Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Commissioning, clinical implementation, and initial experience with a new brain tumor treatment package on a low-field MR-linac.

To evaluate the image quality, dosimetric properties, setup reproducibility, and planar cine motion detection of a high-resolution brain coil and integrated stereotactic brain immobilization system that constitute a new brain treatment package (BTP) on a low-field magnetic resonance imaging (MRI) linear accelerator (MR-linac). Image quality of the high-resolution brain coil was evaluated with the 17 cm diameter spherical phantom and the American College of Radiology (ACR) Large MRI Phantom. Patient imaging studies approved by the institutional review board (IRB) assisted in selecting image acquisition parameters. Radiographic and dosimetric evaluation of the high-resolution brain coil and the associated immobilization devices was performed using dose calculations and ion chamber measurements. End-to-end testing was performed simulating a cranial lesion in a phantom. Inter-fraction setup variability and motion detection tests were evaluated on four healthy volunteers. Inter-fraction variability was assessed based on three repeat setups for each volunteer. Motion detection was evaluated using three-plane (axial, coronal, and sagittal) MR-cine imaging sessions, where volunteers were asked to perform a set of specific motions. The images were post-processed and evaluated using an in-house program. Contrast resolution of the high-resolution brain coil is superior to the head/neck and torso coils. The BTP receiver coils have an average HU value of 525 HU. The most significant radiation attenuation (3.14%) of the BTP, occurs through the lateral portion of the overlay board where the high-precision lateral-profile mask clips attach to the overlay. The greatest inter-fraction setup variability occurred in the pitch (average 1.08 degree) and translationally in the superior/inferior direction (average 4.88 mm). Three plane cine imaging with the BTP was able to detect large and small motions. Small voluntary motions, sub-millimeter in magnitude (maximum 0.9 mm), from motion of external limbs were detected. Imaging tests, inter-fraction setup variability, attenuation, and end-to-end measurements were quantified and performed for the BTP. Results demonstrate better contrast resolution and low contrast detectability that allows for better visualization of soft tissue anatomical changes relative to head/neck and torso coil systems.

Total Neoadjuvant Therapy With Short-Course Radiation: US Experience of a Neoadjuvant Rectal Cancer Therapy.

BACKGROUND: Short-course radiation followed by chemotherapy as total neoadjuvant therapy has been investigated primarily in Europe and Australia with increasing global acceptance. There are limited data on this regimen's use in the United States, however, potentially delaying implementation. OBJECTIVE: This study aimed to compare clinical performance and oncologic outcomes of 2 rectal cancer neoadjuvant treatment modalities: short-course total neoadjuvant therapy versus standard chemoradiation. DESIGN: This is a retrospective cohort study. SETTING: This study was performed at a National Cancer Institute-designated cancer center. PATIENTS: A total of 413 patients had locally advanced rectal cancers diagnosed from June 2009 to May 2018 and received either short-course total neoadjuvant therapy or standard chemoradiation. INTERVENTIONS: There were 187 patients treated with short-course total neoadjuvant therapy (5 × 5 Gy radiation followed by consolidation oxaliplatin-based chemotherapy) compared with 226 chemoradiation recipients (approximately 50.4 Gy radiation in 28 fractions with concurrent fluorouracil equivalent). MAIN OUTCOME MEASURES: Primary end points were tumor downstaging, measured by complete response and "low" neoadjuvant rectal score rates, and progression-free survival. Secondary analyses included treatment characteristics and completion, sphincter preservation, and recurrence rates. RESULTS: Short-course total neoadjuvant therapy was associated with higher rates of complete response (26.2% vs 17.3%; p = 0.03) and "low" neoadjuvant rectal scores (40.1% vs 25.7%; p < 0.01) despite a higher burden of node-positive disease (78.6% vs 68.9%; p = 0.03). Short-course recipients also completed trimodal treatment more frequently (88.4% vs 50.4%; p < 0.01) and had fewer months with temporary stomas (4.8 vs 7.0; p < 0.01). Both regimens achieved comparable local control (local recurrence: 2.7% short-course total neoadjuvant therapy vs 2.2% chemoradiation, p = 0.76) and 2-year progression-free survival (88.2% short-course total neoadjuvant therapy (95% CI, 82.9-93.5) vs 85.6% chemoradiation (95% CI, 80.5-90.7)). LIMITATIONS: Retrospective design, unbalanced disease severity, and variable dosing of neoadjuvant consolidation chemotherapy were limitations of this study. CONCLUSIONS: Short-course total neoadjuvant therapy was associated with improved downstaging and similar progression-free survival compared with chemoradiation. These results were achieved with shortened radiation courses, improved treatment completion, and less time with diverting ostomies. Short-course total neoadjuvant therapy is an optimal regimen for locally advanced rectal cancer. See Video Abstract at http://links.lww.com/DCR/B724.TERAPIA NEOADYUVANTE TOTAL CON RADIACIÓN DE CORTA DURACIÓN: EXPERIENCIA ESTADOUNIDENSE DE UNA TERAPIA NEOADYUVANTE CONTRA EL CÁNCER DE RECTO. ANTECEDENTES: La radiación de corta duración seguida de quimioterapia como terapia neoadyuvante total se ha investigado principalmente en Europa y Australia con una aceptación mundial cada vez mayor. Sin embargo, datos limitados sobre el uso de este régimen en los Estados Unidos, han potencialmente retrasando su implementación. OBJETIVO: Comparar el desempeño clínico y los resultados oncológicos de dos modalidades de tratamiento neoadyuvante del cáncer de recto: terapia neoadyuvante total de corta duración versus quimioradiación. estándar. DISEO: Cohorte retrospectivo. AJUSTE: Centro oncológico designado por el NCI. PACIENTES: Un total de 413 cánceres rectales localmente avanzados diagnosticados entre junio de 2009 y mayo de 2018 que recibieron cualquiera de los regímenes neoadyuvantes. INTERVENCIONES: Hubo 187 pacientes tratados con terapia neoadyuvante total de ciclo corto (radiación 5 × 5 Gy seguida de quimioterapia de consolidación basada en oxaliplatino) en comparación con 226 pacientes de quimiorradiación (aproximadamente 50,4 Gy de radiación en 28 fracciones con equivalente de fluorouracilo concurrente). PRINCIPALES MEDIDAS DE RESULTADO: Los criterios primarios de valoración fueron la disminución del estadio del tumor, medido por la respuesta completa y las tasas de puntuación rectal neoadyuvante "baja", y la supervivencia libre de progresión. Los análisis secundarios incluyeron las características del tratamiento y las tasas de finalización, conservación del esfínter y recurrencia. RESULTADOS: La terapia neoadyuvante total de corta duración, se asoció con tasas más altas de respuesta completa (26,2% versus 17,3%, p = 0,03) y puntuaciones rectales neoadyuvantes "bajas" (40,1% versus 25,7%, p < 0,01) a pesar de una mayor carga de enfermedad con ganglios positivos (78,6% versus 68,9%, p = 0,03). Los pacientes de ciclo corto también completaron el tratamiento trimodal con mayor frecuencia (88,4% versus 50,4%, p < 0,01) y tuvieron menos meses con estomas temporales (4,8 versus 7,0, p < 0,01). Ambos regímenes lograron un control local comparable (recidiva local: 2,7% de SC-TNT versus 2,2% de TRC, p = 0,76) y supervivencia libre de progresión a 2 años (88,2% de SC-TNT [IC: 82,9 - 93,5] versus 85,6% CRT [CI: 80,5 - 90,7]). LIMITACIONES: Diseño retrospectivo, gravedad de la enfermedad desequilibrada y dosificación variable de quimioterapia neoadyuvante de consolidación. CONCLUSIONES: La terapia neoadyuvante total de ciclo corto se asoció con una mejora en la reducción del estadio y una supervivencia libre de progresión similar en comparación con la quimioradiación. Estos resultados se lograron con ciclos de radiación más cortos, tratamientos mejor finalizados y menos tiempo en ostomías de derivación. La terapia neoadyuvante total de corta duración es un régimen óptimo para el cáncer de recto localmente avanzado. Consulte Video Resumen en http://links.lww.com/DCR/B724. (Traducción- Dr. Fidel Ruiz Healy).

Predictors of Survival after Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases.

PURPOSE: To identify clinical parameters that are prognostic for improved overall survival (OS) after yttrium-90 radioembolization (RE) in patients with liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS: A total of 131 patients who underwent RE for liver metastases from CRC, treated at 2 academic centers, were reviewed. Twenty-one baseline pretreatment clinical factors were analyzed in relation to OS by the Kaplan-Meier method along with log-rank tests and univariate and multivariate Cox regression analyses. RESULTS: The median OS from first RE procedure was 10.7 months (95% confidence interval [CI], 9.4-12.7 months). Several pretreatment factors, including lower carcinoembryonic antigen (CEA; ≤20 ng/mL), lower aspartate transaminase (AST; ≤40 IU/L), neutrophil-lymphocyte ratio (NLR) <5, and absence of extrahepatic disease at baseline were associated with significantly improved OS after RE, compared with high CEA (>20 ng/mL), high AST (>40 IU/L), NLR ≥5, and extrahepatic metastases (P values of <.001, <.001, .0001, and .04, respectively). On multivariate analysis, higher CEA, higher AST, NLR ≥5, extrahepatic disease, and larger volume of liver metastases remained independently associated with risk of death (hazard ratios of 1.63, 2.06, 2.22, 1.48, and 1.02, respectively). CONCLUSIONS: The prognosis of patients with metastases from CRC is impacted by a complex set of clinical parameters. This analysis of pretreatment factors identified lower AST, lower CEA, lower NLR, and lower tumor burden (intra- or extrahepatic) to be independently associated with higher survival after hepatic RE. Optimal selection of patients with CRC liver metastases may improve survival rates after administration of yttrium-90.

Utility of a multidisciplinary tumor board in the management of pancreatic and upper gastrointestinal diseases: an observational study.

BACKGROUND & OBJECTIVES: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions. METHODS: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines. RESULTS: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190. CONCLUSIONS: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.

A comparative study of automatic image segmentation algorithms for target tracking in MR-IGRT.

On-board magnetic resonance (MR) image guidance during radiation therapy offers the potential for more accurate treatment delivery. To utilize the real-time image information, a crucial prerequisite is the ability to successfully segment and track regions of interest (ROI). The purpose of this work is to evaluate the performance of different segmentation algorithms using motion images (4 frames per second) acquired using a MR image-guided radiotherapy (MR-IGRT) system. Manual con-tours of the kidney, bladder, duodenum, and a liver tumor by an experienced radiation oncologist were used as the ground truth for performance evaluation. Besides the manual segmentation, images were automatically segmented using thresholding, fuzzy k-means (FKM), k-harmonic means (KHM), and reaction-diffusion level set evolution (RD-LSE) algorithms, as well as the tissue tracking algorithm provided by the ViewRay treatment planning and delivery system (VR-TPDS). The performance of the five algorithms was evaluated quantitatively by comparing with the manual segmentation using the Dice coefficient and target registration error (TRE) measured as the distance between the centroid of the manual ROI and the centroid of the automatically segmented ROI. All methods were able to successfully segment the bladder and the kidney, but only FKM, KHM, and VR-TPDS were able to segment the liver tumor and the duodenum. The performance of the thresholding, FKM, KHM, and RD-LSE algorithms degraded as the local image contrast decreased, whereas the performance of the VP-TPDS method was nearly independent of local image contrast due to the reference registration algorithm. For segmenting high-contrast images (i.e., kidney), the thresholding method provided the best speed (< 1 ms) with a satisfying accuracy (Dice = 0.95). When the image contrast was low, the VR-TPDS method had the best automatic contour. Results suggest an image quality determination procedure before segmentation and a combination of different methods for optimal segmentation with the on-board MR-IGRT system.

Comparison of onboard low-field magnetic resonance imaging versus onboard computed tomography for anatomy visualization in radiotherapy.

BACKGROUND: Onboard magnetic resonance imaging (OB-MRI) for daily localization and adaptive radiotherapy has been under development by several groups. However, no clinical studies have evaluated whether OB-MRI improves visualization of the target and organs at risk (OARs) compared to standard onboard computed tomography (OB-CT). This study compared visualization of patient anatomy on images acquired on the MRI-(60)Co ViewRay system to those acquired with OB-CT. MATERIAL AND METHODS: Fourteen patients enrolled on a protocol approved by the Institutional Review Board (IRB) and undergoing image-guided radiotherapy for cancer in the thorax (n = 2), pelvis (n = 6), abdomen (n = 3) or head and neck (n = 3) were imaged with OB-MRI and OB-CT. For each of the 14 patients, the OB-MRI and OB-CT datasets were displayed side-by-side and independently reviewed by three radiation oncologists. Each physician was asked to evaluate which dataset offered better visualization of the target and OARs. A quantitative contouring study was performed on two abdominal patients to assess if OB-MRI could offer improved inter-observer segmentation agreement for adaptive planning. RESULTS: In total 221 OARs and 10 targets were compared for visualization on OB-MRI and OB-CT by each of the three physicians. The majority of physicians (two or more) evaluated visualization on MRI as better for 71% of structures, worse for 10% of structures, and equivalent for 14% of structures. 5% of structures were not visible on either. Physicians agreed unanimously for 74% and in majority for > 99% of structures. Targets were better visualized on MRI in 4/10 cases, and never on OB-CT. CONCLUSION: Low-field MR provides better anatomic visualization of many radiotherapy targets and most OARs as compared to OB-CT. Further studies with OB-MRI should be pursued.

A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma.

OBJECTIVES: Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. METHODS: After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. CONCLUSIONS: This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.

The Use of MR-Guided Radiation Therapy for Pancreatic Cancer.

The introduction of online adaptive magnetic resonance (MR)-guided radiation therapy (RT) has enabled safe treatment of pancreatic cancer with ablative doses. The aim of this review is to provide a comprehensive overview of the current literature on the use and clinical outcomes of MR-guided RT for treatment of pancreatic cancer. Relevant outcomes included toxicity, tumor response, survival and quality of life. The results of these studies support further investigation of the effectiveness of ablative MR-guided SBRT as a low-toxic, minimally-invasive therapy for localized pancreatic cancer in prospective clinical trials.

Dosimetric comparison of glioblastoma radiotherapy treatment plans on a low-field MRI-guided linear accelerator compared to conventional C-arm linear accelerator.

INTRODUCTION: Magnetic resonance imaging (MRI)-guided radiation therapy has proven to provide many benefits such as real-time tracking, dose escalation, and the ability to perform online adaptive therapy. The objective of this study is to compare curative treatment plans for glioblastoma tumors on a low-field MR-guided linac vs a C-arm linac and evaluate if they are comparable in terms of coverage, organ at risk sparing, delivery time, and deliverability. METHODS: This is a retrospective study that consisted of 15 previously treated patients who received radiation therapy for glioblastoma on a C-arm linac. The CT simulation data used for the original clinical plans was imported into the MR-linac treatment planning system (TPS) and utilized for MR-linac plan generation. The plans were evaluated utilizing the dose volumetric histogram (DVH) and isodose lines, then compared in terms of plan quality consisting of PTV coverage, dose distributions, and OAR constraints. Statistical analysis was performed to compare differences between the two planning techniques. QA was performed on a subset of the plans to verify deliverability. RESULTS: Plans generated on the MR-linac were more heterogenous compared to C-arm linac plans. A statistically significant difference was found in the homogeneity index (HI) and the PTV V105% volume (cc) values. The volume of the normal brain receiving 30 Gy also showed a statistically significant (p = 0.0479) difference, where on average an additional 41.5 cc's of the normal brain tissue received 30 Gy in the MR-linac plans. The maximum dose to the normal brain structure also increased in the MR-linac plans on average by 2.6 Gy (p = 0.0002). Similarly, the average maximum dose to the scalp 4 mm structure was 6.5 Gy higher in the MR-linac plans compared to C-arm linac plans (p = 0.0103). The total MU's were higher in the MR-linac plans compared to the C-arm linac plans (p = 0.0015). CONCLUSIONS: Both MR-linac and C-arm linac plans met constraints for PTV coverage and OAR sparing, were deliverable, and resulted to be clinically acceptable. However, our study showed that MR-linac plans were not as conformal or as homogenous as C-arm linac plans utilizing noncoplanar beams.

Intrafraction Motion Management With MR-Guided Radiation Therapy.

High quality radiation therapy requires highly accurate and precise dose delivery. MR-guided radiotherapy (MRgRT), integrating an MRI scanner with a linear accelerator, offers excellent quality images in the treatment room without subjecting patient to ionizing radiation. MRgRT therefore provides a powerful tool for intrafraction motion management. This paper summarizes different sources of intrafraction motion for different disease sites and describes the MR imaging techniques available to visualize and quantify intrafraction motion. It provides an overview of MR guided motion management strategies and of the current technical capabilities of the commercially available MRgRT systems. It describes how these motion management capabilities are currently being used in clinical studies, protocols and provides a future outlook.

MR-guided stereotactic radiotherapy of infra-diaphragmatic oligometastases: Evaluation of toxicity and dosimetric parameters.

BACKGROUND AND PURPOSE: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE). MATERIALS AND METHODS: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model. RESULTS: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D0.1cc, D1cc, and D20cc. CONCLUSION: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D0.1cc, D1cc, and D20cc were associated with grade ≥ 2 GI toxicity.

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.

Impact of intrafraction motion in pancreatic cancer treatments with MR-guided adaptive radiation therapy.

Purpose: The total time of radiation treatment delivery for pancreatic cancer patients with daily online adaptive radiation therapy (ART) on an MR-Linac can range from 50 to 90 min. During this period, the target and normal tissues undergo changes due to respiration and physiologic organ motion. We evaluated the dosimetric impact of the intrafraction physiological organ changes. Methods: Ten locally advanced pancreatic cancer patients were treated with 50 Gy in five fractions with intensity-modulated respiratory-gated radiation therapy on a 0.35-T MR-Linac. Patients received both pre- and post-treatment volumetric MRIs for each fraction. Gastrointestinal organs at risk (GI-OARs) were delineated on the pre-treatment MRI during the online ART process and retrospectively on the post-treatment MRI. The treated dose distribution for each adaptive plan was assessed on the post-treatment anatomy. Prescribed dose volume histogram metrics for the scheduled plan on the pre-treatment anatomy, the adapted plan on the pre-treatment anatomy, and the adapted plan on post-treatment anatomy were compared to the OAR-defined criteria for adaptation: the volume of the GI-OAR receiving greater than 33 Gy (V33Gy) should be ≤1 cubic centimeter. Results: Across the 50 adapted plans for the 10 patients studied, 70% were adapted to meet the duodenum constraint, 74% for the stomach, 12% for the colon, and 48% for the small bowel. Owing to intrafraction organ motion, at the time of post-treatment imaging, the adaptive criteria were exceeded for the duodenum in 62% of fractions, the stomach in 36%, the colon in 10%, and the small bowel in 48%. Compared to the scheduled plan, the post-treatment plans showed a decrease in the V33Gy, demonstrating the benefit of plan adaptation for 66% of the fractions for the duodenum, 95% for the stomach, 100% for the colon, and 79% for the small bowel. Conclusion: Post-treatment images demonstrated that over the course of the adaptive plan generation and delivery, the GI-OARs moved from their isotoxic low-dose region and nearer to the dose-escalated high-dose region, exceeding dose-volume constraints. Intrafraction motion can have a significant dosimetric impact; therefore, measures to mitigate this motion are needed. Despite consistent intrafraction motion, plan adaptation still provides a dosimetric benefit.

Clinical outcomes of patients with unresectable primary liver cancer treated with MR-guided stereotactic body radiation Therapy: A Six-Year experience.

Purpose: Magnetic resonance-guided stereotactic body radiation therapy (MRgSBRT) with optional online adaptation has shown promise in delivering ablative doses to unresectable primary liver cancer. However, there remain limited data on the indications for online adaptation as well as dosimetric and longer-term clinical outcomes following MRgSBRT. Methods and Materials: Patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CCA) who completed MRgSBRT to 50 Gy in 5 fractions between June of 2015 and December of 2021 were analyzed. The necessity of adaptive techniques was evaluated. The cumulative incidence of local progression was evaluated and survival and competing risk analyses were performed. Results: Ninety-nine analyzable patients completed MRgSBRT during the study period and 54 % had planning target volumes (PTVs) within 1 cm of the duodenum, small bowel, or stomach at the time of simulation. Online adaptive RT was used in 53 % of patients to correct organ-at-risk constraint violation and/or to improve target coverage. In patients who underwent adaptive RT planning, online replanning resulted in superior target coverage when compared to projected, non-adaptive plans (median coverage ≥ 95 % at 47.5 Gy: 91 % [IQR: 82-96] before adaptation vs 95 % [IQR: 87-99] after adaptation, p < 0.01). The median follow-up for surviving patients was 34.2 months for patients with HCC and 10.1 months for patients with CCA/cHCC-CCA. For all patients, the 2-year cumulative incidence of local progression was 9.8 % (95 % CI: 1.5-18 %) for patients with HCC and 9.0 % (95 % CI: 0.1-18) for patients with CCA/cHCC-CCA. Grade 3 through 5 acute and late clinical gastrointestinal toxicities were observed in < 10 % of the patients. Conclusions: MRgSBRT, with the option for online adaptive planning when merited, allows delivery of ablative doses to primary liver tumors with excellent local control with acceptable toxicities. Additional studies evaluating the efficacy and safety of MRgSBRT in the treatment of primary liver cancer are warranted.

Patterns of utilization and clinical adoption of 0.35 Tesla MR-guided radiation therapy in the United States - Understanding the transition to adaptive, ultra-hypofractionated treatments.

Purpose/Objective: Magnetic resonance-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning (oART). Our objective was to describe patterns of 0.35Tesla(T)-MRgRT (MRIdian) utilization in the United States (US) among early adopters of this novel technology. Materials/Methods: Anonymized administrative data from all US MRIdian treatment systems were extracted for patients completing treatment from 2014 to 2020. Detailed treatment information was available for all MRIdian linear accelerator (linac) systems and some cobalt systems. Results: Seventeen systems at 16 centers delivered 5736 courses and 36,389 fractions (fraction details unavailable for 1223 cobalt courses), of which 21.1% were adapted. Ultra-hypofractionation (UHfx) (1-5 fractions) was used in 70.3% of all courses. At least one adaptive fraction was used for 38.5% of courses (average 1.7 adapted fractions/course), with higher oART use in UHfx dose schedules (47.7% of courses, average 1.9 adapted fractions per course). The most commonly treated organ sites were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%). Temporal trends show a compounded annual growth rate (CAGR) of 59.6% in treatment courses delivered, with a dramatic increase in use of UHfx to 84.9% of courses in 2020 and similar increase in use of oART to 51.0% of courses. Conclusions: This is the first comprehensive study reporting patterns of utilization among early adopters of MRIdian in the US. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of adaptive radiation therapy has led to a substantial transition to ultra-hypofractionated regimens. 0.35 T-MRgRT has been predominantly used to treat abdominal and pelvic tumors with increasing use of on-table adaptive replanning, which represents a paradigm shift in radiation therapy.

MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial.

PURPOSE: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation. METHODS AND MATERIALS: We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m2) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m2) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m2). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS). RESULTS: Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m2) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively. CONCLUSIONS: Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.

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.

Motion-compensated estimation of delivered dose during external beam radiation therapy: implementation in Philips' Pinnacle(3) treatment planning system.

PURPOSE: Recent research efforts investigating dose escalation techniques for three-dimensional conformal radiation therapy (3D CRT) and intensity modulated radiation therapy (IMRT) have demonstrated great benefit when high-dose hypofractionated treatment schemes are implemented. The use of these paradigms emphasizes the importance of smaller treatment margins to avoid high dose to surrounding normal tissue or organs at risk (OARs). However, tighter margins may lead to underdosage of the target due to the presence of organ motion. It is important to characterize organ motion and possibly account for it during treatment delivery. The need for real-time localization of dynamic targets has encouraged the use and development of more continuous motion monitoring systems such as kilo-voltage/fluoroscopic imaging, electromagnetic tracking, and optical monitoring systems. METHODS: This paper presents the implementation of an algorithm to quantify translational and rotational interfractional and intrafractional prostate motion and compute the dosimetric effects of these motion patterns. The estimated delivered dose is compared with the static plan dose to evaluate the success of delivering the plan in the presence of prostate motion. The method is implemented on a commercial treatment planning system (Pinnacle(3), Philips Radiation Oncology Systems, Philips Healthcare) and is termed delivered dose investigational tool (DiDIT). The DiDIT implementation in Pinnacle(3) is validated by comparisons with previously published results. Finally, different workflows are discussed with respect to the potential use of this tool in clinical treatment planning. RESULTS: The DiDIT dose estimation process took approximately 5-20 min (depending on the number of fractions analyzed) on a Pinnacle(3) 9.100 research version running on a Dell M90 system (Dell, Inc., Round Rock, TX, USA) equipped with an Intel Core 2 Duo processor (Intel Corporation, Santa Clara, CA, USA). The DiDIT implementation in Pinnacle(3) was found to be in agreement with previously published results, on the basis of the percent dose difference (PDD). This metric was also utilized to compare plan dose versus delivered dose, for prostate targets in three clinically acceptable treatment plans. CONCLUSIONS: This paper presents results from the implementation of an algorithm on a commercially available treatment planning system that quantifies the dosimetric effects of interfractional and intrafractional motion in external beam radiation therapy (EBRT) of prostate cancer. The implementation of this algorithm within a commercial treatment planning system such as Pinnacle(3) enables easy deployment in the existing clinical workflow. The results of the PDD tests validate the implementation of the DiDIT algorithm in Pinnacle(3), in comparison with previously published results.