Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Lateral Pelvic Nodal Management and Patterns of Failure in Patients Receiving Short-Course Radiation for Locally Advanced Rectal Cancer.

BACKGROUND: Management of lateral pelvic lymph nodes in locally advanced rectal cancer is controversial, with limited data indicating the optimal approach. In addition, no data exist regarding the treatment of lateral nodes in the setting of short-course radiation and nonoperative intent. OBJECTIVE: To evaluate a novel approach incorporating simultaneous integrated boost to suspicious lateral nodes. DESIGN: A retrospective study. SETTING: This study was conducted at a large tertiary referral center. PATIENTS: Patients treated with radiation therapy and consolidation chemotherapy were included. All primary tumors underwent biopsy confirmation and disease staging with pelvic MRI. INTERVENTIONS: Primary tumors were biopsy proven and staged with pelvic MRI. A subset of lateral pelvic lymph node patients received a simultaneous integrated boost of 35 Gy in 5 fractions. Then, chemotherapy was administered, with the majority receiving modified folinic acid, fluorouracil, and oxaliplatin. Clinical partial response required total mesorectal excision. MAIN OUTCOME MEASURES: Patterns of failure and survival analyses by subgroup were assessed. Outcomes based on receipt of radiation were compared across node status. RESULTS: Between January 2017 and January 2022, 155 patients were treated with short-course chemotherapy, with 121 included in the final analysis. Forty-nine percent of patients underwent nonoperative management. The median follow-up was 36 months and the median age was 58 years. Thirty-eight patients (26%) had positive lateral pelvic lymph nodes. Comparing lateral node status, progression-free survival was significantly worse for patients with positive disease ( p < 0.001), with a trend for worse overall survival. Receipt of nodal boost in patients with lateral nodes resulted in meaningful locoregional control. Nodal boost did not contribute to additional acute or late GI toxicity. LIMITATIONS: Limitations include retrospective nature and lack of lateral node pathology; however, a thorough radiographic review was performed. CONCLUSIONS: Lateral node-positive rectal cancer is correlated with worse oncologic outcomes and higher locoregional failure. Boost to clinically positive lateral nodes is a safe approach in the setting of short course radiation and in those receiving nonoperative intent. See Video Abstract. MANEJO DE LOS GANGLIOS PLVICOS LATERALES Y PATRONES DE FALLA EN PACIENTES QUE RECIBEN RADIACIN DE CICLO CORTO PARA EL CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El manejo de los ganglios linfáticos pélvicos laterales en el cáncer de recto localmente avanzado es controvertido, con datos limitados que indiquen el abordaje óptimo. Además, no existen datos sobre el tratamiento de los ganglios linfáticos laterales en el contexto de la radiación de curso corto y la intención no operatoria.OBJETIVO:Evaluamos un enfoque novedoso que incorpora sobreimpresión integrada simultánea (SIB) a los linfonodos laterales sospechosos.DISEÑO:Este fue un estudio retrospectivo.ESCENARIO:Este estudio se realizó en un gran centro de referencia terciario.PACIENTES:Se incluyeron pacientes tratados con radiación y quimioterapia de consolidación. Todos los tumores primarios se confirmaron mediante biopsia y la enfermedad se estadificó con resonancia magnética pélvica.INTERVENCIONES:Los tumores primarios se confirmaron mediante biopsia y se estadificaron con RM pélvica. Un subconjunto de pacientes con linfonodos pélvicos laterales (LPLN) recibió SIB a 35 Gy en 5 fracciones. Luego, se administró quimioterapia y la mayoría recibió mFOLFOX. La respuesta clínica parcial requirió la escisión total del mesorrecto.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron los patrones de fracaso y los análisis de supervivencia por subgrupo. Los resultados basados en el esquema de radiación se compararon según el estado de los ganglios.RESULTADOS:Entre enero de 2017 y enero de 2022, 155 pacientes fueron tratados con ciclo corto y quimioterapia con 121 incluidos en el análisis final. El 49% se sometió a manejo no operatorio. La mediana de seguimiento fue de 36 meses y la mediana de edad fue de 58 años. 38 pacientes (26%) tuvieron LPLN positivos. Comparando el estado de los ganglios laterales, la supervivencia libre de progresión fue significativamente peor para los pacientes con LPLN positiva ( p < 0,001) con una tendencia a una peor supervivencia global. La recepción de refuerzo nodal en pacientes con nodos laterales dio como resultado un control locorregional significativo. La sobreimpresión ganglionar no contribuyó a la toxicidad GI aguda o tardía adicional.LIMITACIONES:Las limitaciones incluyeron la naturaleza retrospectiva y la falta de patología de los ganglios linfáticos laterales; sin embargo, se realizó una revisión radiográfica exhaustiva.CONCLUSIONES:El cáncer de recto con ganglio lateral positivo se correlaciona con peores resultados oncológicos y mayor fracaso locorregional. La sobreimpresión a los ganglios laterales clínicamente positivos es un enfoque seguro en el contexto de un curso corto y en aquellos que siguen un manejo no operatorio. (Traducción-Dr. Felipe Bellolio ).

Feasibility of surface-guidance combined with CBCT for intra-fractional breath-hold motion management during Ethos RT.

PURPOSE: High-quality CBCT and AI-enhanced adaptive planning techniques allow CBCT-guided stereotactic adaptive radiotherapy (CT-STAR) to account for inter-fractional anatomic changes. Studies of intra-fractional respiratory motion management with a surface imaging solution for CT-STAR have not been fully conducted. We investigated intra-fractional motion management in breath-hold Ethos-based CT-STAR and CT-SBRT (stereotactic body non-adaptive radiotherapy) using optical surface imaging combined with onboard CBCTs. METHODS: Ten cancer patients with mobile lower lung or upper abdominal malignancies participated in an IRB-approved clinical trial (Phase I) of optical surface image-guided Ethos CT-STAR/SBRT. In the clinical trial, a pre-configured gating window (± 2 mm in AP direction) on optical surface imaging was used for manually triggering intra-fractional CBCT acquisition and treatment beam irradiation during breath-hold (seven patients for the end of exhalation and three patients for the end of inhalation). Two inter-fractional CBCTs at the ends of exhalation and inhalation in each fraction were acquired to verify the primary direction and range of the tumor/imaging-surrogate (donut-shaped fiducial) motion. Intra-fractional CBCTs were used to quantify the residual motion of the tumor/imaging-surrogate within the pre-configured breath-hold window in the AP direction. Fifty fractions of Ethos RT were delivered under surface image-guidance: Thirty-two fractions with CT-STAR (adaptive RT) and 18 fractions with CT-SBRT (non-adaptive RT). The residual motion of the tumor was quantified by determining variations in the tumor centroid position. The dosimetric impact on target coverage was calculated based on the residual motion. RESULTS: We used 46 fractions for the analysis of intra-fractional residual motion and 43 fractions for the inter-fractional motion analysis due to study constraints. Using the image registration method, 43 pairs of inter-fractional CBCTs and 100 intra-fractional CBCTs attached to dose maps were analyzed. In the motion range study (image registration) from the inter-fractional CBCTs, the primary motion (mean ± std) was 16.6 ± 9.2 mm in the SI direction (magnitude: 26.4 ± 11.3 mm) for the tumors and 15.5 ± 7.3 mm in the AP direction (magnitude: 20.4 ± 7.0 mm) for the imaging-surrogate, respectively. The residual motion of the tumor (image registration) from intra-fractional breath-hold CBCTs was 2.2 ± 2.0 mm for SI, 1.4 ± 1.4 mm for RL, and 1.3 ± 1.3 mm for AP directions (magnitude: 3.5 ± 2.1 mm). The ratio of the actual dose coverage to 99%, 90%, and 50% of the target volume decreased by 0.95 ± 0.11, 0.96 ± 0.10, 0.99 ± 0.05, respectively. The mean percentage of the target volume covered by the prescribed dose decreased by 2.8 ± 4.4%. CONCLUSION: We demonstrated the intra-fractional motion-managed treatment strategy in breath-hold Ethos CT-STAR/SBRT using optical surface imaging and CBCT. While the controlled residual tumor motion measured at 3.5 mm exceeded the predetermined setup value of 2 mm, it is important to note that this motion still fell within the clinically acceptable range defined by the PTV margin of 5 mm. Nonetheless, additional caution is needed with intra-fractional motion management in breath-hold Ethos CT-STAR/SBRT using optical surface imaging and CBCT.

Radiotherapy for Rectal Cancer: How Much is Enough?

Though resection has been the mainstay of treatment for nonmetastatic rectal cancer over the past century, radiation has become an increasingly integral component of care for locally advanced disease. Today, two predominant radiotherapy approaches-hyperfractionated chemoradiotherapy and "short-course" radiation-are widely utilized to reduce local recurrence and, in some cases, cure disease. Both have been incorporated into total neoadjuvant therapy (TNT) regimens and achieved excellent local control and superior complete response rates compared to chemoradiation alone. Additionally, initial results of "watch and wait" protocols utilizing either radiation modality have been promising. Yet, differences do exist; though short course is cheaper and more convenient for patients, recently published data may show superior complete response and local recurrence rates with chemoradiation. Ultimately, direct comparisons of short-course radiotherapy against chemoradiation within the TNT framework are needed to identify optimal radiation regimens in the treatment of locally advanced rectal cancer.

Circumferential Resection Margin as Predictor of Nonclinical Complete Response in Nonoperative Management of Rectal Cancer.

BACKGROUND: Short-course radiation therapy and consolidation chemotherapy with nonoperative intent has emerged as a novel treatment paradigm for patients with rectal cancer, but there are no data on the predictors of clinical complete response. OBJECTIVE: Evaluate the predictors of clinical complete response and survival. DESIGN: Retrospective cohort. SETTINGS: National Cancer Institute-designated cancer center. PATIENTS: Patients with stage I to III rectal adenocarcinoma treated between January 2018 and May 2019 (n = 86). INTERVENTIONS: Short-course radiation therapy followed by consolidation chemotherapy. MAIN OUTCOME MEASURES: Logistic regression was performed to assess for predictors of clinical complete response. The end points included local regrowth-free survival, regional control, distant metastasis-free survival, and overall survival. RESULTS: A positive (+) circumferential resection margin by MRI at diagnosis was a significant predictor of nonclinical complete response (OR: 4.1, p = 0.009) when adjusting for CEA level and primary tumor size. Compared to patients with a negative (-) pathologic circumferential resection margin, patients with a positive (+) pathologic circumferential resection margin had inferior local regrowth-free survival (29% vs 87%, p < 0.001), regional control (57% vs 94%, p < 0.001), distant metastasis-free survival (43% vs 95%, p < 0.001), and overall survival (86% vs 95%, p < 0.001) at 2 years. However, the (+) and (-) circumferential resection margin by MRI subgroups in patients who had a clinical complete response both had similar regional control, distant metastasis-free survival, and overall survival of more than 90% at 2 years. LIMITATIONS: Retrospective design, modest sample size, short follow-up, and the heterogeneity of treatments. CONCLUSIONS: Circumferential resection margin involvement by MRI at diagnosis is a strong predictor of nonclinical complete response. However, patients who achieve a clinical complete response after short-course radiation therapy and consolidation chemotherapy with nonoperative intent have excellent clinical outcomes regardless of the initial circumferential resection margin status. See Video Abstract at http://links.lww.com/DCR/C190 . EL MARGEN DE RESECCIN CIRCUNFERENCIAL COMO PREDICTOR NO CLNICO DE RESPUESTA COMPLETA EN EL MANEJO CONSERVADOR DEL CNCER DE RECTO: ANTECEDENTES:La radioterapia de corta duración y la quimioterapia de consolidación en el manejo conservador, han surgido como un nuevo paradigma de tratamiento, para los pacientes con cáncer de recto, lastimosamente no hay datos definitivos sobre los predictores de una respuesta clínica completa.OBJETIVO:Evaluar los predictores de respuesta clínica completa y de la sobrevida.DISEÑO:Estudio retrospectivo de cohortes.AJUSTES:Centro oncológico designado por el NCI.PACIENTES:Adenocarcinomas de recto estadio I-III tratados entre 01/2018 y 05/2019 (n = 86).INTERVENCIONES:Radioterapia de corta duración seguida de quimioterapia de consolidación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó una regresión logística para evaluar los predictores de respuesta clínica completa. Los criterios de valoración incluyeron la sobrevida libre de recidiva local, el control regional, la sobrevida libre de metástasis a distancia y la sobrevida general.RESULTADOS:Un margen de resección circunferencial positivo (+) evaluado por imagenes de resonancia magnética nuclear en el momento del diagnóstico fue un predictor no clínico muy significativo de respuesta completa (razón de probabilidades/ OR: 4,1, p = 0,009) al ajustar el nivel de antígeno carcinoembrionario y el tamaño del tumor primario. Comparando con los pacientes que presetaban un margen de resección circunferencial patológico negativo (-), los pacientes con un margen de resección circunferencial patológico positivo (+) tuvieron una sobrevida libre de recidiva local (29% frente a 87%, p < 0,001), un control regional (57% frente a 94%, p < 0,001), una sobrevida libre de metástasis a distancia (43% frente a 95%, p < 0,001) y una sobrevida global (86% frente a 95%, p < 0,001) inferior en 2 años de seguimiento. Sin embargo, los subgrupos de margen de resección circunferencial (+) y (-) evaluados por imágenes de resonancia magnética nuclear en pacientes que tuvieron una respuesta clínica completa tuvieron un control regional similar, una sobrevida libre de metástasis a distancia y una sobrevida general >90% en 2 años de seguimiento.LIMITACIONES:Diseño retrospectivo, tamaño modesto de la muestra, seguimiento corto y heterogeneidad de tratamientos.CONCLUSIONES:La afectación del margen de resección circunferencial evaluado por resonancia magnética nuclear al momento del diagnóstico es un fuerte factor predictivo no clínico de respuesta completa. Sin embargo, los pacientes que logran una respuesta clínica completa después de un curso corto de radioterapia y quimioterapia de consolidación como manejo conservador tienen excelentes resultados clínicos independientemente del estado del margen de resección circunferencial inicial. Consulte Video Resumen en http://links.lww.com/DCR/C190 . (Traducción-Dr. Xavier Delgadillo ).

Visually guided respiratory motion management for Ethos adaptive radiotherapy.

PURPOSE: Ethos adaptive radiotherapy (ART) is emerging with AI-enhanced adaptive planning and high-quality cone-beam computed tomography (CBCT). Although a respiratory motion management solution is critical for reducing motion artifacts on abdominothoracic CBCT and improving tumor motion control during beam delivery, our institutional Ethos system has not incorporated a commercial solution. Here we developed an institutional visually guided respiratory motion management system to coach patients in regular breathing or breath hold during intrafractional CBCT scans and beam delivery with Ethos ART. METHODS: The institutional visual-guidance respiratory motion management system has three components: (1) a respiratory motion detection system, (2) an in-room display system, and (3) a respiratory motion trace management software. Each component has been developed and implemented in the clinical Ethos ART workflow. The applicability of the solution was demonstrated in installation, routine QA, and clinical workflow. RESULTS: An air pressure sensor has been utilized to detect patient respiratory motion in real time. Either a commercial or in-house software handled respiratory motion trace display, collection and visualization for operators, and visual guidance for patients. An extended screen and a projector on an adjustable stand were installed as the in-room visual guidance solution for the closed-bore ring gantry medical linear accelerator utilized by Ethos. Consistent respiratory motion traces and organ positions on intrafractional CBCTs demonstrated the clinical suitability of the proposed solution in Ethos ART. CONCLUSION: The study demonstrated the utilization of an institutional visually guided respiratory motion management system for Ethos ART. The proposed solution can be easily applied for Ethos ART and adapted for use with any closed bore-type system, such as computed tomography and magnetic resonance imaging, through incorporation with appropriate respiratory motion sensors.

Direct tumor visual feedback during free breathing in 0.35T MRgRT.

To present a tumor motion control system during free breathing using direct tumor visual feedback to patients in 0.35 T magnetic resonance-guided radiotherapy (MRgRT). We present direct tumor visualization to patients by projecting real-time cine MR images on an MR-compatible display system inside a 0.35 T MRgRT bore. The direct tumor visualization included anatomical images with a target contour and an auto-segmented gating contour. In addition, a beam-status sign was added for patient guidance. The feasibility was investigated with a six-patient clinical evaluation of the system in terms of tumor motion range and beam-on time. Seven patients without visual guidance were used for comparison. Positions of the tumor and the auto-segmented gating contour from the cine MR images were used in probability analysis to evaluate tumor motion control. In addition, beam-on time was recorded to assess the efficacy of the visual feedback system. The direct tumor visualization system was developed and implemented in our clinic. The target contour extended 3 mm outside of the gating contour for 33.6 ± 24.9% of the time without visual guidance, and 37.2 ± 26.4% of the time with visual guidance. The average maximum motion outside of the gating contour was 14.4 ± 11.1 mm without and 13.0 ± 7.9 mm with visual guidance. Beam-on time as a percentage was 43.9 ± 15.3% without visual guidance, and 48.0 ± 21.2% with visual guidance, but was not significantly different (P = 0.34). We demonstrated the clinical feasibility and potential benefits of presenting direct tumor visual feedback to patients in MRgRT. The visual feedback allows patients to visualize and attempt to minimize tumor motion in free breathing. The proposed system and associated clinical workflow can be easily adapted for any type of MRgRT.

Feasibility and safety assessment of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated mild hyperthermia in pelvic targets evaluated using an in vivo porcine model.

Purpose: To evaluate the feasibility and assess safety parameters of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT; heating to 40-45 °C) in various pelvic targets in a porcine model in vivo.Methods: Thirteen HT treatments were performed in six pigs with a commercial MRgHIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) to muscle adjacent to the ventral/dorsal bladder wall and uterus to administer 42 °C (±1°) for 30 min (±5%) using an 18-mm target diameter and 100 W power. Feasibility was assessed using accuracy, uniformity, and MR-thermometry performance-based metrics. Safety parameters were assessed for tissues in the targets and beam-path by contrast-enhanced MRI, gross-pathology and histopathology.Results: Across all HT sessions, the mean difference between average temperature (Tavg) and the target temperature within the target region-of-interest (tROI, the cross-section of the heated volume at focal depth) was 0.51 ± 0.33 °C. Within the tROI, the temperature standard deviation averaged 1.55 ± 0.31 °C, the average 30-min Tavg variation was 0.80 ± 0.17 °C, and the maximum difference between Tavg and the 10th- or 90th-percentile temperature averaged 2.01 ± 0.44 °C. The average time to reach ≥41 °C and cool to ≤40 °C within the tROI at the beginning and end of treatment was 47.25 ± 27.47 s and 66.37 ± 62.68 s, respectively. Compared to unheated controls, no abnormally-perfused tissue or permanent damage was evident in the MR images, gross pathology or histological analysis.Conclusions: MRgHIFU-mediated HT is feasible and safety assessment is satisfactory for treating an array of clinically-mimicking pelvic geometries in a porcine model in vivo, implying the technique may have utility in treating pelvic targets in human patients.

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer.

BACKGROUND: Pretreatment serum squamous cell carcinoma antigen (SCCA) is a prognostic biomarker in women with cervical cancer. SCCA has not been evaluated as an early indicator of response to chemoradiation therapy (CRT). The molecular role of the two SCCA isoforms, SCCA1 (SERPINB3) and SCCA2 (SERPINB4), in cervical cancer is unknown. We hypothesised that changes in serum SCCA during definitive CRT predicts treatment response, and that SCCA1 mediates radiation resistance. METHODS: Patients treated with definitive CRT for cervical squamous carcinoma with serum SCCA measured were included. SCCA immunohistochemistry was performed on tumour biopsies. Post-treatment FDG-PET/CT, recurrence, and overall survival were recorded. Radiation response of cervical tumour cell lines after SCCA1 expression or CRISPR/Cas9 knockout was evaluated by clonogenic survival assay. RESULTS: Persistently elevated serum SCCA during definitive CRT was an independent predictor of positive post-therapy FDG-PET/CT (P=0.043), recurrence (P=0.0046) and death (P=0.015). An SCCA1-expressing vector increased radioresistance, while SCCA knock out increased radiosensitivity of cervical tumour cell lines in vitro. CONCLUSIONS: Early response assessment with serum SCCA is a powerful prognostic tool. These findings suggest that escalation of therapy in patients with elevated or sustained serum SCCA and molecular targeting of SCCA1 should be considered.

BRAF V600E mutational status in pediatric thyroid cancer.

BACKGROUND: Clinical outcome of papillary thyroid carcinoma (PTC) in children differs significantly from that of adults. There is no clear explanation of this difference although previous studies have demonstrated a lower prevalence of the BRAF(V600E) mutation in PTC of children. However, data are limited due to the rarity of this diagnosis. BRAF(V600E) mutation prevalence and its relationship with outcome in pediatric PTC remain unclear. PROCEDURE: BRAF(V600E) mutational status was determined in 27 PTC patients less than 22 years of age using restriction fragment length polymorphism (RFLP) analysis. The relationship between BRAF(V600E) mutation status, patient and tumor characteristics as well as progression-free survival (PFS) were analyzed. RESULTS: BRAF(V600E) was present in 63% of patients and occurred more often in male patients versus females (P = 0.033). Presence of the mutation did not correlate with any difference in extent of disease at diagnosis, tumor size, capsular invasion, vascular invasion, soft tissue invasion, or margin status. At 10 years, PFS for BRAF(V600E) positive versus negative patients was 55.5% versus 70.0%, respectively (P = 0.48). Overall survival was 100% and median follow-up was 13.9 years. CONCLUSIONS: This study of pediatric PTC demonstrates that BRAF(V600E) mutations occur in children at a rate comparable to adults. We found a correlation of BRAF(V600E) with the male gender, but no evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that differences in disease course of PTC in children versus adults are not strongly dependent upon the presence of the BRAF(V600E) mutation.

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

The role of radiotherapy in the management of primary and metastatic liver malignancies has expanded in recent years due to advances such as IGRT and SBRT. MRI-guided radiotherapy (MRgRT) has arisen as an excellent option for the management of hepatocellular carcinoma, cholangiocarcinoma, and liver metastases due to the ability to combine improved hepatic imaging with conformal treatment planning paradigms like adaptive radiotherapy and advanced motion management techniques. Herein we review the data for MRgRT for liver malignancies, as well as describe workflow and technical considerations for the 2 commercially available MRgRT delivery platforms.

Feasibility of simulation free abdominal stereotactic adaptive radiotherapy using an expedited pre-plan workflow.

Background and Purpose: Improved hounsfield-unit accuracy of on-board imaging may lead to direct-to-unit treatment approaches We aimed to demonstrate the feasibility of using only a diagnostic (dx) computed tomography (CT)-defined target pre-plan in an in silico study of simulation-free abdominal stereotactic adaptive radiotherapy (ART). Materials and Methods: Eight patients with abdominal treatment sites (five pancreatic cancer, three oligometastases) were treated using an integrated adaptive O-Ring gantry system. Each patient's target was delineated on a dxCT. The target only pre-plan served primarily to seed the ART process. During the ART session, all structures were delineated. All simulated cases were treated to 50 Gy in 5 fractions to a planning target optimization structure (PTV_OPT) to allow for dose escalation within the planning target volume. Timing of steps during this workflow was recorded. Plan quality was compared between ART treatment plans and a plan created on a CT simulation scan using the traditional planning workflow. Results: The workflow was feasible in all attempts, with organ-at-risk (OAR) constraints met in all fractions despite lack of initial OAR contours. Median absolute difference between the adapted plan and simulation CT plan for the PTV_Opt V95% was 2.0 %. Median absolute difference in the D0.5 cm3 between the adapted plan and simulation CT plan was -0.9 Gy for stomach, 1.2 Gy for duodenum, -5.3 Gy for small bowel, and 0.3 Gy for large bowel. Median end-to-end workflow time was 63 min. Conclusion: The workflow was feasible for a dxCT-defined target-only pre-plan approach to stereotactic abdominal ART.

Dosimetric predictors of acute and late gastrointestinal toxicities in stereotactic online adaptive magnetic resonance-guided radiotherapy (SMART) for locally advanced pancreatic adenocarcinoma.

BACKGROUND AND PURPOSE: A retrospective evaluation of dosimetric predictors and leveraged dose-volume data for gastrointestinal (GI) toxicities for locally-advanced pancreatic cancer (LAPC) treated with daily stereotactic MRI-guided online-adaptive radiotherapy (SMART). MATERIALS AND METHODS: 147 patients with LAPC were treated with SMART at our institution between 2018 and 2021. Patients were evaluated using CTCAE V5.0 for RT-related acute (≤3 months) and late (>3 months) toxicities. Each organ at risk (OAR) was matched to a ≥ grade 2 (Gr2+) toxicity endpoint composite group. A least absolute shrinkage selector operator regression model was constructed by dose-volumes per OAR to account for OAR multicollinearity. A receiver operator curve (ROC) analysis was performed for the combined averages of significant toxicity groups to identify critical volumes per dose levels. RESULTS: 18 of 147 patients experienced Gr2+ GI toxicity. 17 Gr2+ duodenal toxicities were seen; the most significant predictor was a V33Gy odds ratio (OR) of 1.69 per cc (95 % CI 1.14-2.88). 17 Gr2+ small bowel (SB) toxicities were seen; the most significant predictor was a V33Gy OR of 1.60 per cc (95 % CI 1.01-2.53). The AUC was 0.72 for duodenum and SB. The optimal duodenal cut-point was 1.00 cc (true positive (TP): 17.8 %; true negative (TN); 94.9 %). The SB cut-point was 1.75 cc (TP: 16.7 %; TN: 94.3 %). No stomach or large bowel dose toxicity predictors were identified. CONCLUSIONS: For LAPC treated with SMART, the dose-volume threshold of V33Gy for duodenum and SB was associated with Gr2+ toxicities. These metrics can be utilized to guide future dose-volume constraints for patients undergoing upper abdominal SBRT.

A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiation Therapy 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 (National Clinical Trial 05096286). METHODS AND MATERIALS: 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 magnetic resonance imaging (MRI), 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 data sets were used for preplan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary data sets and deformed to patient-specific cone beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brain stem 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. Preplans were then reoptimized through online adaptation to create final, simulation-free plans, which were used 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 "preplan" was 1 weekday (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 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. CONCLUSIONS: Simulation-free HA-WBRT using online adaptive radiation therapy is feasible, safe, and results in dosimetrically comparable treatment plans to simulation CT-based workflows while providing convenience and time savings for patients.

Patient-Reported Outcomes Following Magnetic Resonance-Guided Radiation Therapy for Prostate Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review provides an overview of literature on the impact of magnetic resonance-guided radiation therapy (MRgRT) on patient-reported outcomes (PROs) in patients with prostate cancer (PC). METHODS AND MATERIALS: A systematic search was performed in October 2023 in PubMed, EMBASE, and Cochrane Library. The Patient, Intervention, Comparison, Outcomes, and Study design (PICOS) framework was used to determine eligibility criteria. Included were studies assessing PROs following MRgRT for PC with a sample size >10. Methodological quality was assessed using the Cochrane's Risk of Bias in Nonrandomized Studies - of Interventions and Cochrane's risk of bias tool for randomized trials. Relevant mean differences (MDs) compared with pre-RT were interpreted using minimal important differences. Meta-analyses were performed using random-effects models. Between-study heterogeneity was assessed using the I2 statistic. RESULTS: Eleven observational studies and 1 randomized controlled trial (n = 897) were included. Nine studies included patients with primary PC with MRgRT as first-line treatment (n = 813) and 3 with MRgRT as second-line treatment (n = 84). Substantial risk of bias was found in 5 studies. European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ) core 30 (C30) and EORTC QLQ prostate cancer module (PR25) scores were pooled from 3 studies, and Expanded Prostate Cancer Index Composite (EPIC)-26 scores were pooled from 4 studies. Relevant MDs for the urinary domain were found with the EPIC-26 (MD, -10.0; 95% CI, -12.0 to -8.1; I2 = 0%) and the EORTC QLQ-PR25 (MD, 8.6; 95% CI, -4.7 to 22.0; I2 = 97%), both at end-RT to 1-month follow-up. Relevant MDs for the bowel domain were found with the EPIC-26 (MD, -4.7; 95% CI, -9.2 to -0.2; I2 = 82%) at end-RT or 1-month follow-up, but not with the EORTC QLQ-PR25. For both domains, no relevant MDs were found after 3 months of follow-up. No relevant MDs were found in the general quality of life domains of the EORTC QLQ C30. CONCLUSIONS: MRgRT for PC results in a temporary worsening of patient-reported urinary and bowel symptoms during the first month after treatment compared with pre-RT, resolving at 3 months. No clinically relevant changes were found for general quality of life domains. These results provide important information for patient counseling and can serve as a benchmark for future studies.

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.

Ablative radiotherapy for colorectal liver metastases and intrahepatic cholangiocarcinoma.

The role of radiation therapy in the management of liver cancers, both primary and metastatic, has changed drastically over the past several decades. Although conventional radiation was limited by technology, the advent of advanced image-guided radiotherapy and the rise in evidence for and popularity of stereotactic body radiotherapy have expanded the indications for radiation in these two distinct disease types. Magnetic resonance imaging-guided radiation therapy, daily online adaptive radiotherapy, and proton radiotherapy are some of many modern radiotherapy techniques that allow for increasingly efficacious treatment of intrahepatic disease while simultaneously allowing for increased normal tissue sparing, including sparing of the normal liver and the radiosensitive luminal gastrointestinal tract. Modern radiation therapy should be considered along with approaches such as surgical resection and radiofrequency ablation for the management of liver cancers of diverse histologies. Herein we describe the use of modern radiotherapy in two example settings, colorectal liver metastases and intrahepatic cholangiocarcinoma, and how external beam radiotherapy provides options within multidisciplinary discussions to elect optimal patient-specific treatments.

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.

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.