A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiotherapy Using Diagnostic MRI-Based and Online Adaptive Planning.

PURPOSE: We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (NCTXXX). MATERIALS/METHODS: Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic MRIs, which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT datasets were used for pre-plan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary datasets and deformed to patient-specific cone-beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brainstem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Pre-plans were then re-optimized through online adaptation to create final, simulation-free plans, which were utilized if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. RESULTS: Median time from MRI importation to completion of "pre-plan" was one week-day (range: 1-4). Median on-table workflow duration was 41 minutes (range: 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient's simulation-free plan failed a planning target volume (PTV) coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation-CT-based plans otherwise met constraints, without clinically meaningful differences. CONCLUSION: Simulation-free HA-WBRT using online ART is feasible, safe, and results in dosimetrically comparable treatment plans to simulation-CT-based workflows while providing convenience and time-savings for patients.

Artificial intelligence applications in prostate cancer.

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

In silico trial of simulation-free hippocampal-avoidance whole brain adaptive radiotherapy.

Background and Purpose: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) can be a time-consuming process compared to conventional whole brain techniques, thus potentially limiting widespread utilization. Therefore, we evaluated the in silico clinical feasibility, via dose-volume metrics and timing, by leveraging a computed tomography (CT)-based commercial adaptive radiotherapy (ART) platform and workflow in order to create and deliver patient-specific, simulation-free HA-WBRT. Materials and methods: Ten patients previously treated for central nervous system cancers with cone-beam computed tomography (CBCT) imaging were included in this study. The CBCT was the adaptive image-of-the-day to simulate first fraction on-board imaging. Initial contours defined on the MRI were rigidly matched to the CBCT. Online ART was used to create treatment plans at first fraction. Dose-volume metrics of these simulation-free plans were compared to standard-workflow HA-WBRT plans on each patient CT simulation dataset. Timing data for the adaptive planning sessions were recorded. Results: For all ten patients, simulation-free HA-WBRT plans were successfully created utilizing the online ART workflow and met all constraints. The median hippocampi D100% was 7.8 Gy (6.6-8.8 Gy) in the adaptive plan vs 8.1 Gy (7.7-8.4 Gy) in the standard workflow plan. All plans required adaptation at first fraction due to both a failing hippocampal constraint (6/10 adaptive fractions) and sub-optimal target coverage (6/10 adaptive fractions). Median time for the adaptive session was 45.2 min (34.0-53.8 min). Conclusions: Simulation-free HA-WBRT, with commercially available systems, was clinically feasible via plan-quality metrics and timing, in silico.

Initial clinical experience building a dual CT- and MR-guided adaptive radiotherapy program.

Introduction: Our institution was the first in the world to clinically implement MR-guided adaptive radiotherapy (MRgART) in 2014. In 2021, we installed a CT-guided adaptive radiotherapy (CTgART) unit, becoming one of the first clinics in the world to build a dual-modality ART clinic. Herein we review factors that lead to the development of a high-volume dual-modality ART program and treatment census over an initial, one-year period. Materials and Methods: The clinical adaptive service at our institution is enabled with both MRgART (MRIdian, ViewRay, Inc, Mountain View, CA) and CTgART (ETHOS, Varian Medical Systems, Palo Alto, CA) platforms. We analyzed patient and treatment information including disease sites treated, radiation dose and fractionation, and treatment times for patients on these two platforms. Additionally, we reviewed our institutional workflow for creating, verifying, and implementing a new adaptive workflow on either platform. Results: From October 2021 to September 2022, 256 patients were treated with adaptive intent at our institution, 186 with MRgART and 70 with CTgART. The majority (106/186) of patients treated with MRgART had pancreatic cancer, and the most common sites treated with CTgART were pelvis (23/70) and abdomen (20/70). 93.0% of treatments on the MRgART platform were stereotactic body radiotherapy (SBRT), whereas only 72.9% of treatments on the CTgART platform were SBRT. Abdominal gated cases were allotted a longer time on the CTgART platform compared to the MRgART platform, whereas pelvic cases were allotted a shorter time on the CTgART platform when compared to the MRgART platform. Our adaptive implementation technique has led to six open clinical trials using MRgART and seven using CTgART. Conclusions: We demonstrate the successful development of a dual platform ART program in our clinic. Ongoing efforts are needed to continue the development and integration of ART across platforms and disease sites to maximize access and evidence for this technique worldwide.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Prospective In Silico Evaluation of Cone-Beam Computed Tomography-Guided StereoTactic Adaptive Radiation Therapy (CT-STAR) for the Ablative Treatment of Ultracentral Thoracic Disease.

Purpose: We conducted a prospective, in silico study to evaluate the feasibility of cone-beam computed tomography (CBCT)-guided stereotactic adaptive radiation therapy (CT-STAR) for the treatment of ultracentral thoracic cancers (NCT04008537). We hypothesized that CT-STAR would reduce dose to organs at risk (OARs) compared with nonadaptive stereotactic body radiation therapy (SBRT) while maintaining adequate tumor coverage. Methods and Materials: Patients who were already receiving radiation therapy for ultracentral thoracic malignancies underwent 5 additional daily CBCTs on the ETHOS system as part of a prospective imaging study. These were used to simulate CT-STAR, in silico. Initial, nonadaptive plans (PI) were created based on simulation images and simulated adaptive plans (PA) were based on study CBCTs. 55 Gy/5 fractions was prescribed, with OAR constraint prioritization over PTV coverage under a strict isotoxicity approach. PI were applied to patients' anatomy of the day and compared with daily PA using dose-volume histogram metrics, with selection of superior plans for simulated delivery. Feasibility was defined as completion of the end-to-end adaptive workflow while meeting strict OAR constraints in ≥80% of fractions. CT-STAR was performed under time pressures to mimic clinical adaptive processes. Results: Seven patients were accrued, 6 with intraparenchymal tumors and 1 with a subcarinal lymph node. CT-STAR was feasible in 34 of 35 simulated fractions. In total, 32 dose constraint violations occurred when the PI was applied to anatomy-of-the-day across 22 of 35 fractions. These violations were resolved by the PA in all but one fraction, in which the proximal bronchial tree dose was still numerically improved through adaptation. The mean difference between the planning target volume and gross total volume V100% in the PI and the PA was -0.24% (-10.40 to 9.90) and -0.62% (-11.00 to 8.00), respectively. Mean end-to-end workflow time was 28.21 minutes (18.02-50.97). Conclusions: CT-STAR widened the dosimetric therapeutic index of ultracentral thorax SBRT compared with nonadaptive SBRT. A phase 1 protocol is underway to evaluate the safety of this paradigm for patients with ultracentral early-stage NSCLC.

Knowledge-based adaptive planning quality assurance using dosimetric indicators for stereotactic adaptive radiotherapy for pancreatic cancer.

INTRODUCTION: We aimed to develop knowledge-based tools for robust adaptive radiotherapy (ART) planning to determine on-table adaptive DVH metric variations or planning process errors for stereotactic pancreatic ART. We developed volume-based dosimetric identifiers to identify deviations of ART plans from simulation plans. MATERIALS AND METHODS: Two patient cohorts who were treated on MR-Linac for pancreas cancer were included in this retrospective study; a training cohort and a validation cohort. All patients received 50 Gy in 5 fractions. PTV-OPT was generated by subtracting the critical organs plus a 5 mm-margin from PTV. Several metrics that potentially can identify failure-modes were calculated including PTV & PTV_OPT V95% and PTV & PTV_OPT D95%/D5%. The difference between each DVH metric in each adaptive plan with the DVH metric in simulation plan was calculated. The 95% confidence interval (CI) of the variations in each DVH metric was calculated for the patient training cohort. Variations in DVH metrics that exceeded the 95% CI for all fractions in training and validation cohort were flagged for retrospective investigation for root-cause analysis to determine their predictive power for identifying failure-modes. RESULTS: The CIs for the PTV & PTV_OPT V95% and PTV & PTV_OPT D95%/D5% were ± 13%, ± 5%, ± 0.1, ± 0.03, respectively. We estimated the positive predictive value and negative predictive value of our method to be 77% and 89%, respectively, for the training cohort, and 80% for both in the validation cohort. DISCUSSION: We developed dosimetric indicators for ART planning QA to identify population-based deviations or planning errors during online adaptive process for stereotactic pancreatic ART. This technology may be useful as an ART clinical trial QA tool and improve overall ART quality at an institution.

Patient specific contouring region of interest for abdominal stereotactic adaptive radiotherapy.

Contouring during adaptive radiotherapy (ART) can be a time-consuming process. This study describes the generation of patient specific contouring regions of interest (CRoI) for evaluating the high dose fall-off in stereotactic abdominal ART. An empirical equation was derived to determine the radius of a cylindrical patient specific CRoIs. These CRoIs were applied to 60 patients and their adaptive fractions (301 unique treatment plans). Out of the 301 unique treatment plans, 284 (94%) treatment plans contained the high dose fall-off within the CRoI. There was an expected predicted average timesaving of 2.9-min-per case. Patient specific CRoIs improves the efficiency of ART.

First treatments for Lattice stereotactic body radiation therapy using magnetic resonance image guided radiation therapy.

Two abdominal patients were treated with Lattice stereotactic body radiation therapy (SBRT) using magnetic resonance guided radiation therapy (MRgRT). This is one of the first reported treatments of Lattice SBRT with the use of MRgRT. A description of the treatment approach and planning considerations were incorporated into this report. MRgRT Lattice SBRT delivered similar planning quality metrics to established dosimetric parameters for Lattice SBRT. Increased signal intensity were seen in the MRI treatments for one of the patients during the course of treatment.

Simulated computed tomography-guided stereotactic adaptive radiotherapy (CT-STAR) for the treatment of locally advanced pancreatic cancer.

BACKGROUND AND PURPOSE: We conducted a prospective, in silico imaging clinical trial to evaluate the feasibility and potential dosimetric benefits of computed tomography-guided stereotactic adaptive radiotherapy (CT-STAR) for the treatment of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Eight patients with LAPC received five additional CBCTs on the ETHOS system before or after their standard of care radiotherapy treatment. Initial plans were created based on their initial simulation anatomy (PI) and emulated adaptive plans were created based on their anatomy-of-the-day (PA). The prescription was 50 Gy/5 fractions. Plans were created under a strict isotoxicity approach, in which organ-at-risk (OAR) constraints were prioritized over planning target volume coverage. The PI was evaluated on the patient's anatomy-of-the-day, compared to the daily PA, and the superior plan was selected. Feasibility was defined as successful completion of the workflow in compliance with strict OAR constraints in ≥80% of fractions. RESULTS: CT-STAR was feasible in silico for LAPC and improved OAR and/or target dosimetry in 100% of fractions. Use of the PI based on the patient's anatomy-of-the-day would have yielded a total of 94 OAR constraint violations and ≥1 hard constraint violation in 40/40 fractions. In contrast, 39/40 PA met all OAR constraints. In one fraction, the PA minimally exceeded the large bowel constraint, although dosimetrically improved compared to the PI. Total workflow time per fraction was 36.28 minutes (27.57-55.86). CONCLUSION: CT-STAR for the treatment of LAPC cancer proved feasible and was dosimetrically superior to non-adapted CT-stereotactic body radiotherapy.

Techno-Economic Feasibility Analysis of a Fully Mobile Radiation Oncology System Using Monte Carlo Simulation.

PURPOSE: Disparities in radiation oncology (RO) can be attributed to geographic location, socioeconomic status, race, sex, and other societal factors. One potential solution is to implement a fully mobile (FM) RO system to bring radiotherapy to rural areas and reduce barriers to access. We use Monte Carlo simulation to quantify techno-economic feasibility with uncertainty, using two rural Missouri scenarios. METHODS: Recently, a semimobile RO system has been developed by building an o-ring linear accelerator (linac) into a mobile coach that is used for temporary care, months at a time. Transitioning to a more FM-RO system, which changes location within a given day, presents technical challenges including logistics and quality assurance. This simulation includes cancer census in both northern and southeastern Missouri, multiple treatment locations within a given day, and associated expenditures and revenues. A subset of patients with lung, breast, and rectal diseases, treated with five fractions, was simulated in the FM-RO system. RESULTS: The FM-RO can perform all necessary quality assurance tests as suggested in national medical physics guidelines within 1.5 hours, thus demonstrating technological feasibility. In northern and southeastern Missouri, five-fraction simulations' net incomes were, in US dollars (USD), $1.55 ± 0.17 million (approximately 74 patients/year) and $3.65 USD ± 0.25 million (approximately 98 patients/year), respectively. The number of patients seen had the highest correlation with net income as well as the ability to break-even within the simulation. The model does not account for disruptions in care or other commonly used treatment paradigms, which may lead to differences in estimated economic return. Overall, the mobile system achieved a net benefit, even for the most negative simulation scenarios. CONCLUSION: Our simulations suggest technologic success and economic viability for a FM-RO system within rural Missouri and present an interesting solution to address other geographic disparities in access to radiotherapy.

Commissioning a secondary dose calculation software for a 0.35 T MR-linac.

Secondary external dose calculations for a 0.35 T magnetic resonance image-guided radiation therapy (MRgRT) are needed within the radiation oncology community to follow safety standards set forth within the field. We evaluate the commercially available software, RadCalc, in its ability to accurately perform monitor unit dose calculations within a magnetic field. We also evaluate the potential effects of a 0.35 T magnetic field upon point dose calculations. Monitor unit calculations were evaluated with (wMag) and without (noMag) a magnetic field considerations in RadCalc for the ViewRay MRIdian. The magnetic field is indirectly accounted for by using asymmetric profiles for calculation. The introduction of double-stacked multi-leaf collimator leaves was also included in the monitor unit calculations and a single transmission value was determined. A suite of simple and complex geometries with a variety field arrangements were calculated for each method to demonstrate the effect of the 0.35 T magnetic field on monitor unit calculations. Finally, 25 patient-specific treatment plans were calculated using each method for comparison. All simple geometries calculated in RadCalc were within 2% of treatment planning system (TPS) values for both methods, except for a single noMag off-axis comparison. All complex muilt-leaf collimator (MLC) pattern calculations were within 5%. All complex phantom geometry calculations were within 5% except for a single field within a lung phantom at a distal point. For the patient calculations, the noMag method average percentage difference was 0.09 ± 2.5% and the wMag average percentage difference was 0.08 ± 2.5%. All results were within 5% for the wMag method. We performed monitor unit calculations for a 0.35 T MRgRT system using a commercially available secondary monitor unit dose calculation software and demonstrated minimal impact of the 0.35 T magnetic field on monitor unit dose calculations. This is the first investigation demonstrating successful calculations of dose using RadCalc in the low-field 0.35 T ViewRay MRIdian system.

Implementing stereotactic accelerated partial breast irradiation using magnetic resonance guided radiation therapy.

INTRODUCTION: Accelerated partial breast irradiation (APBI) seeks to reduce irradiated volumes and radiation exposure for patients while maintaining acceptable clinical outcomes. Magnetic resonance image-guided radiotherapy (MRgRT) provides excellent soft-tissue contrast for treatment localization, which can reduce setup uncertainty, thus reducing margins in the external beam setting. Additionally, stereotactic body radiotherapy (SBRT)-style regimens with high gradients can also be executed. This MR-guided stereotactic APBI (MRgS-APBI) approach can be utilized for a lower number of fractions and spare a greater volume of healthy tissues compared to conventional 3D external beam APBI. METHODS: Our MRgS-APBI program was developed for two prospective non-randomized phase I/II clinical trials (20Gyx1 and 8.5Gyx3). Both breast SBRT treatment planning and MRgRT delivery techniques were described in this study. Simulation included both CT and MRI with specialized immobilization to accommodate MR-guided setup and cine-MRI treatment gating. Dosimetry data from 48 single-fraction and 19 three-fraction patients were collected and evaluated. This included planning objectives and SBRT-specific indices. During treatment, setup errors were calculated to evaluate setup reproducibility and duty cycle was calculated using cine-MRI data during gated delivery. RESULTS: In both the single- and three- fraction trials combined, 88.5% of the possible dosimetric objectives across all patients were met during planning. The majority of the planning objectives were easily achievable indicating the potential for stricter objectives for subsequent S-APBI treatments. The average magnitude of setup uncertainties was 1.0 cm ±â€¯0.6 cm across all treatments. In the three-fraction trial, the average beam-on duty-cycle for the MRI-gated delivery was 83.0 ±â€¯13.0%. There were no technical MRgS-APBI related issues that resulted in discontinuation of treatment across all patients. CONCLUSION: SBRT-style dosimetry and delivery for APBI is feasible using MR-guidance. The program development and dosimetric outcomes reported here can serve as a guide for other institutions considering the clinical implementation of MR-guided stereotactic APBI.