Incidence and risk factors for bone metastases at presentation in solid tumors.

Introduction: Bone metastases are associated with increased morbidity and decreased quality of life in patients with solid tumors. Identifying patients at increased risk of bone metastases at diagnosis could lead to earlier interventions. We sought to retrospectively identify the incidence and predictive factors for bone metastases at initial diagnosis in a large population-based dataset. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients 18 years-old or older diagnosed with solid cancers from 2010 to 2019. Patients with hematologic malignancies and primary tumors of the bone were excluded. We calculated the incidence and predictive factors for bone metastases according to demographic and tumor characteristics. Results: Among 1,132,154 patients identified, 1,075,070 (95.0%) had known bone metastasis status and were eligible for the study. Bone metastases were detected in 55,903 patients (5.2% of those with known bone metastases status). Among patients with bone metastases, the most common primary tumors arose from lung (44.4%), prostate (19.3%), breast (12.3%), kidney (4.0%), and colon (2.2%). Bone metastases at presentation were most common in small cell lung cancer (25.2%), non-small cell lung cancer (18.0%), and esophageal adenocarcinoma (9.4%). In addition to stage classification, predictors for bone metastases included Gleason score (OR 95.7 (95% CI 73.1 - 125.4) for Grade Group 5 vs 1 and OR 42.6 (95% CI 32.3 - 55.9) for Group 4 vs 1) and PSA (OR 14.2 (95% CI 12.6 - 16.0) for PSA > 97 vs 0 - 9.9) for prostate cancer, HER2 and hormonal receptor (HR) status (OR 2.2 (95% CI 1.9 - 2.6) for HR+/HER2+ vs HR-/HER2-) for breast cancer, histology (OR 2.5 (95% CI 2.3 - 2.6) for adenocarcinoma vs squamous) for lung cancer, and rectal primary (OR 1.2 (95% 1.1 - 1.4) vs colon primary) and liver metastases (OR 8.6 (95% CI 7.3 - 10.0) vs no liver metastases) for colorectal tumors. Conclusions: Bone metastases at presentation are commonly seen in solid tumors, particularly lung, prostate, breast, and kidney cancers. Clinical and pathologic factors are associated with a significantly increased risk for bone metastases.

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.

Inter-fractional portability of deep learning models for lung target tracking on cine imaging acquired in MRI-guided radiotherapy.

MRI-guided radiotherapy systems enable beam gating by tracking the target on planar, two-dimensional cine images acquired during treatment. This study aims to evaluate how deep-learning (DL) models for target tracking that are trained on data from one fraction can be translated to subsequent fractions. Cine images were acquired for six patients treated on an MRI-guided radiotherapy platform (MRIdian, Viewray Inc.) with an onboard 0.35 T MRI scanner. Three DL models (U-net, attention U-net and nested U-net) for target tracking were trained using two training strategies: (1) uniform training using data obtained only from the first fraction with testing performed on data from subsequent fractions and (2) adaptive training in which training was updated each fraction by adding 20 samples from the current fraction with testing performed on the remaining images from that fraction. Tracking performance was compared between algorithms, models and training strategies by evaluating the Dice similarity coefficient (DSC) and 95% Hausdorff Distance (HD95) between automatically generated and manually specified contours. The mean DSC for all six patients in comparing manual contours and contours generated by the onboard algorithm (OBT) were 0.68 ± 0.16. Compared to OBT, the DSC values improved 17.0 - 19.3% for the three DL models with uniform training, and 24.7 - 25.7% for the models based on adaptive training. The HD95 values improved 50.6 - 54.5% for the models based on adaptive training. DL-based techniques achieved better tracking performance than the onboard, registration-based tracking approach. DL-based tracking performance improved when implementing an adaptive strategy that augments training data fraction-by-fraction.

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment paradigm for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below limits of detection by imaging) and benefit from systemic therapy. To risk-stratify and identify the patients most likely to benefit from locally consolidative RT, we performed a multi-institutional cohort study of 1487 patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). In total, 1880 liquid biopsies were performed and approximately 20% of patients (n = 309) had ctDNA measured prior to RT and after their diagnosis of oligometastatic disease. Patients with undetectable ctDNA (pathogenic or likely pathogenic variants in plasma using the Tempus xF assay) before RT had significantly improved progression-free survival (PFS) (P = 0.004) and overall survival (OS) (P = 0.030). ctDNA maximum variant allele frequency (VAF) pre-RT and ctDNA mutational burden pre-RT were both significantly inversely correlated with PFS (maximum VAF P = 0.008, mutational burden P = 0.003) and OS (maximum VAF P = 0.007, mutational burden P = 0.045). These findings were corroborated by multivariate Cox proportional hazards models that included eight additional clinical and genomic parameters. Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.

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

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

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.

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

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

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 ).

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease can experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below current limits of detection by imaging) that may benefit from further prioritization of systemic therapy. To better risk-stratify this population and identify the patients most likely to benefit from locally consolidative radiation therapy, we performed a multi-institutional cohort study of patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). Among this real-world cohort of 1,487 patients undergoing analysis (using the Tempus xF assay), a total of 1,880 ctDNA liquid biopsies along with paired clinical data were obtained across various timepoints. Approximately 20% (n=309) of patients had ctDNA obtained prior to RT and after their diagnosis of oligometastatic disease. Samples were de-identified and analyzed for mutational burden and variant frequencies of detectable deleterious (or likely deleterious) mutations in plasma. Patients with undetectable ctDNA before RT had significantly improved progression-free survival and overall survival compared to patients with detectable ctDNA prior to RT. In patients that received RT, 598 pathogenic (or likely deleterious) variants were identified. ctDNA mutational burden pre-RT and ctDNA maximum variant allele frequency (VAF) pre-RT were both significantly inversely correlated with both progression-free (P = 0.0031 for mutational burden, P = 0.0084 for maximum VAF) and overall survival (P = 0.045 for mutational burden, P = 0.0073 for maximum VAF). Patients without detectable ctDNA prior to RT had significantly improved progression-free survival (P = 0.004) and overall survival (P = 0.03) compared to patients with detectable ctDNA prior to RT. These data suggest that in patients with oligometastatic NSCLC, pre-radiotherapy ctDNA analysis can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged progression-free and overall survival. Similarly, ctDNA may be useful to identify those patients with undiagnosed micrometastatic disease, in whom it may be appropriate to prioritize systemic therapy.

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

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

Trends in Stage I Lung Cancer.

INTRODUCTION: The American Cancer Society has recently reported an increase in the percentage of patients with localized lung cancer from 2004 to 2018, coinciding with the initial lung cancer screening guidelines issued in 2013. We conducted a National Cancer Database (NCDB) study to further evaluate the trends in stage I according to patient and tumor characteristics. METHODS: We selected patients with lung cancer from the NCDB Public Benchmark Report diagnosed between 2010 and 2017. Patients with stages I to IV according to the AJCC seventh edition were evaluated according to the year of diagnosis, histology, age, sex, race, and insurance. RESULTS: Among the 1,447,470 patients identified in the database, 56,382 (3.9%) were excluded due to stage 0 or unknown, or incorrect histology, leaving 1,391,088 patients eligible. The percentage of patients with stage I increased from 23.5% in 2010 to 29.1% in 2017 for all lung cancers, from 25.9% to 31.8% in non-small-cell lung cancer (NSCLC), and from 5.0% to 5.4% in small-cell lung cancer (SCLC). Patients younger than 70 years, males and blacks had lower percentages of stage I compared to older patients, females, and nonblacks respectively. Patients with no insurance had the lowest percentage of stage I. CONCLUSIONS: There has been a significant increase in the percentage of stage I lung cancer at diagnosis from 2010 to 2017, which occurred mostly in NSCLC. Although the staging shift was observed in all subsets of patients, there were noticeable imbalances according to demographic factors.

The first reported case of a patient with pancreatic cancer treated with cone beam computed tomography-guided stereotactic adaptive radiotherapy (CT-STAR).

BACKGROUND: Online adaptive stereotactic radiotherapy allows for improved target and organ at risk (OAR) delineation and inter-fraction motion management via daily adaptive planning. The use of adaptive SBRT for the treatment of pancreatic cancer (performed until now using only MRI or CT on rails-guided adaptive radiotherapy), has yielded promising outcomes. Herein we describe the first reported case of cone beam CT-guided stereotactic adaptive radiotherapy (CT-STAR) for the treatment of pancreatic cancer. CASE PRESENTATION: A 61-year-old female with metastatic pancreatic cancer presented for durable palliation of a symptomatic primary pancreatic mass. She was prescribed 35 Gy/5 fractions utilizing CT-STAR. The patient was simulated utilizing an end-exhale CT with intravenous and oral bowel contrast. Both initial as well as daily adapted plans were created adhering to a strict isotoxicity approach in which coverage was sacrificed to meet critical luminal gastrointestinal OAR hard constraints. Kilovoltage cone beam CTs were acquired on each day of treatment and the radiation oncologist edited OAR contours to reflect the patient's anatomy-of-the-day. The initial and adapted plan were compared using dose volume histogram objectives, and the superior plan was delivered. Use of the initial treatment plan would have resulted in nine critical OAR hard constraint violations. The adapted plans achieved hard constraints in all five fractions for all four critical luminal gastrointestinal structures. CONCLUSIONS: We report the successful treatment of a patient with pancreatic cancer treated with CT-STAR. Prior to this treatment, the delivery of ablative adaptive radiotherapy for pancreatic cancer was limited to clinics with MR-guided and CT-on-rails adaptive SBRT technology and workflows. CT-STAR is a promising modality with which to deliver stereotactic adaptive radiotherapy for pancreatic cancer.

Oligometastatic Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Chemotherapy With Nonoperative Intent of the Primary for Locoregional Complete Responders.

PURPOSE: Nonoperative management with short-course radiation therapy (SCRT) as a component of definitive therapy for oligometastatic rectal cancer has not been previously reported. This single-institution retrospective analysis evaluates treatment with SCRT in combination with chemotherapy (SCRT-CTX) with nonoperative intent for patients with a locoregional clinical complete response (cCR). METHODS AND MATERIALS: Thirty-six patients with newly diagnosed oligometastatic rectal cancer were treated with SCRT-CTX between January 1, 2018, and May 31, 2020. Digital rectal examination, endoscopy, and imaging (computed tomography or magnetic resonance imaging) were used to determine cCR. Medically operable patients without cCR underwent surgical resection of the primary rectal tumor. Patients with cCR who experienced a local failure received salvage surgery. Rates of hospitalization related to primary tumor disease and pelvic symptoms were reviewed. Overall survival (OS) and progression free survival were evaluated. RESULTS: Seventeen percent (6/36) of patients achieved cCR after SCRT-CTX. Eleven percent (4) of patients experienced a local failure. OS for all patients was 83% (71%-96%) at 12 months and 57% (41%-80%) at 24 months. Progression free survival for all patients was 56% (41%-74%) at 12 months and 10% (3.1%-35%) at 24 months. On multivariate analysis, having received more than 4 months of chemotherapy (hazard ratio = 0.21; 95% confidence interval, 0.06-0.71; P = .01) and definitive treatment of metastatic site (hazard ratio = 0.17; 95% confidence interval, 0.05-0.66; P = .01) predicted for improved OS. The number of patients requiring hospitalization due to obstruction (8/36, 22%), rectal bleeding (5/36, 14%), or need for permanent ostomy placement (5/36, 14%) was low, and there was a decrease in endorsement of obstructive symptoms and rectal bleeding after completion of SCRT-CTX. CONCLUSIONS: SCRT-CTX with nonoperative intent for patients with a locoregional cCR may be a reasonable treatment option for patients with newly diagnosed oligometastatic rectal adenocarcinoma and demonstrates excellent control of pelvic disease and symptoms. Increased duration of chemotherapy within the treatment paradigm may improve oncologic outcomes.

Cost-effectiveness of Total Neoadjuvant Therapy With Short-Course Radiotherapy for Resectable Locally Advanced Rectal Cancer.

Importance: Short-course radiotherapy and total neoadjuvant therapy (SCRT-TNT) followed by total mesorectal excision (TME) has emerged as a new treatment paradigm for patients with locally advanced rectal adenocarcinoma. However, the economic implication of this treatment strategy has not been compared with that of conventional long-course chemoradiotherapy (LCCRT) followed by TME with adjuvant chemotherapy. Objective: To perform a cost-effectiveness analysis of SCRT-TNT vs LCCRT in conjunction with TME for patients with locally advanced rectal cancer. Design, Setting, and Participants: A decision analytical model with a 5-year time horizon was constructed for patients with biopsy-proven, newly diagnosed, primary locally advanced rectal adenocarcinoma treated with SCRT-TNT or LCCRT. Markov modeling was used to model disease progression and patient survival after treatment in 3-month cycles. Data on probabilities and utilities were extracted from the literature. Costs were evaluated from the Medicare payer's perspective in 2020 US dollars. Sensitivity analyses were performed for key variables. Data were collected from October 3, 2020, to January 20, 2021, and analyzed from November 15, 2020, to April 25, 2021. Exposures: Two treatment strategies, SCRT-TNT vs LCCRT with adjuvant chemotherapy, were compared. Main Outcomes and Measures: Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Both costs and QALYs were discounted at 3% annually. Willingness-to-pay threshold was set at $50 000/QALY. Results: During the 5-year horizon, the total cost was $41 355 and QALYs were 2.21 for SCRT-TNT; for LCCRT, the total cost was $54 827 and QALYs were 2.12, resulting in a negative incremental cost-effectiveness ratio (-$141 256.77). The net monetary benefit was $69 300 for SCRT-TNT and $51 060 for LCCRT. Sensitivity analyses using willingness to pay at $100 000/QALY and $150 000/QALY demonstrated the same conclusion. Conclusions and Relevance: These findings suggest that SCRT-TNT followed by TME incurs lower cost and improved QALYs compared with conventional LCCRT followed by TME and adjuvant chemotherapy. These data offer further rationale to support SCRT-TNT as a novel cost-saving treatment paradigm in the management of locally advanced rectal cancer.

A single-institution phase I feasibility study of dose-escalated IMRT for non-operative locally advanced esophageal carcinoma.

BACKGROUND AND PURPOSE: Radiation dose escalation to improve poor outcomes with chemoradiation in locally advanced esophageal carcinoma is limited in part by increased toxicity. This Phase I study investigates the use of IMRT to improve tolerability of dose escalation. MATERIALS AND METHODS: A single-institution, prospective study was conducted between 2007 and 2013 for individuals with inoperable esophageal carcinoma. Gross disease received 60 Gy in 30 fractions and at-risk sites received 54 Gy with simultaneous integrated boost. Concurrent chemotherapy primarily consisted of cisplatin/5-FU. The primary objective was to assess feasibility (<15% rate of grade 4-5 toxicity). Secondary objectives included assessment of overall survival (OS), progression free survival (PFS), and locoregional (LRR) and distant recurrence. RESULTS: Twenty-six patients were enrolled with median follow up of 17.6 months (range 0.1 to 152.0). The majority were AJCC 7th edition Stage III (54%), distal esophagus primary (81%), and adenocarcinoma histology (85%). Twenty-one patients (81%) completed their course of radiation therapy, while only 55% received 2 cycles of concurrent cisplatin/5-FU. One grade 5 and one grade 4 cardiac event occurred, both during chemoradiation and before receiving 50 Gy. The 3-year OS was 48.6% (95% CI: 32.5 to 72.2%) and PFS was 28.5% (95% CI: 14.6 to 55.5%). Half developed distant failure with LRR occurring in 10 patients (38%), isolated in 5 patients. CONCLUSION: While feasibility was demonstrated, toxicity and compliance remained limiting factors with outcomes similar to historical controls. There remains an uncertain role for dose escalation in definitive management of locally advanced esophageal cancer.

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer.

BACKGROUND: Consolidation durvalumab improved overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) in the PACIFIC trial; however, pneumonitis was increased with durvalumab. We sought to examine real-world outcomes with the PACIFIC paradigm, especially factors associated with pneumonitis, using a multi-institutional review. METHODS: Patients with LA-NSCLC treated with CRT followed by durvalumab from January 2017-February 2019 were identified at 2 institutions. We characterized demographics, tumor factors, radiotherapy, and duration of durvalumab. We examined pneumonitis outcomes including re-challenge success, with secondary endpoints of progression-free survival (PFS) and OS. RESULTS: Thirty-four patients were included with median follow-up of 12 months (range, 3 to 20 months); 94% had stage III disease. The cumulative grade >2 pneumonitis rate was 26.5% with 2 patients developing grade 3 pneumonitis and no grade 4/5 events. Median time to pneumonitis after RT was 2.4 months (range, 0 to 4.9 months). Pneumonitis management included median prednisone dose of 60 mg for median taper of 6 weeks with durvalumab held for median of 4.5 weeks (range, 2 to 8 weeks); 70% of pneumonitis patients received durvalumab re-challenge, with pneumonitis recurring in 14% of patients. 3-month and 6-month pneumonitis-free-survival were 76.9% and 73.6%, respectively; 9- and 12-month OS were 96% (75.1-99.8%), 86.6% (63.5-95.5%), respectively; 9- and 12-month PFS were 68% (47.5-82.5%), 48.7% (25.3-68.3%). Pneumonitis development did not significantly impact PFS or OS (P>0.05). CONCLUSIONS: Among LA-NSCLC patients treated with CRT followed by consolidation durvalumab, more than 25% developed symptomatic pneumonitis. In this small case series, pneumonitis did not appear to negatively impact survival, and durvalumab re-challenge appeared feasible after pneumonitis treatment with steroids.

Impact of invasive nodal staging on regional and distant recurrence rates after SBRT for inoperable stage I NSCLC.

PURPOSE/OBJECTIVES: Before definitive stereotactic body radiation therapy (SBRT) for presumably node-negative, early-stage NSCLC, many patients are staged with PET/CT alone. In patients undergoing PET/CT prior to SBRT, the role of invasive nodal staging (INS) with endobronchial ultrasound (EBUS) or mediastinoscopy is uncertain. We sought to characterize the impact of nodal staging modality on outcomes. MATERIALS/METHODS: Patients receiving definitive SBRT for T1-2N0 NSCLC deemed node-negative by either PET/CT plus INS (EBUS or mediastinoscopy) or PET/CT alone were identified. Patients with initially equivocal or positive nodes on PET/CT were excluded from this analysis. All patients received 3-5 fraction SBRT according to institutional guidelines. Control was assessed by at least one follow-up CT in all patients. Multivariable logistic regression (MVA) was performed to identify variables independently associated with use of INS. RESULTS: We identified 651 eligible patients at our institution from 2005-2016. INS was performed in 15.2% of patients (n = 99) with EBUS (n = 78) or mediastinoscopy (n = 21). Median follow-up was 19.4 months (0.2-135.1). Median survival was 28.5 months (0.6-140). Factors predictive of increased likelihood of INS after negative PET/CT on MVA were age (OR for decreasing age 1.033; 95% CI 1.058-1.010), Caucasian race (OR vs. non-white 1.852; 1.044-3.289), male sex (1.629; 1.031-2.575), central location (1.978; 1.218-3.211) and squamous histology (2.564; 1.243-5.287). Nodal and/or distant control at 2 years was similar between PET/CT alone (78%, 95% CI 74-82%) and INS + PET/CT (75%, 95% CI 65-85%) (p = 0.877) as well as on MVA. Overall survival did not differ based on staging modality. CONCLUSIONS: In patients with early-stage NSCLC deemed node-negative by PET/CT, addition of INS did not appreciably alter patterns of failure or survival after definitive SBRT. This study does not question the established value of INS for equivocal or suspicious nodes.

Radiation Therapy Workflow and Dosimetric Analysis from a Phase 1/2 Trial of Noninvasive Cardiac Radioablation for Ventricular Tachycardia.

PURPOSE: A prospective phase 1/2 trial for electrophysiologic guided noninvasive cardiac radioablation treatment of ventricular tachycardia (ENCORE-VT) demonstrating efficacy for arrhythmia control has recently been reported. The treatment workflow, report dose-volume metrics, and overall process improvements are described here. METHODS AND MATERIALS: Patients receiving 25 Gy in a single fraction to the cardiac ventricular tachycardia substrate (identified on presimulation multimodality imaging) on the phase 1/2 trial were included for analysis. Planning target volume (PTV), R50, monitor unit ratio, and gradient measure values were compared over time using statistical process control. Outlier values in the dose-volume histogram (DVH) for PTV and organs at risk were identified by calculating inner fences based on the interquartile range. Median heart substructure doses are also reported. RESULTS: For the 16 trial patients included, the median target volumes for the gross "target" volumes, internal target volumes, and PTVs were 25.1 cm3 (minimum: 11.5 cm3, maximum: 54.9 cm3), 30.1 cm3 (17.7, 81.6), and 97.9 cm3 (66, 208.5), respectively. On statistical process control analysis, there was a significant decrease in PTV volume among the more recent cohort of cases and mean doses to the nontargeted heart (heart - PTV). Two patients had heart-minus-PTV, esophagus, and stomach DVH data significantly higher than inner fence, and 3 patients had spinal cord DVH data higher than the inner fence, but in all cases the deviations were clinically acceptable. Subjective decreases were seen in the R50, gradient measure, and treatment time from the first to last patient in this series. All plans were verified in phantom with ionization chamber measurements within 2.9% of the expected dose value. CONCLUSIONS: Over the duration of this trial, PTV volumes to the cardiac substrate target decreased significantly, and organ-at-risk constraints were met for all cases. Future directions for this clinical process will include incorporating knowledge-based planning techniques and evaluating the need for substructure optimization.

Treatment of T3N0 non-small cell lung cancer with chest wall invasion using stereotactic body radiotherapy.

OBJECTIVES: Chest wall invasion (CWI) is observed in 5% of localized non-small cell lung cancer (NSCLC). The role of stereotactic body radiotherapy (SBRT) in these patients is unknown. We investigate the safety and efficacy of SBRT in patients with T3N0 NSCLC due to CWI. METHODS: Patients with T3N0 NSCLC due to CWI were identified using a prospective registry. CWI was defined as radiographic evidence of soft tissue invasion or bony destruction. We excluded patients with recurrent or metastatic disease. All patients were treated with definitive SBRT. Prescribed dose was 50 Gy in 5 fractions for most patients. Kaplan-Meier analysis was used to estimate survival outcomes. RESULTS: We identified 12 patients treated between 2006 and 2017. Median age was 70 (range, 58-85). Median tumor diameter was 3.0 cm (range, 0.9-7.2). Median survival was 12.0 months (range, 2.4-63). At a median follow-up of 8.9 months (range, 2.1-63), 1-year primary tumor control was 89%, involved lobar control was 89%, local-regional control was 82%, distant control was 91%, and survival was 63%. Of the 4 patients with pre-treatment chest wall pain, 3 reported improvement after SBRT. Two patients reported new grade 1-2 chest wall pain. No grade 3+ toxicity was reported, with 1 patient experiencing grade 1 skin toxicity and 3 patients experiencing grade 1-2 radiation pneumonitis. CONCLUSIONS: SBRT for CWI NSCLC is safe, with high early tumor control and low treatment-related toxicity. Most patients with pre-treatment chest wall pain experienced relief after SBRT, with no grade 3+ toxicity observed.