Effects of incidental low-dose radiation on abscopal responses after stereotactic body radiotherapy in patients with metastatic cancer: a retrospective real-world analysis.

Purpose: To analyze the prognostic factors and optimal response interval for stereotactic body radiotherapy (SBRT) in patients with lung oligometastases (OM) or oligoprogression (OP) from colorectal cancer (CRC).Method: Patients with lung OM or OP from CRC treated by SBRT at our hospital were included in this retrospective review. The local control (LC), response to SBRT in different evaluation interval and regional metastases (RM) was analyzed. The risk factor for LC and RM was calculated using the Kaplan-Meier method and compared using the Log-rank test. Multivariate analysis with a Cox proportional hazards model was used to test independent significance.Results: A total of 53 patients with 105 lung metastases lesions treated from 2012 to 2018 were involved in this retrospective study. The median biologically effective dose (BED) for these patients was 100 Gy (range: 75–131.2 Gy). Complete response (CR) increased from 27 (25.7%) to 46 (43.8%) lesions at 1.8 and 5.3 months following SBRT, and at the last follow-up, 52 (49.5%) lesions achieved CR. The median follow-up duration for all patients was 14 months (range: 5–63 months), and 1-year LC was 90.4%. During the follow-up, 10 lesions suffered local relapse after SBRT (9 of them occurred within 8 months after SBRT). The univariate analysis shows BED ≥ 100 Gy (P = 0.003) and gross tumor volume (GTV) < 1.6 cm3 (P = 0.011) were better predictors for 1-year LC. The patients with lung oligoprogression had higher 1-year RM when compared with patients with lung oligometastases (hazard ratio 2.78; 95% confidence interval [CI] 1.04–7.48, P = 0.042). Until the last follow up, 4 (7.5%) patients suffered grade 2 radiation pneumonitis, and no grade 3–4 toxicity was observed.Conclusions: SBRT provides favorable LC in CRC patients with lung OM or OP, and the GTV and BED can affect the LC. Radiology examinations nearly 5–6 months following SBRT appear to represent the final local effect of SBRT, and the patients with oligoprogression has higher RM.

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study

Consolidative Use of Radiotherapy to Block (CURB) Oligoprogression ― Interim Analysis of the First Randomized Study of Stereotactic Body Radiotherapy in Patients With Oligoprogressive Metastatic Cancers of the Lung and Breast

The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.

&lt;div&gt;AbstractPurpose:&lt;p&gt;The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).&lt;/p&gt;Patients and Methods:&lt;p&gt;The study was a phase 2 randomized trial with Simon’s optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage.&lt;/p&gt;Results:&lt;p&gt;Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6–47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1–21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3–33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group.&lt;/p&gt;Conclusions:&lt;p&gt;Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.&lt;/p&gt;&lt;/div&gt;

554 Background: Pancreatic ductal adenocarcinoma remains one of the most lethal diseases. Investigating novel treatment strategies for patients with metastatic pancreatic cancer (mPC) is crucial. The purpose of this phase II trial study was to evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with mPC. Methods: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status. Primary endpoint was clinical benefit rate (CBR) defined as proportion of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon’s 2-stage phase II optimal design was used independently for both arms with CBR determining expansion to second stage. Secondary endpoints included safety, overall response rate, duration of response (DOR), progression free survival and overall survival (OS). Exploratory analyses included biomarkers related to immune response. Results: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (95% CI, 8.0 to 30.6) for SBRT/nivolumab and 37.2% (95% CI, 24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient in SBRT/nivolumab and lasted for 4.6 months. Six patients in SBRT/nivolumab/ipilimumab obtained a PR with a median DOR of 5.4 months (95% CI, 4.2 - not reached). All responders had mismatch repair proficient tumors. Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) patients in SBRT/nivolumab and in 13 (30.2%) patients in SBRT/nivolumab/ipilimumab. PD-L1 expression by tumor proportion score or combined positivity score of ≥1% was not associated with clinical benefit. On-treatment decrease in serum interleukin (IL)-6, IL-8 and CRP levels was associated with better OS. Conclusions: Clinical meaningful antitumor activity and a manageable safety profile were demonstrated after SBRT/nivolumab/ipilimumab in patients with refractory mPC. Clinical trial information: NCT02866383.

&lt;div&gt;AbstractPurpose:&lt;p&gt;The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).&lt;/p&gt;Patients and Methods:&lt;p&gt;The study was a phase 2 randomized trial with Simon’s optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage.&lt;/p&gt;Results:&lt;p&gt;Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6–47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1–21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3–33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group.&lt;/p&gt;Conclusions:&lt;p&gt;Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.&lt;/p&gt;&lt;/div&gt;

Purpose: To develop a method to study the MRI response of tumor and hepatic parenchyma to stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC). Methods: Two adult patients with HCC who received SBRT were recruited in this IRB-approved study. T1-weighted delayed phase contrast Eovist enhanced MRI were performed immediately prior to and three months after SBRT. The time between contrast injection and MRI acquisition was identical for both pre-and post-SBRT imaging sessions. The patients received 3D conformal SBRT with a total dose of 40 Gy in 5 fractions. Both MRI images were rigidly registered to the planning computed tomography (CT) data set and the 3-dimensional (3D) dosimetry data, focusing on local alignment in the tumor region. The average MRI intensity in the spleen was calculated for the pre-and post-SBRT images, and subtracted to reduce the effects of different imaging conditions. For each 4.9mm by 4.9mm by 6mm voxel in a region of interest (ROI) delimited by the liver contour and the 20 Gy isodose line, the difference in MRI intensity between pre-and post-SBRT images was generated and correlated to radiation dose deposited in that voxel. Results: The Pearson correlation coefficient between MRI intensity change and dose was 0.58 (p<0.0001) for patient A and 0.33 (p<0.0001) for the patient B. Conclusion: We have developed a method to study tumor and hepatic parenchyma response to radiation dose in HCC patients treated with SBRT. Our preliminary data suggest a correlation between the radiologic response and dose in HCC p333atients treated with SBRT, and warrant further study with more patients.

Introduction: The aim of this study was to investigate the clinical outcomes of metastasis-directed therapy (MDT) using stereotactic body radiotherapy (SBRT) in patients with synchronous or metachronous oligometastatic renal cell carcinoma (RCC). Methods: The clinical data of 87 patients with 138 lesions who received MDT between February 2008 and January 2019 were retrospectively analyzed. All patients had ≤5 metastasis at diagnosis (synchronous) or during progression (metachronous) and were treated with SBRT for their metastasis. The primary endpoints were local control (LC) and progression-free survival (PFS). The secondary endpoint was overall survival (OS). Results: Median follow-up was 20.4 months for entire cohort and 27.2 months for survivors. Synchronous oligometastatic disease was observed in 35 patients (40.2%), and 52 patients (59.8%) had metachronous disease. Seventy-two patients (82.8%) received systemic treatment synchronously or after MDT, while 15 patients (17.2%) did not receive any systemic treatment. The 1- and 2-year OS rates were 79.4% and 58.1%, respectively, and the 1- and 2-year PFS rates were 58.6% and 15.1%, respectively. The 1- and 2-year LC rates per lesion were 96.6% and 91.4%, respectively. There were no significant differences in survival between patients with synchronous oligometastasis and those with metachronous oligometastasis. All disease progressions were observed at a median time of 31.6 months (range: 1.9–196.9 months) after the completion of SBRT. Patients with solitary oligometastasis had significantly better OS compared to patients with >1 metastasis (p = 0.04). No patients experienced grade 3 or higher acute or late toxicities. Conclusion: SBRT is a successful treatment for oligometastatic RCC patients due to its excellent LC and minimal toxicity profile. There were no statistically significant survival differences between patients with synchronous and metachronous oligometastasis. Patients with solitary oligometastasis outlived their counterparts.

BackgroundInterleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC). MethodsPatients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%. ResultsTwenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1–7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7–39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4–1.7), and the median overall survival was 5.3 months (95% CI 2.3–8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events. ConclusionThe combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual.

&lt;div&gt;Abstract&lt;p&gt;TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (&lt;i&gt;n&lt;/i&gt; = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8&lt;sup&gt;+&lt;/sup&gt;PD-1&lt;sup&gt;+&lt;/sup&gt;TIGIT&lt;sup&gt;+&lt;/sup&gt; T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (&lt;i&gt;n&lt;/i&gt; = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8&lt;sup&gt;+&lt;/sup&gt;PD-1&lt;sup&gt;+&lt;/sup&gt;TIGIT&lt;sup&gt;+&lt;/sup&gt; T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.&lt;/p&gt;&lt;/div&gt;

To investigate the correlation of conventional MRI, DCE-MRI and clinical features with pain response after stereotactic body radiotherapy (SBRT) in patients with spinal metastases and establish a pain response prediction model. Patients with spinal metastases who received SBRT in our hospital from July 2018 to April 2022 consecutively were enrolled. All patients underwent conventional MRI and DCE-MRI before treatment. Pain was assessed before treatment and in the third month after treatment, and the patients were divided into pain-response and no-pain-response groups. A multivariate logistic regression model was constructed to obtain the odds ratio and 95% confidence interval (CI) for each variable. C-index was used to evaluate the model's discrimination performance. Overall, 112 independent spinal lesions in 89 patients were included. There were 73 (65.2%) and 39 (34.8%) lesions in the pain-response and no-pain-response groups, respectively. Multivariate analysis showed that the number of treated lesions, pretreatment pain score, Karnofsky performance status score, Bilsky grade, and the DCE-MRI quantitative parameter Ktrans were independent predictors of post-SBRT pain response in patients with spinal metastases. The discrimination performance of the prediction model was good; the C index was 0.806 (95% CI: 0.721-0.891), and the corrected C-index was 0.754. Some imaging and clinical features correlated with post-SBRT pain response in patients with spinal metastases. The model based on these characteristics has a good predictive value and can provide valuable information for clinical decision-making. • SBRT can accurately irradiate spinal metastases with ablative doses. • Predicting the post-SBRT pain response has important clinical implications. • The prediction models established based on clinical and MRI features have good performance.

Combining the Best of Both Worlds: The Role of Sequential Stereotactic Radiotherapy Boost for Spinal Metastases

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.