LUNAR: a randomized Phase 2 study of 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (clinical trial protocol).

OBJECTIVE: To assess the efficacy of 177 Lu-PNT2002, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in combination with stereotactic body radiotherapy (SBRT) to all sites of metastasis, vs SBRT alone, in men with oligorecurrent metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: The 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR) trial is an open-label, randomized, stratified, two-arm, single-centre, Phase 2 trial to compare the efficacy and safety of neoadjuvant 177 Lu-PNT2002 plus SBRT vs SBRT alone in men with oligorecurrent mHSPC. Key eligibility criteria include one to five lesions identified on a PSMA positron emission tomography (PET)/computed tomography (CT) scan centrally reviewed by a board-certified nuclear medicine physician. Key exclusion criteria include castrate-resistant disease, de novo oligometastatic disease and receipt of androgen deprivation therapy (ADT) within 6 months of trial enrolment. The trial aims to enrol 100 patients who will be centrally randomized to one of the two treatment arms, in a 1:1 ratio. Patients in the control arm receive SBRT to all sites of disease. Patients in the experimental arm receive two cycles of neoadjuvant 177 Lu-PNT2002 (6.8 GBq) 6-8 weeks apart, followed by an interval PSMA PET/CT in 4-6 weeks and dose-adapted SBRT to all sites of disease 1-2 weeks later. The primary endpoint is progression-free survival. Secondary endpoints are radiographic and prostate-specific antigen-based progression, acute and late physician-scored toxicity, patient-reported quality of life, ADT-free survival, time to progression, overall survival, locoregional control, and duration of response. Enrolment in the study commenced in September 2022. RESULTS AND CONCLUSIONS: The addition of 177 Lu-PNT2002 to metastasis-directed therapy alone may potentially further forestall disease progression. The results of this Phase 2 trial will determine, for the first time in a randomized fashion, the added benefit of 177 Lu-PNT2002 to SBRT in patients with oligorecurrent mHSPC.

Selecting the optimal radiation modality in prostate cancer.

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

BACKGROUND: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. METHODS: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. FINDINGS: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. INTERPRETATION: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. FUNDING: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT. METHODS: Three hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator's discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used. DISCUSSION: The MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020. https://clinicaltrials.gov/ct2/show/NCT04384770 PROTOCOL VERSION: Version 2.1, Aug 28, 2020.

Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin.

The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. SIGNIFICANCE STATEMENT: We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function.

Serine racemase regulated by binding to stargazin and PSD-95: potential N-methyl-D-aspartate-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk.

D-Serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins, postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C terminus. SR also binds to the C terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity. AMPA receptor activation internalizes SR and disrupts its interaction with stargazin, therefore derepressing SR activity, leading to more D-serine production and potentially facilitating NMDA receptor activation. These interactions regulate the enzymatic activity as well as the intracellular localization of SR, potentially coupling the activities of NMDA and AMPA receptors. This shuttling of a neurotransmitter synthesizing enzyme between two receptors appears to be a novel mode of synaptic regulation.

D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase.

d-Serine is an endogenous ligand for NMDARs generated from l-serine by the enzyme serine racemase (Srr). Both neuronal and glial localizations have been reported for d-serine and Srr. 3-Phosphoglycerate dehydrogenase is an exclusively astrocytic enzyme that catalyzes the first committed step of l-serine biosynthesis. Using transgenic mice expressing enhanced green fluorescent protein under the Srr promoter and mice with targeted deletion of Srr or 3-Phosphoglycerate dehydrogenase, we demonstrate predominantly neuronal sources of d-serine dependent on astrocytic supply of l-serine. These findings clarify the cellular basis for the regulation of NMDAR neurotransmission by d-serine.

The expanding role of radiation oncology across the prostate cancer continuum.

Radiotherapy is used in the treatment of prostate cancer in a variety of disease states with significant reliance on imaging to guide clinical decision-making and radiation delivery. In the definitive setting, the choice of radiotherapy treatment modality, dose, and fractionation for localized prostate cancer is determined by the patient's initial risk stratification and other clinical considerations. Radiation is also an option as salvage therapy in patients with locoregionally recurrent disease after prior definitive radiation or surgery. In recent years, the role of radiation has expanded for patients with metastatic disease, including prostate-directed radiotherapy in de novo low volume metastatic disease, metastasis-directed therapy for oligorecurrent disease, and palliative management of symptomatic metastases in the advanced setting. Here we review the expanding role of radiation in the treatment of prostate cancer in the definitive, locoregionally recurrent, and metastatic settings, as well as highlight the role of imaging in clinical reasoning, radiation planning, and treatment delivery.

Dosimetric predictors for genitourinary toxicity in MR-guided stereotactic body radiation therapy (SBRT): Substructure with fraction-wise analysis.

BACKGROUND: MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients. PURPOSE: (1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra. METHODS: Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set. RESULTS: IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance. CONCLUSION: Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation.

Intra-fractional geometric and dose/volume metric variations of magnetic resonance imaging-guided stereotactic radiotherapy of prostate bed after radical prostatectomy.

Background and purpose: Magnetic Resonance Imaging (MRI)-guided Stereotactic body radiotherapy (SBRT) treatment to prostate bed after radical prostatectomy has garnered growing interests. The aim of this study is to evaluate intra-fractional anatomic and dose/volume metric variations for patients receiving this treatment. Materials and methods: Nineteen patients who received 30-34 Gy in 5 fractions on a 0.35T MR-Linac were included. Pre- and post-treatment MRIs were acquired for each fraction (total of 75 fractions). The Clinical Target Volume (CTV), bladder, rectum, and rectal wall were contoured on all images. Volumetric changes, Hausdorff distance, Mean Distance to Agreement (MDA), and Dice similarity coefficient (DSC) for each structure were calculated. Median value and Interquartile range (IQR) were recorded. Changes in target coverage and Organ at Risk (OAR) constraints were compared and evaluated using Wilcoxon rank sum tests at a significant level of 0.05. Results: Bladder had the largest volumetric changes, with a median volume increase of 48.9 % (IQR 28.9-76.8 %) and a median MDA of 5.1 mm (IQR 3.4-7.1 mm). Intra-fractional CTV volume remained stable with a median volume change of 1.2 % (0.0-4.8 %). DSC was 0.97 (IQR 0.94-0.99). For the dose/volume metrics, there were no statistically significant changes observed except for an increase in bladder hotspot and a decrease of bladder V32.5 Gy and mean dose. The CTV V95% changed from 99.9 % (IQR 98.8-100 %) to 99.6 % (IQR 93.9-100 %). Conclusion: Despite intra-fractional variations of OARs, CTV coverage remained stable during MRI-guided SBRT treatments for the prostate bed.

Quantifying Intrafraction Motion and the Impact of Gating for Magnetic Resonance Imaging-Guided Stereotactic Radiation therapy for Prostate Cancer: Analysis of the Magnetic Resonance Imaging Arm From the MIRAGE Phase 3 Randomized Trial.

PURPOSE: Real-time intrafraction tracking/gating is an integral component of magnetic resonance imaging-guided radiation therapy (MRgRT) and may have contributed to the acute toxicity reduction during prostate stereotactic body radiation therapy observed on the MRgRT-arm of the MIRAGE (MAGNETIC RESONANCE IMAGING-GUIDED Stereotactic Body Radiotherapy for Prostate Cancer) randomized trial (NCT04384770). Herein we characterized intrafraction prostate motion and assessed gating effectiveness. METHODS AND MATERIALS: Seventy-nine patients were treated on an MR-LINAC. Real-time cine imaging was acquired at 4Hz in a sagittal plane. If >10% of the prostate area moved outside of a 3-mm gating boundary, an automatic beam hold was initiated. An in-house tool was developed to retrospectively extract gating signal for all patients and identify the tracked prostate in each cine frame for a subgroup of 40 patients. The fraction of time the prostate was within the gating window was defined as the gating duty cycle (GDC). RESULTS: A total of 391 treatments from 79 patients were analyzed. Median GDC was 0.974 (IQR, 0.916-0.983). Fifty (63.2%) and 24 (30.4%) patients had at least 1 fraction with GDC ≤0.9 and GDC ≤0.8, respectively. Incidence of low GDC fractions among patients appeared stochastic. Patients with minimum GDC <0.8 trended toward more frequent grade 2 genitourinary toxicity compared with those with minimum GDC >0.8 (38% vs 18%, P = .065). Prostate intrafraction motion was mostly along the bladder-rectum axis and predominantly in the superior-anterior direction. Motion in the inferior-posterior direction was associated with significantly higher rate of acute grade 2 genitourinary toxicity (66.7% vs 13.9%, P = .001). Gating limited mean prostate motion during treatment delivery in fractions with a GDC <0.9 (<0.8) to 2.9 mm (2.9 mm) versus 4.1 mm (4.7 mm) for ungated motion. CONCLUSIONS: Fractions with large intrafraction motion were associated with increased toxicity and their occurrence among patients appears stochastic. Real-time tracking/gating effectively mitigated this motion and is likely a major contributing factor of acute toxicity reduction associated with MRgRT.

Stereotactic Body Radiation Therapy: A Radiosurgery Society Guide to the Treatment of Localized Prostate Cancer Illustrated by Challenging Cases.

Traditionally, external beam radiotherapy (EBRT) for localized prostate cancer (PCa) involved lengthy courses with low daily doses. However, advancements in radiation delivery and a better understanding of prostate radiobiology have enabled the development of shorter courses of EBRT. Ultrahypofractionated radiotherapy, administering doses greater than 5 Gy per fraction, is now considered a standard of care regimen for localized PCa, particularly for intermediate-risk disease. Stereotactic body radiotherapy (SBRT), a specific type of ultrahypofractionated radiotherapy employing advanced planning, imaging, and treatment technology to deliver in five or fewer fractions, is gaining prominence as a cost-effective, convenient, and safe alternative to longer radiotherapy courses. It is crucial to address practical considerations related to patient selection, fractionation scheme, target delineation, and planning objectives. This is especially important in challenging clinical situations where clear evidence for guidance may be lacking. The Radiosurgery Society endorses this case-based guide with the aim of providing a practical framework for delivering SBRT to the intact prostate, exemplified by two case studies. The article will explore common SBRT dose/fractionation schemes and dose constraints for organs-at-risk. Additionally, it will review existing evidence and expert opinions on topics such as SBRT dose escalation, the use of rectal spacers, the role of androgen deprivation therapy in the context of SBRT, SBRT in special patient populations (e.g., high-risk disease, large prostate, high baseline urinary symptom burdens, and inflammatory bowel disease), as well as new imaging-guidance techniques like Magnetic Resonance Imaging for SBRT delivery.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Web-Based Symptom Monitoring With Patient-Reported Outcomes During Definitive Radiation Therapy With Chemotherapy (SYMPATHY): A Prospective Single-Center Phase 1 Study.

Purpose: We evaluated the feasibility of patient symptom self-reporting using a web-based interface (WBI), with automated message alerts for severe and/or worsening symptoms, in patients undergoing definitive chemoradiation therapy (CRT). Methods and Materials: Patients receiving definitive CRT for gastrointestinal, lung, and head and neck cancers with access to a computer and/or mobile device were eligible. Symptom self-reporting was conducted via a WBI through surveys adapted from the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events: 2 per week during CRT and 1 per week for 3 months after CRT. Nurses were alerted whenever a patient's symptom worsened by ≥2 points or reached a score of ≥3. Patient-Reported Outcomes Measurement Information System (PROMIS) surveys were conducted at baseline, end of CRT, and 3 months after CRT. Patients also completed exit surveys 3 months after CRT. Results: Nineteen patients were enrolled with a median of 30 fractions (range, 28-33). The median survey completion rate was 26% (range, 0%-100%) during CRT and 33% (range, 0%-100%) during the first 3 months after CRT. Five (26%) had acute hospital encounters during CRT or within 3 months of CRT completion. Two patients (11%) experienced CRT treatment interruptions. During CRT, 70 of 81 surveys (86%) were flagged and 61 of 70 (87%) were acted upon by a nurse or physician within 4 days; during the first 3 months after CRT, 47 of 85 (55%) were flagged and 28 of 47 (60%) were acted upon within 7 days. Ninety-two percent of patients found it always easy to access the survey while 58% found the surveys too long or too frequent. None of the PROMIS domains had statistically significant changes during any time points. Conclusions: Symptom self-reporting via a WBI is feasible during definitive chemoradiation with high patient satisfaction. Survey fatigue is common and may be mitigated by improving the WBI to make it more patient-centered and allowing patients to choose which symptoms to report.

Fully automated segmentation of prostatic urethra for MR-guided radiation therapy.

PURPOSE: Accurate delineation of the urethra is a prerequisite for urethral dose reduction in prostate radiotherapy. However, even in magnetic resonance-guided radiation therapy (MRgRT), consistent delineation of the urethra is challenging, particularly in online adaptive radiotherapy. This paper presented a fully automatic MRgRT-based prostatic urethra segmentation framework. METHODS: Twenty-eight prostate cancer patients were included in this study. In-house 3D half fourier single-shot turbo spin-echo (HASTE) and turbo spin echo (TSE) sequences were used to image the Foley-free urethra on a 0.35 T MRgRT system. The segmentation pipeline uses 3D nnU-Net as the base and innovatively combines ground truth and its corresponding radial distance (RD) map during training supervision. Additionally, we evaluate the benefit of incorporating a convolutional long short term memory (LSTM-Conv) layer and spatial recurrent convolution layer (RCL) into nnU-Net. A novel slice-by-slice simple exponential smoothing (SEPS) method specifically for tubular structures was used to post-process the segmentation results. RESULTS: The experimental results show that nnU-Net trained using a combination of Dice, cross-entropy and RD achieved a Dice score of 77.1 ± 2.3% in the testing dataset. With SEPS, Hausdorff distance (HD) and 95% HD were reduced to 2.95 ± 0.17 mm and 1.84 ± 0.11 mm, respectively. LSTM-Conv and RCL layers only minimally improved the segmentation precision. CONCLUSION: We present the first Foley-free MRgRT-based automated urethra segmentation study. Our method is built on a data-driven neural network with novel cost functions and a post-processing step designed for tubular structures. The performance is consistent with the need for online and offline urethra dose reduction in prostate radiotherapy.

Race-dependent association of clinical trial participation with improved outcomes for high-risk prostate cancer patients treated in the modern era.

It is unclear whether cancer patients enrolled in clinical trials have improved outcomes compared with non-study patients. We compared prostate cancer-specific mortality (PCSM) in patients in a real-world setting (SEER-Medicare database) versus on a trial (NRG/RTOG 0521). The 7-year freedom from PCSM was superior in trial patients (92.4% vs. 88.1%, sHR = 1.77 [95% CI 1.05-2.97], P = 0.03). Black trial patients had significantly superior freedom from PCSM than Black real-world patients (sHR 6.52, 95% CI 1.43-29.72, P = 0.02), which was not seen among non-Black patients. Trial patients may have improved outcomes, and racial disparities are accentuated in the real world.

Application of a genetic signature of late GU toxicity in SCIMITAR, a Post-op SBRT trial.

Predictors of genitourinary toxicity after post-prostatectomy radiotherapy remain elusive. A previously defined germline DNA signature (PROSTOX) has shown predictive ability for late grade ≥ 2 GU toxicity after intact prostate stereotactic body radiotherapy. We explore whether PROSTOX would predict toxicity among patients receiving post-prostatectomy SBRT on a phase II clinical trial.

Experience of Telemedicine Visits in Radiation Oncology During the COVID-19 Pandemic: A US National Survey and Lessons Learned for Incorporating Telemedicine Post-COVID-19.

Purpose: We sought to survey the attitudes and perceptions of US radiation oncologists toward the adoption of telemedicine during the COVID-19 pandemic and offer suggestions for its integration in the postpandemic era. Methods and Materials: A 25-question, anonymous online survey was distributed nationwide to radiation oncologists. Results: One hundred and twenty-one respondents completed the survey, with 92% from academia. Overall, 79% worked at institutions that had implemented a work-from-home policy, with which 74% were satisfied. Despite nearly all visit types being conducted in-person before COVID-19, 25%, 41%, and 5% of the respondents used telemedicine for more than half of their new consultations, follow-up, and on-treatment visits, respectively, during the COVID-19 pandemic. Most (83%) reported being comfortable integrating telemedicine. Although telemedicine was appreciated as being more convenient for patients (97%) and reducing transmission of infectious agents (83%), the most commonly perceived disadvantages were difficulty in performing physical examinations (90%), patients' inability to use technology adequately (74%), and technical malfunctions (72%). Compared with in-person visits, telemedicine was felt to be inferior in establishing a personal connection during consultation (90%) and assessing for toxicity while on-treatment (88%) and during follow-up (70%). For follow-up visits, genitourinary and thoracic were perceived as most appropriate for telemedicine while gynecologic and head and neck were considered the least appropriate. Overall, 70% were in favor of more telemedicine, even after pandemic is over. Conclusions: Telemedicine will likely remain part of the radiation oncology workflow in most clinics after the pandemic. It should be used in conjunction with in-person visits, and may be best used for conducting follow-up visits in certain disease sites such as genitourinary and thoracic malignancies.

The role of adaptive planning in margin-reduced, MRI-guided stereotactic body radiotherapy to the prostate bed following radical prostatectomy: Post-hoc analysis of a phase II clinical trial.

BACKGROUND AND PURPOSE: We examined the interfractional variations of clinical target volumes (CTVs), planning target volumes (PTVs), and organs-at-risk (OARs) in patients receiving MRI-guided stereotactic body radiotherapy (SBRT) to the prostate bed and evaluated the potential role of adaptive planning. MATERIALS AND METHODS: 31 patients received 30-34 Gy in five fractions to the prostate bed on a phase II clinical trial. OARs, CTVs, and PTVs were retrospectively contoured on daily pretreatment MRIs (n = 155). Geometric comparisons were made between initial planning contours and daily pretreatment contours. Predicted treatment plans for each fraction were evaluated using the following constraints: CTV V95%>93%, PTV V95%>90%, bladder Dmax < 36.7 Gy, bladder V32.5 Gy < 35%, rectum Dmax < 36.7 Gy, rectum V27.5 Gy < 45%, rectum 32.5 Gy < 30%, and rectal wall V24Gy < 50%. Adaptive planning was simulated for all fractions that failed to meet these criteria. Plans were then re-evaluated. RESULTS: Median change in volume was 0.48% for CTV, -24.5% for bladder, and 6.95% for rectum. Median DSC was 0.89 for CTV, 0.79 for bladder, and 0.76 for rectum. 145/155 fractions (93.5%) met CTV V95%>93%. 75/155 fractions (48.4%) failed at least one OAR dose constraint. Overall, 83/155 fractions (53.5%) met criteria for adapting planning. This affected 24/31 patients (77.4%). Following adaptive planning, all fractions met CTV V95%>93% and PTV V95%>90% and 120/155 fractions (77.4%) met all OAR constraints. CONCLUSION: Due to significant interfractional variations in anatomy, a majority of fractions failed to meet both target volume and OAR constraints. However, adaptive planning was effective in overcoming these anatomic changes. Adaptive planning should be routinely considered in prostate bed SBRT.

Racial and Ethnic Disparities in Use of Novel Hormonal Therapy Agents in Patients With Prostate Cancer.

Importance: Novel hormonal therapy (NHT) agents have been shown to prolong overall survival in numerous randomized clinical trials for patients with advanced prostate cancer (PCa). There is a paucity of data regarding the pattern of use of these agents in patients from different racial and ethnic groups. Objective: To assess racial and ethnic disparities in the use of NHT in patients with advanced PCa. Design, Setting, and Participants: This cohort study comprised all men diagnosed with de novo advanced PCa (distant metastatic [M1], regional [N1M0], and high-risk localized [N0M0] per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE] trial criteria) with Medicare Part A, B, and D coverage between January 1, 2011, and December 31, 2017, in a Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database including prescription drug records. Data analysis took place from January through May 2023. Exposures: Race and ethnicity (Black [non-Hispanic], Hispanic, White, or other [Alaska Native, American Indian, Asian, Pacific Islander, or not otherwise specified and unknown]) abstracted from the SEER data fields. Main Outcomes and Measures: The primary outcome was receipt of an NHT agent (abiraterone, enzalutamide, apalutamide, or darolutamide) using a time-to-event approach. Results: The study included 3748 men (median age, 75 years [IQR, 70-81 years]). A total of 312 (8%) were Black; 263 (7%), Hispanic; 2923 (78%), White; and 250 (7%) other race and ethnicity. The majority of patients had M1 disease (2135 [57%]) followed by high-risk N0M0 (1095 [29%]) and N1M0 (518 [14%]) disease. Overall, 1358 patients (36%) received at least 1 administration of NHT. White patients had the highest 2-year NHT utilization rate (27%; 95% CI, 25%-28%) followed by Hispanic patients (25%; 95% CI, 20%-31%) and patients with other race or ethnicity (23%; 95% CI, 18%-29%), with Black patients having the lowest rate (20%; 95% CI, 16%-25%). Black patients had significantly lower use of NHT compared with White patients, which persisted at 5 years (37% [95% CI, 31%-43%] vs 44% [95% CI, 42%-46%]; P = .02) and beyond. However, there was no significant difference between White patients and Hispanic patients or patients with other race or ethnicity in NHT utilization (eg, 5 years: Hispanic patients, 38% [95% CI, 32%-46%]; patients with other race and ethnicity: 41% [95% CI, 35%-49%]). Trends of lower utilization among Black patients persisted in the patients with M1 disease (eg, vs White patients at 5 years: 51% [95% CI, 44%-59%] vs 55% [95% CI, 53%-58%]). After adjusting for patient, disease, and sociodemographic factors in multivariable analysis, Black patients continued to have a significantly lower likelihood of NHT initiation (adjusted subdistribution hazard ratio, 0.76; 95% CI, 0.61-0.94, P = .01). Conclusions and Relevance: In this cohort study of Medicare beneficiaries with advanced PCa, receipt of NHT agents was not uniform by race, with decreased use observed in Black patients compared with the other racial and ethnic groups, likely due to multifactorial obstacles. Future studies are needed to identify strategies to address the disparities in the use of these survival-prolonging therapies in Black patients.