases the measurement and calculation were within error (with the measurement smaller than the calculation in 10 of 12 cases), assuming a relative placement error of <1.8 mm. In 10 of 12 cases the measurement and calculation were within error assuming a relative placement error of <1.3 mm. Conclusion Given the magnitude of the measured dose at 5 mm distance from the outermost source, there appears to be no safety concern for use of DaRT even in the rare cases where higher doses than predicted are delivered as all measurements are very low and have no clinical significance.

Abstract Background Adaptive radiation therapy (ART) offers a dynamic approach to address structural and spatial changes that occur during radiotherapy (RT) for locally advanced head and neck cancers. The integration of daily ART with Cone-Beam CT (CBCT) imaging presents a solution to enhance the therapeutic ratio by addressing inter-fractional changes. Methods We evaluated the initial clinical experience of daily ART for patients with head and neck cancer using an online adaptive platform with intelligence-assisted workflows on daily CBCT. Treatment included auto-contour and structure deformation of Organs at Risk (OARs) and target structures, with adjustments by the treating physician. Two plans were generated: one based on the initial CT simulation with the edited structures (scheduled) and a re-optimized plan (adaptive). Both plans were evaluated and the superior one approved and delivered. Clinical and dosimetric outcomes were reviewed. Results Twenty two patients with head and neck cancers (7 Nasopharynx, 6 Oropharynx, 1 oral cavity, 8 larynx) stages I-IVA were treated with daily ART. 770 adaptive and scheduled radiotherapy plans were generated. 703 (91.3%) adaptive plans were chosen. Median time to deliver ART was 20 minutes (range: 18-23). Adaptive compared to scheduled plans demonstrated improved mean V95 values for the PTV70, PTV59.5, and PTV56 by 1.2%, 7.2%, and 6.0% respectively and a mean 1.4% lower maximum dose in PTV70. Fourteen of 17 OARs demonstrated improved dosimetry with adaptation, with select OARs reaching statistical significance. At a median follow up of 14.1 months, local control was 95.5%, two patients developed metastatic disease and four patients died. 9.1% of patients had acute grade 3 dysphagia and 13.6% had grade 2 chronic xerostomia. Discussion These findings provide real world evidence of the feasibility and dosimetric benefit of incorporating daily ART on CBCT in the treatment of head and neck cancer. Prospective study is needed to determine if these dosimetric improvements translate into improved outcomes.

Purpose/Objective(s) The standard treatment for oral cavity squamous cell carcinoma (OSCC) has remained surgery for decades and the accepted approaches are often challenging in older patients. The present research evaluated the efficacy and safety of Diffusing Alpha-Emitter Radiation Therapy (DaRT) as a novel method of treating these solid tumors using alpha-particle interstitial radiotherapy. Materials/Methods Data from patients with OSCC were collected from three prospective clinical trials at multiple medical centers in Israel and Italy. Tumor response was determined by Response Evaluation Criteria in Solid Tumors guidelines (RECIST v1.1). Safety was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Results Twenty-three patients (11 female and 12 male) were treated with DaRT for OSCC across the participating clinical sites. Subjects were elderly, with a mean age of 85 (range 60-102), with 78% having a cardiovascular history and 43% with diabetes. Tumor locations included the lip, tongue and buccal mucosa, with mean baseline tumor volume of 3.1 cubic cm. All procedures were performed under local anesthesia in an outpatient setting. The objective response rate was 100% for the 19 tumors which were evaluated (the remaining cases were withdrawn prior to evaluation due to unrelated serious adverse events, withdrawal of consent or election to proceed with alternative therapy), with 18 (95%) showing a complete response and 1 (5%) a partial response. All related adverse events were Grade 1 or 2. Conclusion All patients tolerated DaRT therapy with 95% complete response rate and favorable safety profile. DaRT has the potential to serve as a treatment for OSCC, particularly in the elderly population.

478 Background: Radiation therapy (RT) is an integral component of the multimodal therapy of pelvic malignancies, either as primary treatment or in combination with surgical resection. In addition to local treatment effects on nearby pelvic organs, RT has been established to be a risk factor for delayed secondary malignancies. In this study, we examine the rate of any secondary malignancies following RT for primary pelvic malignancies, with a specific emphasis on secondary pelvic malignancies Methods: Using the SEER (Surveillance, Epidemiology, and Ends Results) database, we retrospectively examined 2,102,192 patients with primary pelvic malignancies (prostate, bladder, uterine, rectal, cervical). For each disease site, we compared the rate of all secondary malignancies in radiated patients to non-radiated patients. Secondary malignancies were then stratified as pelvic and non-pelvic, in order to determine the local effect of RT on malignancy risk. Results: A total of 2,102,192 patients were examined (1,189,108 prostate, 315,026 bladder, 88,809 cervical, 249,535 uterine, 259,714 rectal). A total of 113,322 patients developed secondary malignancies after RT (Table), with 26,299 developing secondary pelvic malignancies after RT (18,411 prostate, 1,026 bladder, 1,410 cervical, 2,179 uterine, 3,273 rectal) (Table). The overall relative risk (RR) of RT on developing a secondary malignancy was 1.79 (1.77-1.80 CI, P<0.0001), particularly in patients with prostate (RR 2.57), uterine (RR 1.24) and cervical cancer (1.09). The overall RR of RT on developing a secondary pelvic malignancy was 2.09 (2.06-2.13 CI, P<0.0001), particularly in patients with bladder (RR 6.90), prostate (RR 2.74), and uterine cancer (RR 1.21). Conclusions: Radiation treatment for pelvic malignancies increases the risk of developing secondary malignancies over the patient’s lifetime. Further work needs to done to identify at risk populations.[Table: see text]

INTRODUCTION:Prostate Specific Membrane Antigen (PSMA) imaging with Positron Emission Tomography (PET) plays a crucial role in prostate cancer management. However, there is a lack of comprehensive data on how PSMA PET/CT (Computed Tomography) influences radiotherapeutic decisions, particularly in node-positive prostate cancer cases. This study aims to address this gap by evaluating two primary objectives: (1) Mapping the regional and non-regional lymph nodes (LNs) up to the aortic bifurcation and their distribution using conventional methods with CT compared to PSMA PET/CT, and (2) assessing the impact of PSMA PET/CT findings on radiotherapeutic decisions. METHODS:A retrospective analysis of 95 node-positive prostate cancer patients who underwent both CT and PSMA PET/CT imaging prior to primary radiotherapy and androgen deprivation therapy (ADT) was conducted. The analysis focused on identifying LNs in various regions including the common iliac, external iliac, internal iliac, obturator, presacral, mesorectal, inguinal, and other stations. Treatment plans were reviewed for modifications based on PSMA PET/CT findings, and statistical analysis was performed to identify predictors for exclusive nodal positivity on PSMA PET/CT scans. RESULTS:PSMA PET/CT identified additional positive nodes in 48% of cases, resulting in a staging shift from N0 to N1 in 29% of patients. The most frequent metastatic LNs were located in the external iliac (76 LNs; 34%), internal iliac (43 LNs; 19%), and common iliac (35 LNs; 15%) stations. In patients with nodes only detected on PSMA PET the most common nodes were in the external iliac (27, 40%), internal iliac (13, 19%), obturator (11, 15%) stations. Within the subgroup of 28 patients exclusively demonstrating PSMA PET-detected nodes, changes in radiotherapy treatment fields were implemented in 5 cases (18%), and a dose boost was applied for 23 patients (83%). However, no discernible predictors for exclusive nodal positivity on PSMA PET/CT scans emerged from the analysis. DISCUSSION:The study underscores the pivotal role of PSMA PET/CT compared to CT alone in accurately staging node-positive prostate cancer and guiding personalized radiotherapy strategies. The routine integration of PSMA PET/CT into diagnostic protocols is advocated to optimize treatment precision and improve patient outcomes.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2–51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63–87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Purpose Diffusing alpha-emitters radiation therapy (DaRT) is a unique treatment modality for solid tumors capitalizing on Radium-224-loaded (Alpha DaRT) sources designed to disperse alpha-emitting atoms into the tumor tissue. These diffused radioactive atoms create a destructive 'kill-zone' millimeters away from the source, without harming adjacent tissue. This treatment was reported to effectively inhibit tumor growth in various human and murine cancers in pre-clinical testing. Here, the effect of Alpha DaRT was investigated in-vitro and in-vivo using subcutaneous (s.c.) Glioblastoma Multiforme (GBM) tumors in combination with GBM ‘standard of care’ treatments (Temozolomide, TMZ or Bevacizumab, BEV). We also studied the effect of the Alpha DaRT monotherapy in orthotopic GBM tumors. Methods and Materials The effect of alpha radiation with TMZ was evaluated in human U87 cells by cytotoxicity and colony formation assays. VEGF secretion was assessed using ELISA assay. U87 s.c. tumor-bearing mice were treated with Alpha DaRT or inert (non-radioactive) sources in combination with TMZ or BEV, and monitored for efficacy. To assess tumor vasculature, we performed immunohistochemical staining of the vascular marker CD31. Alpha DaRT effective diameter receiving high dose (>10 Gy) was determined by autoradiography. The clearance of radioactive atoms from the tumor was determined by radioactivity measurements of the tumor and source 4 days post implantation compared with the initial activity. Murine GL-261 GBM cells were used for the inoculation of orthotopic GBM, and their growth was monitored using MRI before they were treated with Alpha DaRT or Inert sources. Results The combined treatment of alpha radiation and TMZ doubled the cytotoxic effect compared to the monotherapies. U87 cells treated with the combined treatment showed lower survival fraction than the monotherapies or than x-ray combined with TMZ treatment. U87 s.c. tumor bearing mice treated with Alpha DaRT and TMZ showed increased delay in tumor growth compared to the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion by U87 cells. As expected, BEV administration decreased CD31 staining and when combined with Alpha DaRT, the effective diameter was increased and the clearance of the radioactivity was reduced. In-vivo studies showed that administration of BEV a few days after Alpha DaRT insertion improved tumor control - in comparison to Alpha DaRT or BEV alone. Improved results were obtained in larger tumors when the BEV protocol was initiated before the Alpha DaRT insertion. We were able to establish an orthotopic model of GBM and fabricate a designated Alpha DaRT applicator and source suitable for mice brains. We successfully monitored tumor growth and Alpha DaRT insertion using MRI as well as in-vivo real-time imager. Conclusions Our results demonstrated the feasibility of Alpha DaRT therapy in the mouse brain and suggest that Alpha DaRT in combination with 'standard of care' therapies constitutes a promising approach for the treatment of GBM.

Objective. To examine one academic institution’s experiences with SpaceOAR placement, its associated complications, and periprocedural characteristics that affect outcomes for the purpose of quality improvement. Materials and Methods. We conducted a retrospective review of 233 patients who received SpaceOAR from four surgeons and one radiation oncologist between 2018 and 2021. Variables such as demographics, oncologic parameters, radiation plan, and radiographic assessment of hydrogel placement were recorded. The Charlson Comorbidity Index (CCI) was used to assess comorbidity risk. Mann–Whitney and Fisher’s exact tests were performed to compare patients with and without complications. Results. Of the 233 patients who received SpaceOAR, 24 (10.3%) experienced toxicity. All complications were Clavien I or II, such as pelvic pain postplacement, pelvic fullness, bleeding, and lower urinary tract symptoms. 16 patients (6.9%) had some portion of the hydrogel injected into the rectal wall, but it was never clinically significant. The average CCI was 3.2 ± 0.95 for patients who experienced complications; the average CCI was 3.6 ± 1.6 (p = 0.48) in the group without complications. Of the physicians with higher procedure volumes, Physician #1 had the highest rate of patient‐reported complications at 11 out of 68 (16.2%) and Physician #2 had the lowest rate of complications at 4 out of 96 placements (4.2%). Multivariate analysis found that patients who had received hormone therapy previously had less odds of reporting complications after SpaceOAR placement. Conclusions. The listed attending on the procedure had a significant correlation to complications with SpaceOAR placement on univariate analysis, and hormone therapy had some benefits to the tolerance for the procedure on multivariate analysis. Overall, the hydrogel placement was well tolerated with low incidence of mild and transient procedure‐related toxicity.

<p>Supplemental Figure 3. NFκB is retained in the cytoplasm in the presence of an IκB dominant negative.</p>

Supplementary Table 1 - PDF file 282K, Supplemental table listing primer sequences utilized throughout study

Differential enrichment of a benign prostate specific gene signature.

<p>Supplemental Figure 4. PLK3 expression promotes apoptotic cell death in the setting of RB loss.</p>

<p>Supplemental Methods and Material</p>

Supplementary Figure 1,2 - PDF file 56K, Supplemental data demonstrating that scheduling of IR and ADT treatment does not alter cell survival and DNA damage induces AR mediated gene transcription in a dose dependent fashion