Stereotactic Body Radiation Therapy Dose Research Articles

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 < 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 < 0.001; p = 0.004]. Higher rate of ILP associated with an increasing year of diagnosis (HR = 2.03, p < 0.005) and younger age of diagnosis (HR = 0.922, p = 0.011). The median time to SBRT was 116 days. Early (< 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]

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.

A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

Palliative radiotherapy for hepatic tumors: a narrative review of indications and recommendations.

Primary and metastatic liver cancer presents heterogeneously. New radiotherapy techniques have reduced toxicity concerns, leading to increased use of liver radiotherapy. This review synthesizes available evidence and offers recommendations for palliative radiotherapy for liver cancer. PubMed, Ovid Medline, Embase, Cochrane Central, and Web of Science were searched from from inception to December 28th, 2022. Articles reporting local control (LC), survival, toxicity, symptom control, and response after stereotactic body radiotherapy (SBRT), partial-liver, or whole-liver radiotherapy (WLRT) techniques were reviewed. We also identified nomograms identifying patients who may benefit from radiotherapy. Nine randomized-controlled trials were found, in addition to many retrospective, feasibility, and phase I or II studies. Patients with favorable prognosis may receive SBRT using 30-50 Gray (Gy) in 3-5 fractions for primary cancer and up to 60 Gy for metastases, provided normal-tissue constraints are met. Select patients with multiple (>5) or large (>10 cm) lesions or macrovascular invasion (MVI) may be considered, but with potentially reduced LC and increased toxicity. Lower SBRT doses (i.e., 25 Gy in 5 fractions) can be considered on a cautionary basis for patients with poorer liver function or health. Patients with larger tumor burden, poor performance status (PS), or inability to tolerate SBRT positioning or motion-management can consider partial-liver three-dimensional conformal radiotherapy (3DCRT). For patients with extremely guarded prognosis and/or extremely poor performance, WLRT provides pain and symptom relief over several weeks. Combining radiotherapy and systemic therapy may allow radiotherapy de-escalation while maintaining good outcomes. Radiotherapy has a definite role for palliation of liver cancer with practical research providing guidance in the use of techniques and different regimens in various patient subgroups. Future investigation, including randomized trials, is needed to optimize patient selection, radiotherapy techniques, and integration with other therapies.

Abscopal effect in metastatic breast cancer treated with stereotactic body radiotherapy in the absence of immunotherapy.

In this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy. We reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment. The median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis. One out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.

Treatment of ambulatory patients with metastatic epidural spinal cord compression: a systematic review and meta-analysis.

Approximately 10% of patients with spinal metastases develop metastatic epidural spinal cord compression (MESCC), which left undiagnosed and untreated can lead to the loss of ambulation. Timely diagnosis and efficient multidisciplinary treatment are critically important to optimize neurological outcomes. This meta-analysis aimed to determine the most efficient treatment for ambulatory patients with MESCC. The authors conducted a systematic review and meta-analysis of the treatment of mobile patients with MESCC in terms of outcomes described as local control (LC), ambulatory function, quality of life (QOL), morbidity, and overall survival (OS). Overall, 54 papers (4101 patients) were included. A trend toward improved LC with stereotactic body radiotherapy (SBRT) compared with conventional external beam radiotherapy (cEBRT) was demonstrated: random effects modeling 1-year LC rate 86% (95% CI 84%-88%) versus 81% (95% CI 74%-86%) (p > 0.05), respectively, and common effects modeling 1-year LC rate 85% (95% CI 82%-87%) versus 76% (95% CI 74%-78%) (p < 0.05). Surgery followed by adjuvant radiotherapy, either cEBRT or SBRT, showed no significant benefit in either LC (OR 0.88, 95% CI 0.65-1.19) or ambulatory function (OR 1.51, 95% CI 0.83-2.74) compared with radiotherapy without surgery. There was a significant benefit of surgery compared with cEBRT regarding QOL, and furthermore SBRT alone provided long-term improvement in QOL. The type of treatment was not a significant predictor of OS, but fully ambulatory status was significantly associated with improved OS (HR 0.46-0.52, relative risk 1.79-2.3). Radiation-induced myelopathy is a rare complication of SBRT (2 patients [0.1%] in the included papers). The morbidity rate associated with surgery was relatively high, with a 10% wound complication rate and 1.6% hardware-failure rate. SBRT is an extremely promising treatment modality being integrated into treatment algorithms and provides durable LC. In mobile patients with MESCC, surgery does not improve LC, survival, or ambulatory function; nonetheless, there is a significant benefit of surgery in terms of QOL. In patients with MESCC without neurological deficit, the role of surgery is still debatable as studies demonstrate good LC for patients who undergo SBRT without preceding surgery. However, surgery can provide safe margins for the administration of the ablative dose of SBRT to the entire tumor volume within the constraints of spinal cord tolerance. Further randomized controlled trials are needed on the benefit of surgery before SBRT in mobile patients with MESCC. With the excellent results of separation surgery and SBRT, the role of highly invasive vertebrectomy is diminishing given the complication rate and morbidity of these procedures.

Utility of Stereotactic Body Radiation Therapy (SBRT) in Establishing Local Control for Invasive Breast Cancer Patients Not Undergoing Definitive Surgery

Breast cancer (BC) treatment involves a multi-modal approach where surgical resection is the backbone of therapy. However, due to medical comorbidities precluding surgery, unresectable disease, or patient preference, some patients do not undergo surgery. In the absence of resection, it is paramount to improve local control (LC) of the primary tumor. To that end, this study explored the role of ablative RT dose delivered with SBRT. Between 2015-2022, 21 patients (10 metastatic, 11 stage IA-IIIC) received 23 SBRT courses to primary BC lesions without planned surgery at our institution. One patient had undergone whole breast RT 20 years prior to SBRT. 7 patients were analyzed retrospectively; 15 are currently enrolled in a prospective study. SBRT dose was 40 Gy/5 fractions delivered every other day. Follow-up imaging (PET, CT, MRI, MMG/US) was reviewed to evaluate the response. CTCAE v.3 was used to document any acute (≤3 months) and late toxicities. Kaplan-Meier curves were used to estimate local control (LC) and overall survival (OS). Median age was 78.4 (45.9-97.3) years. Median follow-up was 14.7 (3.3-70.3) months after RT completion. Initial post-treatment imaging was available for all cases and was performed at a median of 4.0 (0.6-11.9) months after SBRT. The median pre-SBRT index lesion size was 3.1 (0.5-14.5) cm and PTV was 32.4 (11.5-522.4) cc. At a median 4 months post-SBRT, the median decrease in index lesion size was 20.8 (0-100) % and SUV reduction was 65.2 (20.8-100) %. Further improvement was seen on the 2nd follow-up scans at a median 7.8 months post-SBRT, with 62 (0-100) % and 88 (33.3-100) % median reduction in the tumor size and SUV, respectively, compared to pre-SBRT values. The estimated LC rate was 100% at 6 months and 93.3% at 12 months. The sole case of local progression occurred 9.5 months after SBRT, after an initial interval decrease in the primary lesion. Among the patients with available systemic follow-up scans, regional progression occurred in 4 (17.4%) cases at a median 18.6 (5.2-22.7) months post-SBRT. Six (37.5%) patients developed distant progression at a median 4.8 (0.9-16.2) months, all of whom had metastatic disease at diagnosis. The estimated OS was 85.7% at 6 months and 63.8% at 12 months. Most patients tolerated the treatment well. There was no grade 4 toxicity. Complete acute toxicity data is presented in Table 1. Only one patient experienced late grade 2 breast edema. Based on our preliminary results, definitive SBRT to the primary BC appears to have a role in providing LC in the treatment of non-surgical patients and is well-tolerated. Since the disease progression tends to occur outside the treated primary tumor, additional approaches to improve regional and distant control should be investigated.

Adrenal Stereotactic Body Radiation Therapy: Do Dosimetric Factors Predict for Grade 2+ Lymphopenia?

Recent studies suggest improvement in outcomes in multiple oligometastatic tumor sites with immunotherapy (IO) and radiation therapy (RT). However, RT may induce lymphopenia that can be immunosuppressive and dosimetric consensus is lacking on parameters predicting grade ≥2 lymphopenia. In this study, we evaluated lymphopenia post receipt of stereotactic body RT (SBRT) for adrenal metastases to see if we could identify any modifiable treatment planning factors. Patients with adrenal oligometastases who were treated with conventional SBRT or MRI-guided (MRgSBRT), had absolute lymphocyte count (ALC) and white blood cell count (WBC) data available within 6 weeks before and after their radiation treatment, and had contouring data available for review were included in this IRB approved retrospective study. Lymphopenia was graded for ALC as: Grade 1 (1.0-0.8 no/ul), Grade 2 (<0.8 - 0.5 no/ul), Grade 3 (<0.5-0.2 no/ul), Grade 4 (<0.2 no/ul). The vertebral bodies (VB), at the level of the planning treatment volume (PTV) and one above and below, and the spleen were contoured. Dosimetric variables of interest included spleen and VB mean dose (Gy) as well as V2.5-20 Gy in 2.5 Gy increments. Regression analyses were used to identify dosimetric variables associated with absolute and relative difference in ALC post-SBRT. A total of 30 patients were identified with a slight male predominance (N = 17, 57%) and most commonly left adrenal (N = 17) versus right adrenal (N = 10, 33%) or bilateral metastases (N = 3, 10%). Grade 2+ lymphopenia was observed in N = 7 patients pre-SBRT (23%) and N = 17 patients post-SBRT (57%). N = 26 (87%) of the patients had previous chemotherapies and N = 17 (57%) had previous immunotherapy. Multiple primary tumor types were represented with the most common non-small cell lung cancer (N = 14, 47%), followed by melanoma (N = 4, 13%) and small cell lung cancer (N = 3, 10%). Most patients were treated with non-MRgSBRT (N = 19, 63%) vs MRgRT (N = 11, 37%) and all received SBRT in 5 fractions with median dose 50 Gy (Range: 25 - 60 Gy). The median pre-SBRT ALC was 1.13 (Range: 0.39 - 2.96) and median post-SBRT ALC was 0.72 (Range: 0.11 - 4.15). On linear regression analysis, there was no significant association between post SBRT ALC nor lymphopenia grade with splenic or vertebral body dose, treatment laterality, or SBRT dose. In this retrospective series of predominately metastatic lung cancer patients treated with adrenal SBRT, we observed high rates of post SBRT grade 2+ lymphopenia, yet no dosimetric parameter was predictive, not even for left-sided lesions. Future work includes clinical validation of these findings in a larger population, likely with multi-institutional collaboration, and further study of the investigation of the IO/RT sequencing issues in such heavily pre-treated patients.

Fracture Risk Following Lumbosacral Spine SBRT in Patients Having Received Previous Whole Pelvis Radiation Therapy

Stereotactic body radiation therapy (SBRT) for metastatic spinal disease provides local control with palliative effects1. Previous studies have demonstrated a posttreatment fracture rate range of roughly 5.7-39%2, with 14-17% the most commonly cited fracture risk range. However, the rate of spine fracture after lumbosacral SBRT in patients having received prior pelvic radiation therapy (RT) is unclear. The purpose of this study is to investigate the incidence of fracture in patients receiving lumbosacral spine SBRT following previous whole pelvic RT. This study was a single institution retrospective chart review. All lumbar and sacral spine SBRT cases over a 5-year period (from January 2018 through September 2022) with at least three months of post-treatment follow-up were identified. Patients having previously received pelvic RT were assessed; the development of a vertebral fracture was recorded as was the time to fracture and potential intervention (if any). A total of 35 lumbosacral spine SBRT cases were identified. Of those eight (23%) previously received whole pelvic RT, ranging from 20-70 Gy/5-35 fractions. Of the lumbosacral spine SBRT patients having received prior pelvic RT, two (25%) developed a fracture post-treatment. The average time to fracture was 7.5 months. Both fractures were treated with conservative management; neither required vertebroplasty/kyphoplasty or operative stabilization. The mean dose per SBRT fraction for patients who suffered a fracture (8.5 Gy) did not significantly differ from that for patients who did not suffer a fracture (9 Gy). In the first examination of lumbosacral fracture risk following SBRT to patients having received previous pelvic RT, the fracture rate in this patient population was 25%. Noteworthy is that the SBRT dose per fraction did not differ between patients having suffered a fracture versus those without fracture. These findings indicate that patients having received previous whole pelvis RT should be counseled on the potential increased risk of fracture; however, there is no evidence that decreasing SBRT dose per fraction reduces the likelihood of fracture in this patient population. This increased fracture rate is of concern, and further investigation in larger studies to identify potential risk factors for vertebral fracture such as systemic therapy, age and gender is warranted.

Treatment Efficacy Outcomes Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Survival Analysis of a Phase IB trial

Aggressivelocal treatment to a limited number of metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies have shown the safety of combining high dose stereotactic body radiation therapy (SBRT) with single agent anti-PD1/PD-L1 therapy. Here, we report secondary survival endpoint outcomes from a phase Ib clinical trial investigating the safety of combining ablative, high dose radiation with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. Patients with up to 6 sites of extracranial metastatic disease were eligible for trial enrollment. All sites of disease were treated with stereotactic body radiation therapy to a dose of 30 - 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until dose limiting toxicity or progression was observed. Primary toxicity outcomes were previously reported. Progression free and overall survival was analyzed using Kaplan Meier statistical methods. Fifteen patients were treated with SBRT and received at least one dose of dual agent immunotherapy per protocol. The median follow up was 43 months. The median number of extracranial metastatic sites was 2. Seven patients had 3 or more sites of extracranial disease. The most commonly treated sites were separate metastatic pulmonary lesions or osseous metastatic lesions. Median progression free survival (PFS) was 42 months and median overall survival (OS) was 48 months. Seven patients remain alive without evidence of progressive disease. Prior history of brain metastases was associated with significantly worse PFS (Median PFS 4 months vs 42 months, HR 6.1 (95% CI 1.6 - 37.0) p = 0.0248), but no difference in OS (Median OS 24 vs 42 months, HR 1.9 (95% CI 0.3 - 10.4). Ablative SBRT radiation to up to 6 sites of disease followed by dual checkpoint immunotherapy in oligometastatic NSCLC resulted in a favorable progression free survival (42 months) and overall survival (48 months) compared to historical controls. These findings suggest potential benefit to patient outcomes compared to immunotherapy or radiation alone in this patient population and warrant further investigation.

Frequent Friers: Outcomes in Patients Who Receive Multiple Courses of Lung SBRT

Stereotactic body radiation therapy (SBRT) is a definitive therapy for early-stage non-small cell lung cancer and solitary pulmonary metastases with high tolerability and excellent survival rates. With longer survival and patients developing subsequent primaries or oligometastatic disease, patients are receiving multiple repeat lung SBRT courses. This study aims to assess safety and efficacy of high-frequency SBRT (HF-SBRT) to the lung, defined as >3 courses. A retrospective review was performed of patients who received >3 courses of lung SBRT. Logistic regression was performed to identify predictors of radiation pneumonitis (RP) and worsening pulmonary function (WPF). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method. Ninety-four courses of HF-SBRT to the lung were identified among 28 patients. 78% of patients received 3 SBRT courses, 12% received 4 courses, and 7.1% received >5 courses. Median follow-up was 4.4 years. Median age at time of treatment was 73 years-old; 58% males; 42% had an underlying pulmonary comorbidity; 39% prior lung surgery; 52% history of cardiac disease; 52% prior tobacco use; median ECOG 0. Median SBRT dose was 48 Gy. Median interval between courses was 5.6 months. Zero patients experienced greater than grade 2 acute CTCAE v5 toxicity. 7.2% (7) of patients developed RP at median time of 2.6 months [IQR: 1.4,7.4]; grade 1: 3 patients, grade 2: 1 patient, grade 3: 2 patients. Of patients who developed RP, 42% (3) went on to receive further SBRT without experiencing significant adverse events (AEs). History of pulmonary disease, prior lung surgery, and history of tobacco use strongly correlated with WPF but not RP (WPF p-values: <0.001, 0.003, <0.001, respectively). History of cardiac disease did not correlate with WPF or RP. Receiving bilateral lung SBRT treatment (vs unilateral) trended towards correlation with WPF (p = 0.06) and RP (p = 0.08). Time between SBRT courses did not significantly differ for those who developed RP (p = 0.62) or WPF (p = 0.42). No individual or plan sum dosimetric constraint (GTV, PTV, unilateral lung V5, lung V10, lung V20, unilateral mean lung dose, or total lung V20) significantly differed in those who experienced RP. WPF correlated with the plan sum unilateral lung V10 (p = 0.05). LC at 1-year was 100%, 1 local failure occurred at 13 months; 2-year OS was 91.7%, median OS 5.4 years. Overall, HF-SBRT was well tolerated. Development of RP did not correlate with a specific individual or plan sum dosimetric parameter, with patients receiving subsequent courses of SBRT without increased AEs. WPF increasingly occurred with subsequent SBRT courses and correlated with unilateral plan sum V10. This study suggests that in appropriately selected patients, SBRT after RP can still be provided as definitive care, while further studies should validate this and focus attention on mitigating long-term WPF in patients who receive HF-SBRT.

Borderline Resectable Pancreatic Cancer: Impact on Neoadjuvant Response Post Integration of MRI Guided Adaptive Radiation Therapy

The optimal neoadjuvant therapy regimen for patients with borderline resectable pancreas cancer (BRPC) remains to be defined, with a recent ALLIANCE study reporting that chemotherapy alone prior to resection is an acceptable standard of care. However, pathologic differences in response between patients receiving chemotherapy alone and chemotherapy with radiation with stereotactic technique is not clear. In this study, we sought to compare differences in pathologic outcomes between patients undergoing surgery in 2018 compared with 2021 at our comprehensive cancer center, after the new data of chemotherapy alone had been reported and after our center integrated stereotactic MRI guided online adaptive radiotherapy (SMART). Newly diagnosed BRPC patients were included on this IRB approved study if they were treated on our institutional clinical pathway with initial chemotherapy (FOLFIRINOX or Gemcitabine based) followed by 5 fraction stereotactic body radiation therapy (SBRT) with the intention of primary tumor resection. After surgical resection, tumor response was classified by the Tumor Regression Grading (TRG) System of the College of American Pathology on a scale from 0 (complete response) to 3 (poor response). In 2018 when patients were treated on a conventional Linac, the median SBRT dose was 40.5 Gy compared with 46.1 Gy in 2021 after SMART integration. In 2018, 54 BRPC patients were treated and 52% were explored. Of those, 72% were resected with a 95% (19/20) rate of R0 resection. In 2021, 66 BRPC patients were treated and 45% were explored. Of those, 74% were resected with a 100% (22/22) rate of R0 resection. In 2018, pathological results showed that 55% (11/20) had lymphovascular invasion (LVI) and 90% (18/20) had perineural invasion (PNI) with a median tumor size of 2.5 cm. The average lymph node ratio in 2018 was 0.06 in 2018 and 0.05 in 2021. In 2021, pathological results showed that 36% (8/22) had LVI and 64% (14/22) had PNI with a median tumor size of 2.2 cm. In 2018, 43% of surgeries required portal vein (PV) resection compared with 27% in 2021. In 2018, of those patients who underwent surgery, 65% (13/20) received both chemotherapy and SBRT compared to 10% (2/20) with chemotherapy alone. In 2021, 73% (16/22) received chemotherapy and SBRT prior to surgery compared with 27% (6/22) who received chemotherapy only. Patients who received chemotherapy only (n = 8) had an average TRG of 2.1 compared to the patients receiving combination therapy (29) with an average TRG of 1.8. This data suggests that higher ablative dose delivery with SMART following systemic therapy may be associated with improved pathologic outcomes, with less LVI, PNI, portal vein resection and improved TRG scores. Further prospective study is needed to confirm improved pathologic outcomes with SMART and to optimize patient selection regarding which patients benefit the most from the combination of chemotherapy and SBRT.

An Update of Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Squamous Cell Carcinoma (SCC)

We report the treatment outcomes of palliative Stereotactic Body Radiation Therapy (SBRT) in patients with primary mucosal head and neck cancer (HNC) who were not eligible to receive conventional radiation therapy (RT). This is a retrospective study that reviewed the medical records of patients with primary SCC mucosal HNC who were treated with SBRT between 2011 and 2022. Patients with other histologies, skin cancer, parotid tumors, or recurrent previously irradiated tumors were excluded from the study. A total of 74 patients and 77 tumors were treated with SBRT in this cohort. The median age in the study was 81 (52-97) years and the median follow-up was 7.2 months. The most common site of HNC was the oral cavity (62%), followed by the oropharynx (18%), hypopharynx (8%), larynx (5%), nasal cavity/sinonasal cancer (3%), and unknown primary (1%). T3-4 lesions were found in most patients (76%). SBRT doses ranged from 35-50 Gy in 5 fractions, and the most common prescription dose was ≥45 Gy in 5 fractions (60%) for the GTV prescription. An elective nodal volume of 25 Gy in 5 fractions was infrequently (17%) used. Most patients (81%) who were treated twice a week completed in ≤14 days. The predominant symptoms at presentation were: pain (41%), mass effect (39%), dysphagia/odynophagia (14%), headache/nasal obstruction (1.4%), bleeding (1.4%), stridor (1.4%), asymptomatic (1.4%), and unknown (1.4%). 84% of patients had symptomatic response to treatment with 24% of them having complete symptom response. Cumulative incidence of local failure (LF) was 6.7% and at 6 months and 17.9% at 12 months, respectively. Cumulative incidence of distant metastasis was 7.3% and 10.5% at 6 and 12 months. Cancer was the most common cause of death in 29 patients (51%). The median overall survival (OS) was 8 months with 6 and 12-month OS rates of 67% and 36%, respectively. 39% of patients developed acute G3 toxicity, including 30% with G3 mucositis, 5% with G3 dysphagia, and 4% with G3 dermatitis. A crude rate of late G ≥3 toxicity was observed in 11% of patients including (5%, n = 4) with osteoradionecrosis, and a single case of dysphagia, soft tissue necrosis, supraglottic ulceration, and mucosal necrosis. This study highlights the feasibility of SBRT as a treatment option for primary mucosal head and neck cancer patients who are not eligible for conventional radiation therapy. The results indicate that SBRT was effective in achieving local control and symptom relief, but larger prospective studies are needed to confirm the findings. The Canadian Cancer Trials Group has endorsed HN-13, a randomized control trial comparing HN SBRT to palliative RT.