Fraction Stereotactic Body Radiation Therapy Research Articles

Change in Quality of Life after Stereotactic Body Radiation Therapy (SBRT) on a Prospective Trial of Peripheral Stage I or II Non-Small Cell Lung Cancer Predicts Survival

We previously reported the results of a randomized, multi-institutional phase II clinical trial evaluating one versus three fractions of SBRT for peripheral Stage I to II non-small cell lung cancer (NSCLC). A secondary objective to compare quality of life (QOL) data and its association with survival outcomes is reported. Medically inoperable patients with biopsy-proven peripheral T1-2N0M0 NSCLC were enrolled. Patients were randomized to 30 Gy in 1 fraction (arm 1) or 60 Gy in 3 fractions (arm 2) and stratified by performance status. QOL scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ Lung Cancer-Specific Module (EORTC QLQ-LC13) questionnaires were required at baseline and each follow-up visit. Univariate models were generated to evaluate associations between QOL scores and survival with 95% confidence intervals (CI) calculated at each time point. Among 98 patients enrolled (49 in each arm), 88 patients had data available for QOL analysis. At 6 month follow up, patients with stable or decreased (n = 49) versus those with increased global QOL scores (n = 27) had worse progression-free survival (HR [Hazards' Ratio] 2.32 [CI, 1.14-4.73], p = 0.021) and overall survival (HR 2.13 [CI, 1.01-4.51], p = 0.048). Similar results persisted at the 12 month follow up for progression-free survival (HR 3.90 [CI, 1.52-10.04], p = 0.016) and overall survival (HR 3.25 [CI, 1.25-8.43], p = 0.016). Median overall survival for patients with stable or decreased global QOL versus increased global QOL at 6 month follow up was 39.0 vs 60.3 months (p = 0.032). Change in QOL is an early predictor of survival following SBRT for patients with peripheral early-stage NSCLC.

Longitudinal Radiomics-Based Prediction of Local Recurrence after Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

Computed tomography (CT)-based radiomic analysis is an emerging tool that can help predict recurrence after radiation in non-small cell lung cancer (NSCLC). Most studies have focused on using radiomic features obtained from pre-treatment CT scans but not on post-treatment CTs. Our goal was to determine if radiomic features derived from post-treatment CTs perform better than those from pre-treatment CTs in predicting local recurrence after stereotactic body radiation therapy (SBRT) in patients with early-stage NSCLC. Patients with T1/T2 N0 early-stage NSCLC were retrospectively reviewed. Criteria for selection included patients with biopsy-proven NSCLC, non-ground glass solid lesions, 4-5 fraction SBRT treatments, and non-contrast thin-slice CTs available at pre-treatment baseline and at 3 and 6 months post-SBRT. Clinical and tumor characteristics were compared using Chi-square and Student's t-tests. CT image pre-processing was performed and 107 radiomic features were extracted using 3D Slicer and open-source software. Univariate analysis for local recurrence was determined by Cox regression with death as a competing risk. The Benjamini-Hochberg Procedure was applied to control the false discovery rate. Pearson correlation analysis was used to exclude redundant features (r > 0.8), and multivariate analysis was conducted with Random Forest on the top-performing features found on univariate logistic regression. Models were trained on a class-balanced loss to account for class imbalance. Twenty iterations of stratified 3 k-fold cross-validation were used to select the best model by the area under the receiver operating characteristic curve (AUC). We identified and analyzed 86 patient tumors, including 76 non-local recurrences and 10 local recurrences (49 males, 37 females; age, median 72, range 52-91 years). No differences in age, histology, standardized uptake values on positron emission tomography scans, gross tumor volume, and radiation dose were found between patients with and without local recurrence (all p >0.05). The median time to local recurrence was 18.9 months (range 5.5-45.6 months). At the baseline, 3-month, and 6-month timepoints, 2, 10, and 10 radiomic features predicted local recurrence on Cox regression univariate analysis, respectively (all q <0.01). On multivariate analysis of top-performing radiomic features, the 3-month timepoint performed the best with a mean (±standard deviation) AUC score of 0.82 (±0.13) compared to a mean AUC of 0.73 (±0.086) at baseline and a mean AUC of 0.74 (±0.10) at 6 months. Post-treatment radiomic features at 3 months outperformed pre-treatment radiomic features in predicting local recurrence after SBRT for NSCLC. These results suggest radiomic data from follow-up CTs may be helpful when developing radiomic models to predict local recurrence in patients with NSCLC.

Clinical Efficacy and Safety of Once-Weekly Fractionation in Stereotactic Body Radiotherapy for Pulmonary Oligometastatic Lesions

As the oligometastatic disease paradigm has become more widely accepted, further investigation is needed to risk-stratify patients within this spectrum of disease and define optimal treatment methods. Stereotactic Body Radiotherapy (SBRT) has emerged as an efficacious and safe modality to control individual lesions and improve clinical outcomes in the setting of oligometastatic disease. There is scant literature describing ideal SBRT inter-fraction time intervals or their impact on clinical outcomes, especially for treating pulmonary oligometastases. Most institutions appear to offer treatments on consecutive days or every other day. In this abstract, we sought to evaluate the efficacy and safety of delivering SBRT treatments in a once-weekly fractionation scheme. The study was undertaken via retrospective review at a single institution. We included patients with pulmonary metastatic lesions treated with SBRT at our institution between 2015 and 2019. Patients with oligometastatic disease were included, defined as patients with 5 or fewer total metastatic lesions. Treatments were delivered between 3 and 5 fractions and using at least 5 Gy per fraction. Per institutional protocol, all treatments were delivered 7 days apart. From a single institution, 204 lesions from 111 patients were included. Median follow-up was 16.5 months [IQR 7 - 36.3]. Median dose was 40 Gy [IQR 30 - 50], median BED was 80 Gy [IQR 60-100], median dose per fraction was 10 Gy [IQR 8-11]. Median internal target volume (ITV) was 18.5 cc [IQR 9.3 - 45.8]. The most common tumor histologies were lung adenocarcinoma (38.2%), colorectal adenocarcinoma (15.6%), lung squamous cell carcinoma (12.7%), renal cell carcinoma (5.9%), breast invasive ductal carcinoma (5.4%), small cell lung cancer (3.9%), and melanoma (2.9%). 2-year local control (LC) rate was 85.7% and 5-year LC rate was 84.3%. 2-year regional control (RC) rate was 53.9% and 5-year RC was 49%. Median overall survival (OS) was 20 months [IQR 9 - 37.3]. Cox regression analysis revealed biologically effective dose (BED) (HR 0.99 [0.98 - 0.99] p = 0.001) as well as dose per fraction (HR 0.92 [0.86 - 0.97] p = 0.003) were both associated with improved OS. Longest tumor dimension was associated with worse OS independent of BED and dose per fraction (HR 1.26 [1.1 - 1.4] p = 0.001). Total toxicity incidence was 7.3%, which consisted only of G1-G2 cough, dyspnea, and fatigue. Treatment of pulmonary oligometastatic lesions with SBRT delivered via once-weekly fractionation is associated with excellent local control and minimal toxicity. Larger studies are warranted to directly compare clinical outcomes of weekly SBRT fractionation to other conventional SBRT treatment schedules.

Cardiac and Great Vessel Toxicity with Single Fraction Stereotactic Body Radiotherapy in Early-Stage Lung Cancer

The relationship between thoracic radiotherapy and cardiovascular (CV) morbidity is an area of interest. When considering stereotactic body radiotherapy (SBRT) in the management of early-stage lung cancer, reports suggest CV dose may correlate with survival. To study this association for single fraction SBRT (SF-SBRT), we performed a retrospective review of patients treated at our institution assessing for associations between this dose schedule and CV toxicity. For the interval 2010-2022, we surveyed our IRB-approved prospective registry for SF-SBRT patients with tumors within 1 cm of the heart or any of the great vessels (GVs). Distance of the tumor to these structures was stratified as: directly contacting, within 0.5 cm, from 0.5-1 cm, or > 1 cm. Medical records were reviewed post-SBRT for CV events including: myocardial infarction (MI), heart failure (HF), structural heart damage (valvular or wall abnormalities), vascular damage (aneurysm, dilation, other abnormalities), hemoptysis, and arrhythmia which were correlated with lesion location and history. Four hundred four patients treated with SF-SBRT to 34 Gy in 1 fraction were identified. 35 patients (8.7%) had 36 lesions within 1 cm of the heart or GVs. 68.6% of patients were female and 74.3% were Caucasian. The median age was 72.5 years (range: 60-91), median Charlson comorbidity score was 6, median KPS was 80, and median ASCVD score was 21.0%. 33 patients had a smoking history with a median of 50 pack years. 12 patients (34.3%) had an arrhythmia prior to SBRT, 5 (14.2%) had prior HF, and 9 (25.7%) had prior MI or CV disease. All cases were non-small cell lung cancer or radiographic malignancy with 1 case of small cell lung cancer. Median tumor size was 1.6 cm. 91.4% of patients had stage I disease. Median follow-up was 2.26 years (0.37-4.0). Seven lesions (19.4%) were abutting the heart or GVs, 14 (38.9%) were within 0.5 cm, and 15 (41.7%) were from 0.5-1 cm. 54 events were observed with a median of 1 event per patient (0-5). The most common events were arrhythmia (15), vascular damage (9), structural damage (12), heart failure (9), and MI (6). The most commonly associated vascular structure was the aortic arch, while the most commonly involved substructures of the heart were the right atrium and left ventricle. 12 events occurred in the direct contact group, 17 in the < 0.5 cm group, and 25 in the 0.5-1 cm group. Patients with heart associated lesions accounted for 8 events, while those with vessel associated tumors accounted for 46. While cardiac events are relatively common in the medically inoperable SBRT population, they did not appear to be more common with tumors directly contacting major cardiovascular structures than for those with some separation. Most events could be attributed to medical causes other than SBRT. Further study is needed to clarify the potential role of radiation in events without direct explanation.

Optimal Radiation Therapy Fractionation Regimens for Early-Stage Non-Small Cell Lung Cancer

A series of radiobiological models were developed to study tumor control probability (TCP) for stereotactic body radiation therapy (SBRT) of early-stage non-small cell lung cancer (NSCLC) per the Hypofractionated Treatment Effects in the Clinic (HyTEC) working group. This study was conducted to further validate 3 representative models with the recent clinical TCP data ranging from conventional radiation therapy to SBRT of early-stage NSCLC and to determine systematic optimal fractionation regimens in 1 to 30 fractions for radiation therapy of early-stage NSCLC that were found to be model-independent. Recent clinical 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data of 9808 patients from 56 published papers were collected for radiation therapy of 2 to 4 Gy per fraction and SBRT of early-stage NSCLC. This data set nearly triples the original HyTEC sample, which was used to further validate the HyTEC model parameters determined from a fit to the clinical TCP data. TCP data from the expanded data set are well described by the HyTEC models with α/β ratios of about 20 Gy. TCP increases sharply with biologically effective dose and reaches an asymptotic maximal plateau, which allows us to determine optimal fractionation schemes for radiation therapy of early-stage NSCLC. The HyTEC radiobiological models with α/β ratios of about 20 Gy determined from the fits to the clinical TCP data for SBRT of early-stage NSCLC describe the recent TCP data well for both radiation therapy of 2 to 4 Gy per fraction and SBRT dose and fractionation schemes of early-stage NSCLC. A steep dose response exists between TCP and biologically effective dose, and TCP reaches an asymptotic maximum. This feature results in model-independent optimal fractionation regimens determined whenever safe for SBRT and hypofractionated radiation therapy of early-stage NSCLC in 1 to 30 fractions to achieve asymptotic maximal tumor control, and T2 tumors require slightly higher optimal doses than T1 tumors. The proposed optimal fractionation schemes are consistent with clinical practice for SBRT of early-stage NSCLC.

Plasma YKL-40 is associated with prognosis in patients with metastatic pancreatic cancer receiving immune checkpoint inhibitors in combination with radiotherapy.

YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is a secreted glycoprotein produced by various cell types including stromal, immune, and cancer cells. It contributes to cancer progression through tumor-promoting inflammation and has been shown to inhibit the cytotoxicity of T and NK lymphocytes. In vivo studies have demonstrated synergistic anti-cancer effects of blocking YKL-40 in combination with immune checkpoint inhibitors (ICIs). Biomarkers for the prediction of the response to ICIs are highly needed. We investigated the association between plasma YKL-40 and clinical benefit and survival in patients with metastatic pancreatic cancer (mPC) receiving ICIs and stereotactic body radiotherapy (SBRT). Blood samples were collected from 84 patients with mPC who participated in the randomized phase II CheckPAC study, in which patients received nivolumab with or without ipilimumab combined with a single fraction of SBRT. Plasma YKL-40 was measured using a commercial ELISA kit. Elevated baseline plasma YKL-40 was an independent predictor of shorter overall survival (OS) (HR 2.19, 95% CI 1.21-3.95). A ≥ 40% decrease in plasma YKL-40 during treatment was associated with longer progression-free survival (p = 0.009) and OS (p = 0.0028). There was no correlation between plasma YKL-40 and the tumor burden marker CA19-9 at baseline or during treatment. This study contributes new knowledge regarding YKL-40 as a predictor of clinical benefit from ICIs and radiotherapy. These exploratory results warrant further investigation of YKL-40 as a biomarker for patients treated with immunotherapies. Clinicaltrials.gov, identifier NCT02866383.

Neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreas adenocarcinoma: influence of vascular margin status and type of chemotherapy

BackgroundThe influence of chemotherapy type and vascular margin status after sequential chemotherapy and stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic cancer (BRPC) is unknown. MethodsA retrospective review was performed on BRPC patients treated with chemotherapy and 5-fraction SBRT from 2009 to 2021. Surgical outcomes and SBRT-related toxicity were reported. Clinical outcomes were estimated by Kaplan–Meier with log rank comparisons. ResultsA total of 303 patients received neoadjuvant chemotherapy and SBRT to a median dose of 40 Gy prescribed to the tumor–vessel interface and median dose of 32.4 Gyto 95% of the gross tumor volume. One hundred and sixty-nine patients (56%) were resected and benefited from improved median OS (41.1 vs 15.5 months, P < 0.001). Close/positive vascular margins were not associated with worse OS or FFLRF. Type of neoadjuvant chemotherapy did not influence OS for resected patients, but FOLFIRINOX was associated with improved median OS in unresected patients (18.2 vs 13.1 months, P = 0.001). ConclusionFor BRPC, the effect of a positive or close vascular margin may be mitigated by neoadjuvant therapy. Shorter duration neoadjuvant chemotherapy as well as the optimal biological effective dose of radiotherapy should be prospectively explored.

Stereotactic body radiotherapy for spine metastases: a review of 24 Gy in 2 daily fractions.

Stereotactic body radiotherapy (SBRT) has proven to be a highly effective treatment for selected patients with spinal metastases. Randomized evidence shows improvements in complete pain response rates and local control with lower retreatment rates favoring SBRT, compared to conventional external beam radiotherapy (cEBRT). While there are several reported dose-fractionation schemes for spine SBRT, 24 Gy in 2 fractions has emerged with Level 1 evidence providing an excellent balance between minimizing treatment toxicity while respecting patient convenience and financial strain. We provide an overview of the 24 Gy in 2 SBRT fraction regimen for spine metastases, which was developed at the University of Toronto and tested in an international Phase 2/3 randomized controlled trial. The literature summarizing global experience with 24 Gy in 2 SBRT fractions suggests 1-year local control rates ranging from 83-93.9%, and 1-year rates of vertebral compression fracture ranging from 5.4-22%. Reirradiation of spine metastases that failed prior cEBRT is also feasible with 24 Gy in 2 fractions, and 1-year local control rates range from 72-86%. Post-operative spine SBRT data are limited but do support the use of 24 Gy in 2 fractions with reported 1-year local control rates ranging from 70-84%. Typically, the rates of plexopathy, radiculopathy and myositis are under 5% in those series reporting mature follow up, with no cases of radiation myelopathy (RM) reported in the de novo setting when the spinal cord avoidance structure is limited to 17 Gy in 2 fractions. However, re-irradiation RM has been observed following 2 fraction SBRT. More recently, 2-fraction dose escalation with 28 Gy, with a higher dose constraint to the critical neural tissues, has been reported suggesting improved rates of local control. This regimen may be important in those patients with radioresistant histologies, high grade epidural disease, and/or paraspinal disease. The dose-fractionation of 24 Gy in 2 fractions is well-supported by published literature and is an ideal starting point for centers looking to establish a spine SBRT program.

Stereotactic body radiation therapy (SBRT) for spinal metastases: 12years of a single center experience.

To assess the clinical outcomes of patients with spine metastases treated with SBRT at our institution. Patients with spine metastases treated with SBRT (1 fraction/18Gy or 5 fractions/7Gy) during the last 12years have been analyzed. All patients were simulated supine in a vacuum cushion or with a shoulder mask. CT scans and MRI image registration were performed. Contouring was based on International Spine-Radiosurgery-Consortium-Consensus-Guidelines. Highly conformal-techniques (IMRT/VMAT) were used for treatment planning. Intra and interfraction (CBCT or X-Ray-ExacTrac) verification were mandatory. From February 2010 to January 2022, 129 patients with spinal metastases were treated with SBRT [1 fraction/18Gy (75%) or 5 fractions/7Gy] (25%). For patients with painful metastases (74/129:57%), 100% experienced an improvement in pain after SBRT. With a median follow-up of 14.2months (average 22.9; range 0.5-140) 6 patients (4.6%) experienced local relapse. Local progression-free survival was different, considering metastases's location (p < 0.04). The 1, 2 and 3years overall survival (OS) were 91.2%, 85.1% and 83.2%, respectively. Overall survival was significantly better for patients with spine metastases of breast and prostate cancers compared to other tumors (p < 0.05) and significantly worse when visceral metastases were present (p < 0.05), when patients were metastatic de novo (p < 0.05), and in those patients receiving single fraction SBRT (p: 0.01). According to our experience, SBRT for patients with spinal metastases was effective in terms of local control and useful to reach pain relief. Regarding the intent of the treatment, an adequate selection of patients is essential to propose this ablative approach.

Estimation of patient-size dependent imaging dose for stereoscopic/monoscopic real-time kV image guidance in lung and prostate SBRT

Purpose. The purpose of this work is to quantify the dependence of patient-specific imaging dose on patient-size from ExacTrac stereoscopic/monoscopic real-time tumor monitoring during lung and prostate stereotactic body radiotherapy (SBRT). Approach. Thirty lung and 30 prostate SBRT patients that were treated with volumetric modulated arc therapy (VMAT) were selected and divided into three patient size categories. Imaging doses from all SBRT fractions were calculated retrospectively assuming patients went through real-time tumor monitoring during their actual VMAT treatment times. Treatment times were divided into periods of stereoscopic and monoscopic real-time imaging depending on the imaging view with linac gantry blockage. The computed tomography (CT) images and contours of the planning target volume (PTV) and organs at risk (OARs) were exported from the treatment planning system. Based on the CT data, patient-specific 3D imaging dose distributions were calculated in a validated Monte Carlo model using DOSEXYZnrc. Vendor-recommended imaging protocols (lung: 120–140 kV, 16–25 mAs; prostate: 110–130 kV, 25 mAs) were used for each patient size category. Patient-specific imaging doses received by PTV and OARs were evaluated using dose volume histograms, dose delivered to 50% of organ volume (D50), and 2% of organ volume (D2). Results. Bone and skin received the highest imaging dose. For the lung patients, the highest D2 for bone and skin were 4.30% and 1.98% of the prescription dose respectively. For prostate patients, the highest D2 were 2.53% and 1.35% of the prescription for bone and skin. Additional imaging dose to PTV as a percentage of the prescribed dose was at most 2.42% for lung and 0.29% for prostate patients. T-test results showed statistically significant difference in D2 and D50 between at least two patient size categories for PTVs and all the OARs. Larger patients received more skin dose in both lung and prostate patients. For the internal OARs, larger patients received more dose in lung treatment while the trend was opposite in prostate treatment. Conclusion. Patient-specific imaging dose was quantified for monoscopic/stereoscopic real-time kV image guidance in lung and prostate patients with respect to patient size. Additional skin dose was 1.98% (in lung patients) and 1.35% (in prostate patients) of the prescription which is within 5% recommended value by the AAPM Task Group 180. For internal OARs, larger patients received more dose in lung patients while the trend was the opposite for prostate patients. Patient size was an important factor to determine additional imaging dose.

Stereotactic body irradiation for metastasis from renal carcinoma: A retrospective study

Background Renal cell carcinoma (RCC) has traditionally been considered to be radioresistant. Response rates are believed to be improved by a high dose of stereotactic body radiotherapy (SBRT). A retrospective analysis was conducted of patients treated with SBRT for metastatic disease from RCC. Material and methods We reviewed records from 20 patients who underwent SBRT for a total of 30 RCC metastases from 2015 to 2020. Patients were included who had a confirmed primary RCC and radiographic evidence of metastasis, either synchronous or metachronous. The most common SBRT fractionation was 30 Gy in 3 fractions. Results Median age was 60 years (range, 40–77 years) and 60% were male. After a median follow-up of 18 months (range, 3–36 months), overall survival was estimated to be 85% and 70%, at 1 and 2 years, respectively, and local control at 2 years was 83.33%. Only 5 patients had documented progression of disease, all of whom received biologically effective dose inferior to 100 Gy, and no patients treated with a higher biologically effective dose had disease, which progressed. The most common acute toxicity was grade 1 fatigue (20%). No grade 3 or higher acute toxicity occurred. Conclusions Treatment with SBRT in patients with RCC metastases yielded a high local control rate, promising survival rate, and low toxicity.

Biochemical disease control outcomes of stereotactic body radiation therapy (SBRT) or moderate hypo-fractionation (HFRT) for low- and intermediate-risk prostate cancer (PrCa): Retrospective analysis of 12 years of experience at two Canadian cancer centers.

363 Background: SBRT uses highly conformal radiotherapy to deliver high dose per fraction treatment. Advantages of SBRT include short treatment times, decreased costs and limited toxicity. Randomized trial outcomes of 7-fraction SBRT for low or intermediate PrCa were reported but results of studies that compared 5-fraction SBRT with conventional and HFRT are pending. Here, we reviewed the 12-year experience with SBRT and HFRT at the Juravinski and Walker Family Cancer Centers in Ontario. Methods: We reviewed patients with low or intermittent-risk PrCa treated with SBRT alone or HFRT alone in the period of July 2010 and February 2022. Database search criteria included treatments with SBRT 35-40Gy in 5 fractions and HFRT 60-62Gy in 20 fractions. Overall survival (OS), time to biochemical failure (per Phoenix criteria: i.e., 2ng/mL above PSA nadir) and biochemical failure-free survival (bFFS) were reviewed. Kaplan-Meier curves were used to assess OS and bFFS. Results: We identified 314 patients with low or intermediate-risk PrCa who were treated with SBRT and 258 patients who were treated with HFRT. Intermediate-risk category composed 86.0% and 95.7% of the SBRT and HFRT cohorts. ISUP Grade Group (GG) distributions for the SBRT and HFRT patients were: GG1: 19.4% and 9.3%, GG2: 72.9% and 74.0%, and GG3: 7.6% and 16.7%, respectively. OS rates at 5 years were 96.6% for SBRT vs. 95.8% for HFRT-treated patients. The 5-year bFFS rates for SBRT and HFRT were 92.3% and 90.1%, respectively. The 7-year bFFS rate for the SBRT cohort was 90.2%. Mean time to biochemical failure was 40.4 months after SBRT vs. 35.8 months after HFRT. Conclusions: SBRT is an effective treatment option for low to intermediate-risk PrCa with encouraging OS and bFFS rates comparable with HFRT. Pending randomized trial results will determine whether SBRT is the new standard of care for this population.

A phase I clinical trial of stereotactic body radiotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.

TPS626 Background: Systemic therapy with atezolizumab and bevacizumab (atezo/bev) has improved outcomes for advanced HCC, but results in objective responses in fewer than 30% of patients. Stereotactic body radiotherapy (SBRT) is currently used for small HCC tumors that do not require systemic therapy but has also been shown in a number of clinical trials of other solid tumors to enhance the anti-cancer immune response. Of particular interest, our prior experience with SBRT in a 17Gy fraction has demonstrated the ability to restore sensitivity to immunotherapy in advanced solid tumors, even those previously refractory to immunotherapy. We hypothesize that repeated high dose fractions of radiation will act as an immune booster and will improve on outcomes of patients with advanced HCC. Since the combination of SBRT and atezo/bev has not yet been tested prospectively in patients with HCC, and because bevacizumab is a known radiosensitizer, we are conducting a phase I trial to evaluate the safety of repeated SBRT doses. Methods: This is a single-site phase I clinical trial utilizing a Rolling 6 design to determine the safety of 1, 2, or 3 doses of SBRT fractions in combination with atezo/bev. Up to 18 total patients will be enrolled (n=6 per cohort). Patients must be naïve to systemic therapy with Child-Pugh A or B liver function, at least one lesion amenable to radiation, and a measurable lesion that will not receive radiation. Patients with uncontrolled ascites or hepatic encephalopathy are excluded. Atezo/bev is administered at the standard doses every 21 days. SBRT will start 1 week after the first infusion of this combination. Patients will receive 1, 2, or 3 17Gy fractions of SBRT at 4-week intervals (cohorts 2 and 3 only). Patients will undergo serial collections of circulating cell-free DNA (ccfDNA), methylated DNA, and peripheral blood mononuclear cells to investigate the application of these markers as a predictor of response. Following completion of SBRT, patients will continue with atezo/bev until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the proportion of patients experiencing dose-limiting toxicities (grade 3 or higher radiation-related toxicities graded by the Common Terminology Criteria for Adverse Events, Version 5). Secondary endpoints are overall survival, progression-free survival, objective response rate, duration of response, and toxicity rates. Enrollment began 9/2022 and complete accrual is expected by June 2024. NCT05488522. Clinical trial information: NCT05488522 .

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience

Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Stereotactic body radiation therapy for colorectal cancer liver metastases.

The management of colorectal cancer liver metastases requires a multidisciplinary approach, which may incorporate systemic therapy, surgery, or local ablative therapies. Stereotactic body radiation therapy (SBRT) is a non-invasive highly conformal radiation technique that enables the delivery of large doses of radiation in a few fractions to well-defined targets using image-guidance and motion management. For selected patients with colorectal cancer liver metastases, stereotactic body radiation therapy can be delivered safely, with excellent long-term local control and overall survival. The purpose of this clinical practice review is to review the background, indications, and treatment details of stereotactic body radiation therapy for the treatment of colorectal liver metastases. SBRT for colorectal cancer liver metastases may be considered for patients with oligometastatic colorectal cancer in combination with surgery or other locally ablative therapies; for patients who are not candidates for surgical resection; or after failure of resection or other ablative therapies. When planning SBRT both a computed tomography and magnetic resonance imaging simulation may be obtained, where feasible, for target delineation. One or 3 fraction SBRT can be considered for lesions away from the central liver and luminal organs at risk, whereas 5 fraction SBRT is preferred otherwise. Image-guidance and motion management strategies are essential components of liver SBRT and will guide the creation of relevant internal and planning target volume margins. For lesions in close proximity to or overlapping with organs-at-risk, the balance between adequate local control and potential for cure with potential acute and late toxicity must be carefully considered.

Development and validation of a recursive partitioning analysis-based pretreatment decision-making tool identifying ideal candidates for spine stereotactic body radiation therapy.

This study was aimed at developing and validating a decision-making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases. Three hundred sixty-one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies. The final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p<.001), and each 1-point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25; p<.0001). The concordance value was 0.75 (95% CI, 0.71-0.78). The scores were discretized into three groups-favorable (score = 0-1), intermediate (score = 2), and poor survival (score = 3-5)-with 2-year OS rates of 84% (95% CI, 79%-90%), 46% (95% CI, 36%-59%), and 21% (95% CI, 14%-32%), respectively (p<.0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p<.0001). Increasing SINS<zaq;6> was predictive of decreased OS as a continuous variable (p<.0001). This novel score is proposed as a decision-making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

The dosimetric error due to uncorrected tumor rotation during real-time adaptive prostate stereotactic body radiation therapy.

During prostate stereotactic body radiation therapy (SBRT), prostate tumor translational motion may deteriorate the planned dose distribution. Most of the major advances in motion management to date have focused on correcting this one aspect of the tumor motion, translation. However, large prostate rotation up to 30° has been measured. As the technological innovation evolves toward delivering increasingly precise radiotherapy, it is important to quantify the clinical benefit of translational and rotational motion correction over translational motion correctionalone. The purpose of this work was to quantify the dosimetric impact of intrafractional dynamic rotation of the prostate measured with a six degrees-of-freedom tumor motion monitoringtechnology. The delivered dose was reconstructed including (a) translational and rotational motion and (b) only translational motion of the tumor for 32 prostate cancer patients recruited on a 5-fraction prostate SBRT clinical trial. Patients on the trial received 7.25 Gy in a treatment fraction. A 5 mm clinical target volume (CTV) to planning target volume (PTV) margin was applied in all directions except the posterior direction where a 3 mm expansion was used. Prostate intrafractional translational motion was managed using a gating strategy, and any translation above the gating threshold was corrected by applying an equivalent couch shift. The residual translational motion is denoted as . Prostate intrafractional rotational motion was recorded but not corrected. The dose differences from the planned dose due to + , ΔD( + ) and due to alone, ΔD( ), were then determined for CTV D98, PTV D95, bladder V6Gy, and rectum V6Gy. The residual dose error due to uncorrected rotation, was then quantified: = ΔD( + ) - ΔD( ). Fractional data analysis shows that the dose differences from the plan (both ΔD( + ) and ΔD( )) for CTV D98 was less than 5% in all treatment fractions. ΔD( + ) was larger than 5% in one fraction for PTV D95, in one fraction for bladder V6Gy, and in five fractions for rectum V6Gy. Uncorrected rotation, induced residual dose error, , resulted in less dose to CTV and PTV in 43% and 59% treatment fractions, respectively, and more dose to bladder and rectum in 51% and 53% treatment fractions, respectively. The cumulative dose over five fractions, ∑D( + ) and ∑D( ), was always within 5% of the planned dose for all four structures for everypatient. The dosimetric impact of tumor rotation on a large prostate cancer patient cohort was quantified in this study. These results suggest that the standard 3-5 mm CTV-PTV margin was sufficient to account for the intrafraction prostate rotation observed for this cohort of patients, provided an appropriate gating threshold was applied to correct for translational motion. Residual dose errors due to uncorrected prostate rotation were small in magnitude, which may be corrected using different treatment adaptation strategies to further improve the dosimetricaccuracy.

Evaluation of 5 Fraction Stereotactic Body Radiation Therapy (SBRT) for Osseous Renal Cell Carcinoma Metastases.

The best fractionation for stereotactic body radiotherapy (SBRT) in renal cell carcinoma (RCC) metastases has not been well defined. In addition, the literature on outcomes using 5-fraction SBRT in the setting of osseous metastases has not been well reported. Thirty-nine patients with 69 RCC osseous metastases were treated using 5-fraction SBRT at a single institution using 2 dose-fractionation schemes. Overall survival and local-control (LC) outcomes of the 2 fractionation schemes were studied using Kaplan-Meier curves. Of the 69 lesions included in the study, 20 were treated with 30 grays (Gy) in 5 fractions and 49 were treated with 40 Gy in 5 fractions. The median age of patients at diagnosis was 58.4 years. The 1-year LC rate for all treated lesions was 85.5% (59/69) with an LC of 90% (18/20) for lesions receiving 30 Gy and 83.7% (41/49) in lesions receiving 40 Gy. There was no statistically significant difference in 1-year LC rate between the 2 fractionation schemes (P-value, 0.553). Patients with osseous RCC metastases undergoing 5 fractions of SBRT had favorable LC outcomes. There was no difference in survival or LC between the 40 Gy and 30 Gy treatment arms.

Mature Local Control and Reirradiation Rates Comparing Spine Stereotactic Body Radiotherapy to Conventional Palliative External Beam Radiotherapy

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) improves complete pain response for painful spinal metastases compared to conventional external beam radiotherapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT vs. cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control (SC).24 phase II/III trial. <h3>Materials/Methods</h3> 137/229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT, and 71 patients (169 segments) treated with cEBRT. The primary outcomes were MR-based local control and reirradiation rates for each treated spine segment. <h3>Results</h3> The median follow-up was 11.3 months (IQR:5.3-27.7 months), and median OS in the SBRT and cEBRT cohorts were 21.6 and 18.9 months (p=0.428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of "Mass" (paraspinal and/or epidural disease extension). Risk of local failure after SBRT vs. cEBRT at 6, 12 and 24 months were 2.8% vs. 11.2%, 6.1% vs. 28.4% and 14.8% vs. 35.6%, respectively (p<0.001). cEBRT (HR:3.48, 95%CI:1.94-6.25, p<0.001) and presence of "Mass" (HR:2.07, 95%CI:1.29-3.31, p=0.002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT vs. cEBRT, were 2.2% vs 15.8% (p=0.002) and 22.9 months vs. 9.5 months respectively. Radioresistant histology (HR:2.66, 95%CI:1.43-4.94, p=0.002) and cEBRT (HR:2.34, 95%CI:1.14-4.78, p=0.002) independently predicted for reirradiation. 8/12 iatrogenic vertebral compression fractures (VCFs) were after SBRT and 4/12 after cEBRT; Grade 3 toxicities were isolated to the SBRT cohort (5/12). <h3>Conclusion</h3> Risk of local failure and reirradiation is lower with SBRT compared to cEBRT for spinal metastases. Although the iatrogenic VCF rates were within expectations, Grade 3 VCF were isolated to the SBRT cohort.

An Externally Validated RPA-Based Pre-Treatment Decision-Making Tool Identifying Ideal Candidates for Spine SBRT

<h3>Purpose/Objective(s)</h3> We sought to develop and validate a novel decision-making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases. <h3>Materials/Methods</h3> Treatments were performed at two institutions and most commonly involved one or three fractions of spine SBRT. Recursive partitioning analysis (RPA) was conducted using decision-tree analysis. Potential correlations between variables were assessed with a correlation heatmap. OS was analyzed using the Kaplan-Meier method. Exclusion criteria included: treatments with proton therapy, benign primary histologies, missing variables of interest, and patients with the first course of spine SBRT outside of the participating institutions. <h3>Results</h3> The initial dataset consisted of 424 patients with 522 treated lesions. Of these, 361 patients were used for the RPA and initial model development because not all components of the SINS score were available for 63 patients. After consideration of 9 candidate variables, the final model consisted of the following variables and corresponding scores: SINS ≥ 6 (1); time from primary diagnosis < 21 months (1); ECOG performance status = 1 and ECOG > 1 (1 and 2, respectively); and > 1 organ systems involved (1). Each variable was an independent predictor of OS (p<0.001), and each 1-point increase in score was associated with a hazard ratio of 2.01 (95% confidence interval (CI): 1.79-2.25, p<0.0001) (Table). The concordance value was 0.75 (95% CI: 0.71-0.78). The scores were then discretized into 3 groups: favorable (score: 0-1), intermediate (score: 2), and poor (score: 3-5) survival, with 2-year OS of 84% (95% CI: 79-90%), 46% (95% CI: 36-59%), and 21% (95% CI: 14-32%), respectively (p<0.0001 for each). In the external validation set (182 patients), the score was predictive of OS (p<0.0001). The favorable, intermediate, and poor survival groups each demonstrated statistical significance (p<0.002), with 2-year OS of 77%, 50%, and 36%. Increasing SINS score was predictive of decreased OS as a continuous variable, with a hazard ratio of 1.17 (95% CI: 1.12-1.23, p<0.0001). Of the 6 components of the SINS score, 4 demonstrated associations with OS: pain, type of bone lesion, vertebral body collapse, and posterior spinal element involvement. <h3>Conclusion</h3> We propose this novel score as a decision-making tool to help optimize patient selection for spine SBRT. The SINS score may be an independent predictor of OS.