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).

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.

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.

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.

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.

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.

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.

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.

MRI-guided Radiotherapy (MRgRT) for Treatment of Oligometastases: Review of Clinical Applications and Challenges.

PURPOSE: Early clinical results on the application of magnetic resonance imaging (MRI) coupled with a linear accelerator to deliver Magnetic Resonance-guided Radiation Therapy (MRgRT) have demonstrated feasibility for safe delivery of stereotactic body radiation therapy in treatment of oligometastatic disease. Here, we set out to review the clinical evidence and challenges associated with MRgRT in this setting. METHODS AND MATERIALS: We performed a systematic review of the literature pertaining to clinical experiences and trials on the use of MRgRT primarily for the treatment of oligometastatic cancers. We reviewed the opportunities and challenges associated with the use of MRgRT. RESULTS: Benefits of MRgRT pertaining to superior soft-tissue contrast, real-time imaging and gating, and online adaptive radiation therapy facilitate safe and effective dose escalation to oligometastatic tumors while simultaneously sparing surrounding healthy tissues. Challenges concerning further need for clinical evidence and technical considerations related to planning, delivery, quality assurance of hypofractionated doses, and safety in the MRI environment must be considered. CONCLUSIONS: The promising early indications of safety and effectiveness of MRgRT for stereotactic body radiation therapy-based treatment of oligometastatic disease in multiple treatment locations should lead to further clinical evidence to demonstrate the benefit of this technology.

Effect of mid-scan breathing changes on quality of 4DCT using a commercial phase-based sorting algorithm.

PURPOSE: Though it is known that irregular breathing can introduce artifacts in commercial 4DCT, this has not been systematically explored. The purpose of this study is to investigate the effect of variations in basic parameters of the breathing wave on 4DCT imaging quality. METHODS: A four-dimensional motion platform holding an acrylic sphere was scanned while moving in a trajectory modeled from a lung cancer patient. A bellows device was used as a respiratory surrogate, and the images were sorted by a commercial phase-based sorting algorithm. Motion during the first half of the scan was produced at a baseline trajectory with a consistent frequency and amplitude of 15 breaths per minute and 1 cm, peak to peak. The two parameters were then varied mid-scan to new frequency and amplitude values, with frequencies ranging from 7.5 to 22 bpm and amplitudes ranging from 0.5 to 1.5 cm. Image sets representing four respiratory phases were contoured. Each set was analyzed to compare centroid displacement, density homogeneity, and volumetric and geometric distortions of the imaged sphere. Undercoverage of the target ITV and overcoverage of healthy tissue was also evaluated. RESULTS: Changes in amplitude of 25% or more, with or without changes in frequency, consistently caused measurable distortions in shape, position, and density of the imaged sphere. Frequency changes over 50% showed a similar trend. CONCLUSIONS: This study suggests that basic breathing statistics can be used to quickly assess the quality of a 4DCT scan prior to image reconstruction. Such information can help give indication of the proper course of action when irregular breathing patterns are observed during CT scanning.

The correlation of tissue motion within the lung: implications on fiducial based treatments.

In radiation therapy many motion management and alignment techniques rely on the accuracy of an internal fiducial acting as a surrogate for target motion within the lung. Although fiducials are routinely used as surrogates for tumor motion, the extent to which varying spatial locations in the lung move similarly to other locations has yet to be quantitatively analyzed. In an attempt to analyze the motion correlation throughout the lung, ten primary lung cancer patients underwent IRB-approved 4DCT scans in the supine position. Deformable registration produced motion vectors for each voxel between exhalation and inhalation. Modeling was performed for each vector and all surrounding vectors within the lung in order to determine the mean 3D Euclidean distance necessary for an implanted fiducial to correlate with surrounding tissue motion to within 3 mm (left lower: 1.7 cm, left upper: 2.1 cm, right lower 1.6 cm, and right upper 2.9 cm). No general implantation rule of where to position a fiducial with respect to the tumor was found as the motion is highly patient and lobe specific. Correlation maps are presented showcasing spatial anisotropy of the motion of tissue surrounding the tumor.

Development and Assessment of a Clinical Calculator for Estimating the Likelihood of Recurrence and Survival Among Patients With Locally Advanced Rectal Cancer Treated With Chemotherapy, Radiotherapy, and Surgery.

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

AAPM Task Group 264: The safe clinical implementation of MLC tracking in radiotherapy.

The era of real-time radiotherapy is upon us. Robotic and gimbaled linac tracking are clinically established technologies with the clinical realization of couch tracking in development. Multileaf collimators (MLCs) are a standard equipment for most cancer radiotherapy systems, and therefore MLC tracking is a potentially widely available technology. MLC tracking has been the subject of theoretical and experimental research for decades and was first implemented for patient treatments in 2013. The AAPM Task Group 264 Safe Clinical Implementation of MLC Tracking in Radiotherapy Report was charged to proactively provide the broader radiation oncology community with (a) clinical implementation guidelines including hardware, software, and clinical indications for use, (b) commissioning and quality assurance recommendations based on early user experience, as well as guidelines on Failure Mode and Effects Analysis, and (c) a discussion of potential future developments. The deliverables from this report include: an explanation of MLC tracking and its historical development; terms and definitions relevant to MLC tracking; the clinical benefit of, clinical experience with and clinical implementation guidelines for MLC tracking; quality assurance guidelines, including example quality assurance worksheets; a clinical decision pathway, future outlook and overall recommendations.

Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions.

INTRODUCTION: Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC. METHODS: A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications. RESULTS: Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed. CONCLUSIONS: The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.

Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial.

PURPOSE: Short-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality. METHODS: Patients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function. RESULTS: From June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects. CONCLUSIONS: Treatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects. NCT02641691.

Fiducial placement for stereotactic radiation by using EUS: feasibility when using a marker compatible with a standard 22-gauge needle.

BACKGROUND: Stereotactic radiation by using fiducial markers permits higher doses of radiation while reducing the exposure of uninvolved, adjacent structures. EUS has been used to deploy fiducials, although a 19-gauge needle has traditionally been required. OBJECTIVE: To report a new technique and the feasibility of deploying a fiducial compatible with a 22-gauge needle under EUS guidance. DESIGN: Single-center, case series. SETTING: Tertiary care referral center. PATIENTS: Thirteen patients with primary or metastatic cancer referred for stereotactic radiation. INTERVENTIONS: EUS-guided placement of a single fiducial marker that is compatible with a 22-gauge EUS-FNA needle. MAIN OUTCOME MEASUREMENTS: Technical success and complications. RESULTS: Thirteen patients referred for EUS-guided placement of a fiducial marker were identified in the endoscopic database. Targeted lesions measured 27 +/- 13 mm (range 8-50) x 21 +/- 10 mm (range 6-42). All fiducials were successfully deployed, 9 using a transgastric and 4 using a transduodenal approach. There were no EUS-associated complications. Two patients did not proceed to radiation therapy as a result of interval peritoneal metastasis. However, all fiducials were visible on the roentogram. Eleven of 13 patients (85%) required placement of 1 fiducial, whereas 2 patients (15%) required 2 fiducials. LIMITATIONS: Uncontrolled feasibility study with limited sample size and follow-up. CONCLUSION: EUS-guided placement of a fiducial using a 22-gauge needle is technically feasible and may permit greater access compared with the 19-gauge needle technique.