Stereotactic Body Radiation Therapy Dose Research Articles

Prognostic evaluation using radiomics after stereotactic body radiotherapy in early-stage lung cancer

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths, is the most common subtype of lung cancer with an incidence of 85%. Stereotactic body radiotherapy (SBRT) is a curative treatment option for patients with early-stage NSCLC who cannot undergo surgery due to medical reasons or who refuse surgery. Radiomics non-invasively extracts advanced imaging features invisible to the human eye from medical images. Radiomics has prognostic value in predicting oncological outcomes after lung SBRT. Although studies on this subject are available in the literature, they are quite heterogeneous. There is a need for large-scale multicenter studies in which standard imaging techniques are used to obtain radiomic features, artificial intelligence-based segmentations are used to eliminate differences between contours, and SBRT dose schemes with appropriate therapeutic indexes are applied. This review aimed to interpret the existing studies and emphasize the clinical importance of radiomics, which can contribute to personalized treatment. A comprehensive literature search was conducted through the PubMed database using a wide range of keywords, which yielded 11 peer-reviewed articles published between 2017 and 2024. Seven articles evaluated computed tomography radiomics, and four evaluated fluorodeoxyglucose positron emission tomography-computed tomography radiomics. Oncological outcomes are not always identical in patients with a similar history receiving similar treatments at the same stage and age. Clinical, demographic, or treatment-related data are insufficient to predict prognosis and determine personalized treatment. Incorporating radiomics to these data can help establish models with higher accuracy and achieve personalized treatment.

Long-Term Outcome of a Multicenter Prospective Study on Efficacy and Safety of High-Dose Stereotactic Body Radiation Therapy ≥48-h Interfraction Interval for ≤5 cm Hepatocellular Carcinoma

Introduction: The goal of this study was to evaluate the efficacy and safety of high-dose stereotactic body radiation therapy (SBRT) with an extended (48 h or more) interfraction interval for hepatocellular carcinoma (HCC) ≤5 cm in size after incomplete response to transarterial chemoembolization (TACE). Methods: This multicenter prospective study included 54 patients with inoperable HCC of ≤5 cm size between July 2012 and June 2015. A total SBRT dose of 60 Gy in 3 fractions was administered within 14 days with ≥48-h interfraction interval to patients who showed an incomplete response after 1–5 sessions of TACE. Treatment responses were defined according to the modified Response Evaluation Criteria for Solid Tumors. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results: Forty-eight patients were evaluated with a median follow-up period of 66 months (range, 2–126 months). The median tumor size was 2.0 cm (range, 1.0–4.5 cm), and most patients (87.5%) had a single lesion. The 1-, 2-, and 5-year local control (LC) rates were 100%, 94.8%, and 90.7%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates were 63.4%, 56.9%, and 24.9%, respectively. The 1-, 2-, and 5-year overall survival (OS) rates were 95.6%, 90.9%, and 76.5%, respectively. None of the patients experienced grade 3+ gastrointestinal toxicity, while 1 patient developed non-classic radiation-induced liver disease 2 months after SBRT. Conclusion: High-dose SBRT with a ≥48-h interfraction interval after incomplete response to TACE is effective for HCC ≤5 cm in size as evidenced by the high rates of LC and OS and acceptable treatment-related toxicity.

The optimal stereotactic body radiotherapy dose with immunotherapy for pulmonary oligometastases: a retrospective cohort study.

Stereotactic body radiotherapy (SBRT) is a precise and effective treatment for pulmonary oligometastases, offering high local control (LC) rates. However, the optimal SBRT dose when combined with immunotherapy remains unclear, and there is a lack of comprehensive studies focusing on dose optimization in this setting. This study addresses this knowledge gap by exploring different SBRT dose regimens and their impact on progression-free survival (PFS), overall survival (OS), and LC in patients receiving concurrent immunotherapy, offering novel insights into the synergistic effects of these treatments. A retrospective cohort study was conducted of 101 patients with 141 pulmonary oligometastases treated from April 2018 to April 2022. Inclusion criteria included patients with a maximum of five lung metastases and an Eastern Cooperative Oncology Group performance status of ≤2. Patients received SBRT with doses ranging from 50-70 Gy in 5-10 fractions. Follow-up was performed quarterly, and the best dose was determined by comparing survival outcomes across different dose groups. The patients received SBRT with doses ranging from 50-70 Gy in 5-10 fractions. Patient demographics, tumor characteristics, treatment details, and outcomes were collected. The Kaplan-Meier method was used for the survival analysis, and Cox regression models were used to identify prognostic factors for LC, PFS, and OS. The median follow-up for the 101 patients was 22.4 months (range, 1-58 months). The cohort comprised 82.2% male patients with a median age of 64 years (range, 36-81 years). The majority of the patients (64.4%) had primary tumors originating from non-lung sites, with adenocarcinoma being the predominant histological subtype (47.5%). The median tumor size was 13.5 mm. Across the entire cohort, the median OS was 39 months, and the median PFS was 11 months. Pre-treatment with immunotherapy significantly improved outcomes: the PFS increased to 13 months compared to 7 months for those who did not receive immunotherapy [P=0.02, hazard ratio (HR) = 0.523, 95% confidence interval (CI): 0.302-0.906], and the OS was also significantly improved (P=0.008, HR =0.411, 95% CI: 0.214-0.792). The SBRT regimen of 60 Gy in 10 fractions provided the best outcomes, with a median OS of 39 months, a median PFS of 10 months, and a LC rate of 92.4%, with relatively low toxicity compared to other regimens. SBRT is a potent, minimally invasive option for managing pulmonary oligometastases, especially when preceded by immunotherapy. The 60 Gy in 10 fractions regimen demonstrated significant efficacy in terms of OS and LC, while maintaining manageable toxicity. Although the retrospective nature of the study introduces some selection bias, this dose regimen appears to offer a promising therapeutic option for pulmonary oligometastases. Further validation through well-designed prospective studies would help confirm the optimal SBRT dose and clarify the role of immunotherapy in this setting.

Feasibility, safety and outcomes of stereotactic radiotherapy for ultra-central thoracic oligometastatic disease guided by linear endobronchial ultrasound-inserted fiducials

Background & purposeLocal treatment of oligometastases has been found to improve survival and prognosis. Stereotactic body radiotherapy (SBRT) has emerged as a treatment option for oligometastases but its use in ultra-central (UC) areas can cause significant toxicity and mortality. Fiducial markers (FM) can be used to improve SBRT accuracy, and can be inserted in the central thorax using linear endobronchial ultrasound (EBUS) bronchoscopy. Outcomes of FM-guided SBRT for UC thoracic oligometastases is unknown. MethodsA single-centre retrospective study investigating the feasibility, safety and outcomes of both linear EBUS-inserted FMs and subsequent FM-guided SBRT for UC-oligometastatic disease. Motion analyses of FMs were also performed. ResultsThirty outpatients underwent 32 EBUS-FM insertion procedures with 100 % success, and no major procedural mortality or morbidity. Minor complications were 4.8 % incidence of delayed FM-displacement. UC FM-guided SBRT was completed in 20 patients with 99.9 % fractions delivered. Median SBRT dose delivered was 40 Gy over a median of 8 fractions. Majority of adverse events were Grade 1 and there was no SBRT-related mortality. Local control with SBRT was 95 %, with overall survival at 1-year and 3-years of 90 % and 56.3 % respectively. Median overall survival after SBRT was 43.6 months. FM movements in UC areas were recorded being greatest in the superior-inferior axis. ConclusionCombined linear EBUS sampling and FM-insertion in UC thoracic oligometastatic disease is feasible and safe. UC-SBRT to oligometastases using FM guidance was found to have minimal complications and associated with moderate survival up to 3 years post-treatment.

Oligometastatic Urothelial Cancer and Stereotactic Body Radiotherapy: A Systematic Review and an Updated Insight of Current Evidence and Future Directions.

Stereotactic body radiation therapy (SBRT) is the most commonly used metastasis-directed therapy (MDT) for oligometastatic urothelial carcinoma (omUC). Despite efforts in defining this disease entity, open questions remain concerning the role of MDT and the use of biomarkers, imaging, and its combination with systemic therapies. The aim of the present systematic review is to provide an updated overview of the current clinical evidence on SBRT for omUC in terms of survival and local control benefits. We also aim to provide updates on controversial areas and future directions in this emerging field. With a systematic approach, following PRISMA recommendations, we searched two databases to identify and select articles published up until March 2024 reporting the use of SBRT for omUC with or without concomitant systemic therapies. Prospective randomized or non-randomized studies as well as retrospective studies were included. Eight studies were selected for data extraction and 293 omUC patients treated with SBRT were collectively analyzed. In metachronous omUC patients, SBRT delivered with ablative doses (BED10 ≥ 78 Gy) was associated with a 2-year overall survival (OS) rate of 50.7% (95% CI 35.1-64.4%). The use of sub-ablative SBRT doses (BED10 = 43.2 Gy) in combination with immunotherapy did not demonstrate significant clinical outcome improvement in two prospective studies. The overall tolerance was good, with only one study reporting toxicity of grade 3 in up to 18% of the patients treated with SBRT in combination with immunotherapy. SBRT is an effective and widely available MDT option in omUC, although this is based on a limited number of studies. Despite the attempt to use SBRT as an immune response trigger in combination with immunotherapy, no significant improvement in survival outcomes has been observed. The integration of new systemic agents with MDT will likely define a new scenario for the treatment of omUC. The review protocol was registered in PROSPERO, ID: CRD42024522381.

Stereotactic body radiation therapy for the primary tumor and oligometastases versus the primary tumor alone in patients with metastatic pancreatic cancer

BackgroundLocal therapies may benefit patients with oligometastatic cancer. However, there were limited data about pancreatic cancer. Here, we compared the efficacy and safety of stereotactic body radiation therapy (SBRT) to the primary tumor and all oligometastases with SBRT to the primary tumor alone in patients with metastatic pancreatic cancer.MethodsA retrospective review of patients with synchronous oligometastatic pancreatic cancer (up to 5 lesions) receiving SBRT to all lesions (including all oligometastases and the primary tumor) were performed. Another comparable group of patients with similar baseline characteristics, including metastatic burden, SBRT doses, and chemotherapy regimens, receiving SBRT to the primary tumor alone were identified. The primary endpoint was overall survival (OS). The secondary endpoints were progression frees survival (PFS), polyprogression free survival (PPFS) and adverse events.ResultsThere were 59 and 158 patients receiving SBRT to all lesions and to the primary tumor alone. The median OS of patients with SBRT to all lesions and the primary tumor alone was 10.9 months (95% CI 10.2–11.6 months) and 9.3 months (95% CI 8.8–9.8 months) (P < 0.001). The median PFS of two groups was 6.5 months (95% CI 5.6–7.4 months) and 4.1 months (95% CI 3.8–4.4 months) (P < 0.001). The median PPFS of two groups was 9.8 months (95% CI 8.9–10.7 months) and 7.8 months (95% CI 7.2–8.4 months) (P < 0.001). Additionally, 14 (23.7%) and 32 (20.2%) patients in two groups had grade 3 or 4 treatment-related toxicity.ConclusionsSBRT to all oligometastases and the primary tumor in patients with pancreatic cancer may improve survival, which needs prospective verification.

Multi-institutional analysis of extracranial oligometastatic colorectal cancer patients treated with stereotactic body radiation therapy: TROD 02-008 study.

To investigate the treatment outcomes of extracranial oligometastatic colorectal cancer (CRC) patients treated with stereotactic body radiotherapy (SBRT). The clinical data of 388 extra-cranial oligometastatic CRC (≤ 5lesions) patients and 463 lesions treated with SBRT at 19cancer institutions were retrospectively analyzed. The prognostic factors predicting overall survival (OS), progression-free survival (PFS), and local control (LC) were assessed in uni- and multivariable analyses. The median age was 62years (range, 29-92years). The majority of the patients (90.5%) received surgery and systemic treatment for their primary tumor, had ≤ 2 metastasis (83.3%), had single organ involvement (90.3%), and staged using flouro-deoxyglucose positron emission tomography (FDG-PET/CT) (76%). The median fraction and total radiation doses were 10 Gy (range: 6-34 Gy) and 50 Gy (range: 8-64 Gy), respectively, delivered in amedian of 4fractions (range: 1-8). The median follow-up time for the entire cohort was 30.7 months (interquartile range: 27.0-34.3 months). The 3‑year OS, PFS, and LC rates were 64.0%, 42.3%, and 72.7%, respectively. The 3‑year LC rate was significantly higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (76.0% vs.67.3%; p = 0.04). The 3‑year PFS and OS rates were higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (33.2% vs.25.2%; p = 0.03; 53.7% vs. 44.8%; p = 0.02). Single metastasis and complete response after SBRT were independent prognostic factors for survival in multivariable analysis. In this multi-center study, we demonstrated that SBRT is an effective treatment option of metastatic lesions in oligometastatic CRC patients by providing promising LC rates. Higher SBRT doses beyond BED10 ≥ 100 Gy were associated with improved LC and survival. LC of treated lesion and lower tumor burden after SBRT were associated with better outcomes.

The effect of increasing the prescribed dose in stereotactic body radiotherapy for primary lung cancer without lymph node metastasis.

This study aimed to identify the efficacy of increasing the dose of stereotactic body radiotherapy (SBRT) for lung cancer. Patients who received SBRT for primary lung cancer between 2002 and 2021 were evaluated retrospectively. The patients were categorized into the 48, 50, and 55 Gy groups according to the prescribed dose. Analyses were performed for all matched patients. A total of 323 patients underwent SBRT for lung lesions at doses of 48, 50, and 55 Gy in four fractions. The median follow-up period in the 55 Gy group (32.3 months; Interquartile range (IQR), 15.1-54.1 months, P = 0.01) was significantly shorter than in the 48 Gy (47.0 months; IQR, 16,2-107.7 months) and 50 Gy (78.9 months; IQR 47.2-104.2 months) groups. The 3-year local progression-free survival (LPFS) was 90% in the 55 Gy group (95% confidence interval (CI), 62.4%-94.0%), 75.7% in the 48 Gy group (62.1%-85.0%), and 79.1% in the 50 Gy group (62.2%-89.1%). LPFS in the 55 Gy group was significantly higher than that in the 48 Gy group (hazard ratio (HR), 0.40; 95% CI, 0.20-0.79; P = 0.025). There is no significant difference in the local control rate between the 55 Gy group and the 50 Gy group (HR 0.60, CI 0.27-1.39). After propensity score matching, the 3-year LPFS in the 55 Gy group was 88.3% (CI, 71.2-95.5%). LPFS in the 55 Gy group did not significantly differ from that of the 48 Gy group (HR, 0.47; CI, 0.17-1.35) and the 50 Gy group (HR, 0.83; CI, 0.28-2.51). We conducted the analysis using propensity score matching. It was not apparent whether there was a significant difference in the effect of increasing the dose, owing to a lack of power caused by the small number of cases after propensity score matching. A prospective study is in progress, and the results are awaited.

Phase II Clinical Trial of Second Course of Stereotactic Body Radiotherapy for Spinal Metastases

Purpose: The optimal method for the second course of stereotactic body radiotherapy (SBRT) for spinal metastases remains poorly established. This single-center, single-arm, phase II trial was conducted to propose a safe and effective salvage spine SBRT. Methods: The patients initially treated with SBRT for spine-targeted protocol treatment, or for areas adjacent to the spine, were enrolled. The second SBRT dose was 30 Gy delivered in five fractions; the spinal cord dose constraint was 15.5 Gy at the maximum point dose. The brachial or lumbosacral plexuses were dose-constrained to &lt;30 Gy if the boundary between the nerves and tumors was detected. The primary endpoint was dose-limiting toxicity (DLT) (grade ≥ 3 severe radiation-related toxicity) within a year after the second SBRT. Results: The second SBRT was administered to the same spinal level in 12 patients and to an adjacent spinal level in 8 patients. SBRT2 was performed for 14 painful lesions, 10 MESCC, and 6 oligometastases, with some lesions having multiple indications. The median interval between SBRT sessions was 21 months (range: 6–51 months). The median follow-up duration was 14 months. No radiation myelopathy or local failure was reported during the follow-up period. DLT was confirmed in two patients (10%) within a year, both of whom developed grade 3 lumbosacral plexopathy. These two patients received SBRT twice to the S1–2 and S1–5 vertebrae, respectively, and both experienced paralysis of the tibialis anterior muscle (L5 level). Grade 3 late adverse effects (including lumbosacral plexopathy and vertebral compression fracture) were observed in 25% of the patients throughout the entire follow-up period. Conclusions: The second spine SBRT achieved good local control without causing myelopathy. However, one-quarter of the patients experienced grade 3 late adverse effects, suggesting that the treatment protocol carries a risk of toxicity.

NeoRad(Low): A phase 2 trial of neoadjuvant (NA) ipilimumab + nivolumab (ipi+nivo) with low dose stereotactic body radiation therapy (SBRT) as an immune stimulant in patients with resectable stage IB-III non-small cell lung cancer (NSCLC).

e20081 Background: Standard NA immune checkpoint blockade for patients with resectable NSCLC targets PD1 only and must be combined with platinum-based chemotherapy. In a randomized phase 2 NA study, ipi + nivo demonstrated greater immune-mediated efficacy compared to nivo alone with major pathologic response (MPR) 50% vs. 24%, Cascone T, et al. Nat Med. 2021;27(3):504-14). Preclinical and clinical studies have demonstrated that low doses of radiation enhance immune response by multiple mechanisms (dsDNA breaks, induction of STING, transcription of pro-inflammatory proteins, increased expression of neoantigens while sparing effector T cells). An approach incorporating low dose radiation as an immune stimulant potentially may improve immune-mediated efficacy and shorten the duration of NA treatment compared to approaches that use combined cytotoxic chemotherapy. Methods: This single-arm trial tested NA ipi (1 mg/kg d1) + nivo (3mg/kg d1, 15, 29) plus low-dose SBRT delivered as 2 fractions (4Gy x 2) to the gross primary tumor and nodal disease immediately following day 1 infusion and completed by day 3 in patients with medically operable stage IB-III NSCLC Patients went on to surgical resection between days 49 -63. The primary efficacy outcome measure was pathologic response (including MPR, and complete PR (CPR)). Secondary outcome measures included safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design was employed to stop the study for lack of efficacy if fewer than 3 of the first 9 evaluable patients achieved MPR or experienced undue toxicity. Results: Patients were treated on study: 4 men, 5 women, aged 40-71, stage IB (2), IIB (5), IIIA (1), IIIB (1); adenocarcinoma 7 (all EGFR,ALK -), squamous 2; ECOG PS 0-1 (9); all were former smokers. There were no dose limiting toxicities. Study-related toxicities were ≤ grade 2 including rash (2) and abdominal pain (1). There were no study-related surgical complications. One patient (IIIA, T1N2) experienced clinical and radiologic progression during study treatment and was confirmed to have pleural metastases at surgery. Of 7 patients resected to date, there was 1 CPR, 0 further MPR and 1 patient with surgery pending. All resected patients had some treatment effect, 3 were down staged and these elected not to receive adjuvant cytotoxic chemotherapy. The only patient to progress in 8 months med f/u was the patient progressing during NA therapy. Conclusions: Low-dose radiation with concurrent NA ipi + nivo was safe and well tolerated in this small cohort but did not improve MPR compared to historical phase 2 data of ipi + nivo alone. Standard and exploratory biomarkers of immune response will be presented to determine if patient selection played a role in these results. Clinical trial information: NCT04933903 .

Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET)

The use of stereotactic body radiotherapy (SBRT) for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (BLINDED FOR REVIEW) aimed to determine the maximally tolerated dose (MTD) of SBRT for ultra-central (UC) non-small cell lung carcinoma (NSCLC), using a time-to-event continual reassessment methodology (TITE-CRM). Patients with T1-3N0M0 (≤ 6 cm) NSCLC were eligible. The MTD was defined as the dose of radiotherapy associated with a ≤ 30% rate of grade (G) 3-5 pre-specified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume (PTV); tumors with endobronchial invasion were excluded. This primary analysis occurred two years after completion of accrual. Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range: 65-87) and 17 (57%) were female. PTV was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%) and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range: 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia; the latter had CT findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% confidence interval [CI]: 52.3-85.3%), progression-free survival 66.1% (95% CI: 46.1-80.2%), local control 89.6% (95% CI: 71.2-96.5%), regional control 96.4% (95% CI: 77.2-99.5%) and distant control 85.9% (95% CI: 66.7-94.5%). Quality of life scores declined numerically over time, but the decreases were not clinically or statistically significant. 60 Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the pre-specified acceptability criteria, and results in excellent control for UC tumors.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study

Background and introductionOptimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. Materials and methodsAnalysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). ResultsOf the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3–5) and median dose per fraction was 9.7 (IQR, 7.7–12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. ConclusionThis real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

Stereotactic body radiotherapy for distant metastases to the head and neck.

To report clinical outcomes for patients with metastatic disease to the head and neck (HN) treated with stereotactic body radiation therapy (SBRT). A retrospective review of patients treated with SBRT to HN sites from 2012 to 2020 was conducted. Treatment indications included the following: oligometastases, oligoprogression, and control a dominant area of progression (DAP). Kaplan-Meier method was used to estimate local control (LC), regional control (RC), overall survival (OS), and progression-free survival (PFS). Univariable (UVA) and multivariable analyses (MVA) were performed. Grade 3-4 acute and late toxicities were reported by the Common Terminology Criteria for Adverse Events v5.0. Fifty-six patients (58 lesions) were analysed with a median follow-up of 16months. Primary sites included lung (25.0%), kidney (19.6%), breast (19.6%) and other (35.8%). SBRT indications were as follows: oligometastases (42.9%), oligoprogression (19.6%) and local control of a dominant area of progression (37.5%). Most patients received SBRT to a single neck node (n = 47, 81.0%). Median SBRT dose was 40Gy (range 25-50Gy) in five fractions, with a median biologically effective dose (BED10) of 72Gy (range 37.5-100Gy). One- and 2-year LC and RC rates were 97.6% and 72.7% as well as 100% and 86.7%, respectively. Median OS was 19.2months (95% [CI] 14.8-69.4), and median PFS was 7.4months (95% [CI] 5.2-11.9). The 1-year OS and PFS rates for oligometastases, oligoprogression and DAP were 95.8%, 63.6% and 38.1% (p = 0.0039) as well as 56.5%, 27.3% and 19.1% (p = 0.0004), respectively. On MVA, treatment indication and histology were predictive for OS, while indication and prior systemic therapy were predictive for PFS. Cumulative late grade 3 + toxicity rate was 11.3%, without grade 5 events. The use of SBRT for metastatic disease to the HN provided excellent LC rates with low rates of regional failure and an acceptable toxicity profile, highlighting its utility in these patients. Patients with oligometastatic disease had better OS and PFS than others.

Patterns of Failure in Patients With Borderline Resectable/Locally Advanced Pancreatic Cancer After Preoperative Chemotherapy and Stereotactic Body Radiation Therapy

The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

Stereotactic body radiation therapy (SBRT) for the treatment of primary breast cancer in patients not undergoing surgery

PurposeThe purpose was to explore the role of stereotactic body radiation therapy (SBRT) in providing local control (LC) for primary breast cancer in patients unable to undergo surgery. Materials/methodsBetween 2015 and 2019, 13 non-surgical candidates with 14 lesions were treated with SBRT for primary breast cancer. In 4 cases, SBRT was used after whole breast radiation therapy (WBRT; 40–50 Gy/20–25 fractions). SBRT dose was 30–40 ​Gy in 5 fractions for patients treated with SBRT alone and 25–32 ​Gy in 4–5 fractions for those treated with SBRT ​+ ​WBRT. LC and overall survival (OS) were estimated using Kaplan-Meier curves. Response was also assessed using RECIST guidelines. ResultsMedian follow-up was 32 (range: 3.4–70.4) months. Imaging at median 2.2 (0.6–8.1) months post-SBRT showed median 43.2 ​% (range: 2–100 ​%) decrease in the largest diameter and median 68.7 ​% (range: 27.9–100 ​%) SUV reduction. There were 3 cases of local progression at 8.7–10.6 months. Estimated LC was 100 ​% at 6 months and 71.6 ​% at 12, 24 and 36 months.Estimated median OS was 100 ​% at 6 months, 76.9 ​% at 12 months, and 61.5 ​% at 24 and 36 months. Acute toxicity (n ​= ​13; 92.9 ​%) included grade (G)1 (n ​= ​8), G2 (n ​= ​4), and G4 (necrosis; n ​= ​1). Late toxicity included G2 edema (n ​= ​1) and G4 necrosis (n ​= ​2, including 1 consequential late effect). Only patients treated with SBRT ​+ ​WBRT experienced acute/late G4 toxicity, managed with resection or steroids. ConclusionsSBRT to primary breast cancer resulted in good LC in non-surgical/metastatic patients. Although necrosis (n ​= ​2) occurred in the SBRT ​+ ​WBRT group, it was successfully salvaged.

SBRT with ipilimumab and nivolumab to metastatic MSS colorectal and pancreatic cancer: A pooled analysis of four prospective phase II trials.

752 Background: The role of immunotherapy (IO) in microsatellite stable (MSS) pancreatic and colorectal cancer is limited. Stereotactic body radiation therapy (SBRT) is increasingly used in the limited metastatic setting, however its use with IO remains an area of investigation for both target response and overall systemic response. Here we evaluate the local failure rate of irradiated target lesions with and without IO. Methods: We pooled four prospective phase II single-arm studies of patients with metastatic MSS colorectal or pancreatic cancer treated with SBRT alone or with IO. Those in the first study (NCT01239381) received ablative liver SBRT to a maximum biologically effective dose (BED) of 48-100 Gy. Patients in the remaining studies received low dose SBRT to liver, lung, or nodal metastases with 24 Gy in 3 fractions to a BED of 43.2 Gy in combination with Ipilimumab and Nivolumab during the first (NCT04361162, NCT04575922) or second (NCT03104439) cycles. Local failure rates at the time of first progression were estimated by the cumulative incidence with non-target progression only and death as competing risks and compared using Gray’s test. The best response at the target was measured with the RECIST 1.1 criteria using the largest reduction in target size during follow up. Fisher’s exact test was used to compare objective response (ORR) and disease control rates (DCR), while the Wilcoxon rank sum test was performed to compare target size and percentage of tumor reduction. Results: Across all four studies there were 154 evaluable patients including 50 who received ablative SBRT and 104 patients who received low dose SBRT with IO. There were 92 patients with colorectal and 62 with pancreatic cancer. Median target size was 3.7 cm in the ablative SBRT group and 2.8 cm in the IO group (P=0.04). The 6-month, 1-year, and 2-year local failure rates were 10%, 18%, and 20% respectively following ablative SBRT and 24%, 25%, and 26% following low dose SBRT with IO (P=0.32). The ORR was 50.0% with SBRT alone and 23.1% with the addition of IO (P=0.001). There was no significant difference in the DCR (80.0% vs. 68.3%, P=0.18). The percent decrease in size was significantly higher in those with ablative SBRT (median -53.0% vs. -10.6%, p=0.02). There was no difference in the percent tumor response with respect to primary tumor type (P=0.13), KRAS (P=0.11) or TP53 (P=0.27) status. Conclusions: Despite the use of low dose SBRT with immune checkpoint inhibitors, there was no significant difference in local failure rates compared to ablative SBRT. Ablative SBRT dosing yielded a significantly higher depth of response. As clinical and preclinical studies suggest liver metastases are less responsive to IO, understanding dose and fractionation schemas for optimal local control is critical. Further studies are needed to explore the radiation dose with regards to local control when delivered with IO.

Incorporating stereotactic body radiation therapy for inoperable pancreatic cancer.

656 Background: The management of inoperable pancreatic cancer (PC) is controversial. We sought to compare local progression (LP) for inoperable PC managed with chemotherapy (CHT) and/or stereotactic body radiation therapy (SBRT). Methods: This single-institution retrospective review analyzed 94 patients diagnosed with locally advanced (LA), medically inoperable, or metastatic PC between 2014 and 2022. Patients received CHT alone, sequential (seq) CHT + SBRT, or SBRT alone. The primary endpoints were LP and intervention due to local progression (ILP) from start of treatment. Obstructive symptoms needing intervention, percutaneous endoscopic gastrostomy tube, gastrojejunostomy, or bleeding needing transfusion were considered ILP. Primary tumor growth on imaging or ILP were defined as LP. Fine-Gray regression models with treatment received considered a time-varying covariate were used to compare ILP and LP between treatment groups where death without LP was treated as a competing risk adjusting for ECOG, stage, age and year of diagnosis. In the subgroup of patients who received SBRT, patients were stratified at the median time between diagnosis and receipt of SBRT, and risk of ILP and LP was compared between the groups using cause-specific cumulative incidence functions. Results: Of 94 patients, 51 had CHT alone, 21 received seq CHT + SBRT, and 22 had SBRT alone. The median year of diagnosis was 2019 (range, 2014 - 2022). The median ECOG was 1 with worse ECOG in SBRT alone and seq CHT + SBRT groups (p = 0.012). There were more LA or metastatic cases in the CHT (78%) and seq CHT + SBRT groups (67%) compared to the SBRT group (23%) [p &lt; 0.001]. The median SBRT dose was 36Gy (range, 25 – 40Gy) in 5 fractions. Rates of LP and ILP were higher for CHT alone (68.6%, 39.2%) compared to seq CHT + SBRT (42.9%, 38.1%) or SBRT alone (18.2%, 4.5%) [p &lt; 0.001; p = 0.004]. Higher rate of ILP associated with an increasing year of diagnosis (HR = 2.03, p &lt; 0.005) and younger age of diagnosis (HR = 0.922, p = 0.011). The median time to SBRT was 116 days. Early (&lt; 116 days) vs late SBRT LP rates differed (ILP: 4.8% vs 30%, LP: 14.3% vs 40%). Cause-specific cumulative incidence functions showed that death without LP favored early vs late SBRT (p = 0.009). Additionally, death without ILP favored early vs late SBRT (p=0.011). Conclusions: LP rates are high among patients with inoperable PC. SBRT for inoperable PC provides reasonable local control. Early SBRT reduces the need for ILP before death compared with late SBRT. Further investigation into the role of SBRT for inoperable PC is necessary. [Table: see text]

Early stereotactic body radiation therapy improves progression-free survival of first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated lung cancer: an observational cohort study.

Stereotactic body radiation therapy (SBRT) in treating non-small-cell lung cancer (NSCLC) exhibits a remarkable therapeutic efficacy. However, its effectiveness in overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced EGFR mutations (EGFRm) NSCLC remains uncertain. We aimed to analyze the effect of SBRT on patients with first-line EGFR-TKIs. Eligible patients with advanced NSCLC initially diagnosed with EGFRm were enrolled. Patients in the EGFR-TKIs group received only the first-generation EGFR-TKIs until disease progression or death, while the others in the EGFR-TKIs + SBRT group received EGFR-TKIs and early SBRT (dose of 40-60 Gy/5-8 F) targeting the primary lung tumor at 1 month after EGFR-TKIs. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were treatment-related adverse effects, overall survival (OS), and sites of initial failure. A total of 184 advanced NSCLC patients with EGFRm were enrolled, including 39 patients in the EGFR-TKIs + SBRT group and 145 patients in the EGFR-TKIs group. The median PFS was 15.50 months in the EGFR-TKIs + SBRT group compared to 9.33 months in the EGFR-TKIs group (p = 0.0020). However, the median OS was 29.10 months in the EGFR-TKIs + SBRT group and 26.33 months in the EGFR-TKIs group, with no significant difference observed (p = 0.22). SBRT is an independent positive prognostic factor for PFS in advanced EGFRm NSCLC. EGFR exon 19 deletion mutation (16.33 vs 11.55 months, p = 0.0087) and fewer metastases (0-5) (31.94 vs 9.59 months, p = 0.0059) were associated with improved PFS in EGFR-TKIs + SBRT versus EGFR-TKIs. Combination therapy increased radiation pneumonitis mainly in Grades 1-2 (89.74% vs 0.0%). The EGFR-TKIs + SBRT group mainly had new site failure (57.10% vs 32.10%) rather than the original site failure. Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del. ChiCTR-OIN-17013920.

Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial

IntroductionLarger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase I trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3cm. MethodsA 3+3 dose escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3cm (T2-4) were eligible. Select ipsilateral hilar and single station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute G4+ or persistent G3 toxicities (CTCAE v4.03). Secondary endpoints included local failure (LF), distant-metastases, disease progression and overall survival (OS). ResultsMedian age was 80 years; tumor size was >3cm ≤5cm in 20 (59%) and >5cm in 14 (41%) patients. In cohort A (n=9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose expansion cohort B (n=25), no RT-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year OS was 53%. A biologically effective dose <100 Gy was associated with higher LF (p=0.006); advanced stage and higher neutrophil/lymphocyte ratio (NLR) were associated with greater disease progression (both p=0.004). Conclusions50 Gy in 5 fraSabsctions is the MTD for SBRT to tumors >3cm. A higher BED is associated with less local failures even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy. Trial RegistrationClinicaltrials.gov: xxx

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial

Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. Galera Therapeutics.