Stereotactic Body Radiotherapy Group Research Articles

Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p=.02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

Comparison of outcomes following surgical resection, percutaneous ablation or stereotactic body radiation therapy in early-stage, solitary and small (≤3 cm) treatment-naïve hepatocellular carcinoma.

Stereotactic body radiation therapy (SBRT) is associated with high local control rates in hepatocellular carcinoma (HCC). This study reports the outcomes of SBRT compared to surgical resection (SR) and percutaneous ablation (PA) for treatment-naïve, solitary HCCs ≤3 cm. This was a retrospective study of patients with BCLC stage 0/A HCC with a single ≤3 cm lesion, treated with curative intent between 2016 and 2020. SBRT was used for patients considered unsuitable for SR or PA. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were treatment-related clinical toxicity rates and local control (LC) rates. There were 112 patients included in this study. SBRT was delivered in 36 patients (32.1%), 51 had PA (45.5%) and 25 underwent SR (22.3%). Median follow-up was 23 months (range, 3-60 months) from diagnosis. The 3-year PFS and OS were 67% and 69% following SBRT, 55% and 80% following PA, and 85% and 100% following SR, respectively. Patients in the SR cohort had significantly better 3-year PFS and OS compared to SBRT and PA groups (p = 0.03 and p = 0.04, respectively). There was no significant difference in PFS (p = 0.15) or OS (p = 0.23) between SBRT and PA treated patients. The 3-year LC rate for the entire cohort was 98%. In patients with treatment-naïve, early-stage solitary HCCs ≤3 cm, SBRT was associated with comparable PFS, OS and LC outcomes to PA. SBRT should be considered as a curative intent therapy to avoid treatment stage migration in this favourable prognostic cohort of patients.

Stereotactic body radiotherapy compared to conventionally fractionated radiotherapy for locally advanced or oligometastatic pancreatic cancer.

677 Background: Pancreatic cancer, particularly in its locally advanced and oligometastatic forms, poses a formidable therapeutic challenge. Radiotherapy remains an important treatment in an attempt to gain local control, however there is no consensus on whether stereotactic body radiotherapy (SBRT) is appropriate as compared to conventionally fractionated radiotherapy (CFRT). Herein, we report our experience. Methods: We conducted a retrospective analysis of patients with locally advanced and oligometastatic pancreatic cancer who received definitive radiotherapy at our institution between January 2010 and March 2023 with SBRT 30-50 Gy in 3-5 fractions or CFRT 50-60 Gy in 25-30 fractions. We excluded all patients with resectable disease who underwent surgery. Clinicopathological data, treatment regimens, and radiation parameters were collected and analyzed. Results: A total of 51 patients (17 females, 34 males; median age: 67.9 years). 24 patients (47.1%) were treated with CFRT, and 27 patients (52.9%) were treated with SBRT. Median time of follow-up for the entire cohort was 14.4 months. A total of 13 patients (25%) experienced a Local failure (LF) at a median time of 18.5 months, with no difference observed between CFRT and SBRT groups. Cancer-specific mortality (CSM) was statistically significant with a lower mortality rate in SBRT (37%) vs CFRT group (63%) (p<0.004). Several treatment characteristics and dosimetric factors such as sex, age, receipt of chemotherapy, type of chemotherapy, use of elective nodal irradiation, GTV size, biologically equivalent dose (BED) corrected prescribed dose, minimum dose to GTV, or max dose to GTV did not predict local failure. There was no difference in QOL and toxicity between the two groups. Conclusions: In our cohort, local failure rates remain high and were similar between patients treated with SBRT compared to those treated with conventionally fractionated radiotherapy. We were unable to identify any specific predictors for local recurrence in this patient population. Our observation of a lower CSM rate among patients who received SBRT needs further study. The findings underscore the need to further improve radiotherapeutic approaches in an attempt to improve local control in locally advanced disease.

Comparing resection and stereotactic body radiation therapy for hepatocellular carcinoma with macrovascular invasion: A propensity score matched study.

521 Background: Macrovascular invasion (MVI) in hepatocellular carcinoma (HCC) patients is a poor prognostic factor. Current guidelines endorse systemic therapy for MVI. Local therapies present a potential for obliteration of MVI and improved survival. Surgery has been the standard local therapy at our institution, and stereotactic body radiotherapy (SBRT) has emerged as an alternative local therapy for this patient population. Methods: In this retrospective study, one-to-one optimal pair propensity score matching was used to compare outcomes of HCC patients with MVI who underwent surgery or received SBRT. Matching was done based on sex, age, ECOG, cirrhosis presence, Child-Pugh class, number of tumours, tumour volume, alpha-fetoprotein level, ALBI score, Japanese Classification of portal vein invasion, and hepatic vein invasion. Overall survival was estimated using the Kaplan-Meier method and between group differences determined using the log-rank test. The cumulative incidence of recurrence, accounting for the competing risk of death, was compared using Gray’s test. Results: Ninety of 193 patients were included after matching (45 patients in both the surgery and SBRT groups) (Table). The SBRT group had a median OS of 15 months (95% CI: 10-38), while in the surgery group it was 24 months (95% CI: 11-81). Comparing the 12-, 36-, and 60-month overall survival (OS) rates between the SBRT group (57%, 33%, 15%) and the surgery group (58%, 37%, 34%), there was no statistically significant differences (p=0.16); the 5-year OS was double in the surgical resection group. The 12-, 36-, and 60-month cumulative incidence of HCC recurrence in the SBRT group (47%, 73%, 75%) was comparable to the surgery group (69%, 69%, 69%) (p=0.89). Conclusions: Long term survival is possible in patients with HCC and MVI in a substantial minority of patients with HCC and MVI treated with local therapies. There was no statistical difference in outcomes; however, surgical resection resulted in numerically longer survival outcomes compared to SBRT after propensity score adjustment. There is rationale for investigating both local therapies with systemic therapies in future clinical trials. [Table: see text]

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]

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (>30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

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.

Comparison of Treatment Outcomes Between Thoracoscopic Surgery and Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer.

Objective: To compare the risk of death, tumor recurrence, metastasis, and disease progression in early-stage non-small cell lung cancer (NSCLC) patients treated with thoracoscopic surgery and stereotactic body radiotherapy (SBRT). Methods: Patients who underwent radical surgery and SBRT for NSCLC between April 2010 and November 2021 were retrospectively analyzed. Continuous and categorical variables were compared using the Mann-Whitney U and Chi-square test, respectively. Kaplan-Meier curves were used to evaluate the survival outcomes of each patient group. Cox proportional hazard regression analyses were performed to estimate the risk of death, tumor recurrence, metastasis, and disease progression. Results: A total of 167 patients were enrolled, of whom 75 and 92 underwent SBRT and surgery, respectively. The median follow-up was 45 months (range, 4-105 months). SBRT patients were observed to be significantly older (median, 76.0 vs 67.0 years; P < .001), and associated with significantly higher mortality rate (42.7% vs 26.1%, P = .024). However, no significant difference in overall survival duration was seen between the SBRT and surgery groups (45.0 vs 41.0 months; P = .199). SBRT patients demonstrated significantly lower rates of metastasis (12.0% vs 30.4%, P = .004), and significantly longer metastasis-free survival (39.0 months vs 35.5 months, P = .020). The remaining outcomes, including tumor recurrence and disease progression rates, were similar between the groups. Compared to surgery, SBRT did not significantly associate with death, recurrence, or disease progression. Kaplan-Meier curves showed significant differences in overall, tumor recurrence-free, and disease progression-free survival between the groups (log-rank P < .05). Conclusions: SBRT demonstrated similar overall survival compared to radical surgery, and associated with significantly reduced risk of tumor metastasis. Our study thereby suggests SBRT as the best treatment option for patients with inoperable NSCLC.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute.

Hyperfractionated Accelerated Radiotherapy Versus Stereotactic Body Radiotherapy in the Treatment of Limited-Stage Small Cell Lung Cancer: A Matched-Pair Analysis.

Concurrent chemoradiotherapy based on hyperfractionated accelerated radiotherapy (HART) is the first-line recommended regimen for the treatment of small-cell lung cancer (SCLC). However, Stereotactic Body Radiotherapy (SBRT) is also regarded as an effective treatment for limited-stage (LS) SCLC, and the efficacy and safety of HART versus SBRT stay controversial. In this study, 188 LS-SCLC patients were retrospectively divided into two groups receiving chemotherapy combined with either HART or SBRT. In HART group, patients received 4500 cGy in 30 fractions, administered twice daily for 3 weeks. Whereas in the SBRT group, a total radiation dose of 4000-4500 cGy was delivered in 10 fractions over 2 weeks. Thirty-three pairs of patients were finally included for next analysis. The estimated objective response rates were 63.6 % (21/33) and 78.8 % (26/33) in HART group and SBRT group, respectively (P = 0.269). Furthermore, there was no significant difference between HART and SBRT groups in overall survival (26 months vs. 29 months, P = 0.362) and progression free survival (11 months vs. 15 months, P = 0.223). As for the adverse events, toxicity of both groups is similar and slight that no grade 4 event was observed. Grade 3 pneumonitis cases were all occurred in the HART group (9.1%, 3/33, P = 0.238), and grade 3 esophagitis cases were all occurred in the SBRT group (6.1%, 2/33, P = 0.492). Compared with HART, SBRT could be another effective treatment with satisfactory safety for the concurrent chemoradiotherapy in patients with LS-SCLC.

Early Stereotactic Body Radiotherapy to the Primary Lung Lesion for Patients with Advanced NSCLC Treated with First-Line Systemic Therapy

Although adding consolidative stereotactic body radiotherapy (SBRT) to systemic therapy improves survival in advanced non-small cell lung cancer (NSCLC), the optimal timing of SBRT remains unclear. This study aimed to explore the clinical outcome of early and delayed SBRT to primary lung lesions of advanced NSCLC patients treated with first-line systemic therapy. We identified patients with advanced NSCLC who were suitable to receiveSBRT for the primary lung tumors after first-line systemic therapy. All eligible patients were treated with first-line systemic therapy and SBRT for their primary lung lesions. Early SBRT group was defined as patients who received SBRT for their primary lung tumor at the maximal response of systemic therapy. Delayed SBRT group was defined as patients who received SBRT after the occurrence of oligoprogression in primary lung tumor. The primary endpoints were progression-free survival 1 (PFS1, time from start of first-line systemic therapy to disease progression) and PFS2 (time from start of first-line systemic therapy to disease progression after SBRT). Overall survival (OS) and adverse effects (AEs) were secondary endpoints. A two-sided P value of 0.05 was considered statistically significant. All of the statistical analyses were performed with statistical software. A total of184 patients with advanced NSCLC treated with SBRT for primary tumors were screened, and 49 patients were eligible for enrollment in this study. The median age of the entire cohort was 66 years (range, 37-80 years), and 34 (69.4%) patients were male. Thirty-four patients (69.4%) were treated by target therapy and 15 (30.6%) were treated by chemotherapy and immunotherapy. Of the 49 eligible patients, 28(57.1%) received early SBRT to lung primary tumor and 21(42.9%) received delayed SBRT to lung primary tumor. The early SBRT group showed a significantly prolonged PFS1 as compared with the delayed SBRT group (mPFS1: 30 months vs. 8 months, P<0.001). The median PFS2 of the early SBRT group was longer than that of the delayed SBRT group, but the difference between the two groups did not achieve a statistical significance (mPFS2: 42 months vs. 23 months, P = 0.303). Median OS of both groups has not reached. No severe toxicities (≥grade 3) were observed in early SBRT group and only one patient in the delayed SBRT group experienced grade 3 radiation pneumonitis. Early SBRT to the primary lung lesion significantly improved PFS and is a new potentially effective and tolerable treatment option for patients with advanced NSCLC who had stable disease during first-line systemic therapy.

Final Results from a Prospective Randomized Pilot Trial of Stereotactic Body Radiation Therapy vs. Radiofrequency Ablation for the Management of Small Renal Masses (RADSTER)

The benefits of stereotactic body radiation therapy (SBRT) as a primary treatment modality for small renal masses (SRMs) ≤4cm are unclear. Our objective was to evaluate both SBRT and radiofrequency ablation (RFA) for SRMs to determine the utility of a future Phase III randomized controlled trial (RCT). Patients with SRMs who declined active surveillance, surgery or were deemed inoperable were recruited at a single tertiary academic center. After meeting inclusion/exclusion criteria, participants were assigned 1:1 to SBRT or RFA, with crossover allowed if technical or patient factors precluded either treatment. SBRT included an initial simulation and a single delivered fraction of 25 Gy to the planning target volume. RFA was conducted percutaneously with 2 cycles of up to 8 minutes each upon reaching target temperature. Renal protocol imaging (CT or MRI) was completed q3 months (up to 1 year) post-procedure. Diagnostic and 1-year renal biopsies were also required. The objective of this trial was feasibility of randomization, with the aim of recruiting 24 patients based on this assumption. From January 2020 to June 2021, 33 patients were screened, with 24 recruited and initially randomized (SBRT = 12; RFA = 12). Median age was 67 years (53-85) and 17/24 were male. Seventeen patients had clear cell renal cell carcinoma (RCC), 6 had papillary RCC, and 1 had chromophobe RCC. Following randomization, a total of 14 patients had SBRT, 7 had RFA, and 3 declined treatments. Crossover mainly occurred from RFA to SBRT due to technical inability to perform RFA. One grade 2 acute pain flare occurred in the SBRT group (none in the RFA group). No late toxicity up to 1 year was reported in either group. At 1 year, no radiographic local failure (RECIST) was observed, although RFA patients were more likely to have loss of arterial enhancement (83.3% vs 23%, p = 0.041). Mean reduction of estimated glomerular filtration rate was similar at 1 year (RFA -3 mL/min, SBRT -5.3 mL/min, p = 0.7). Biopsies were performed in 20/24 patients at 1 year, on per-protocol analysis 7/7 (100%) of RFA patients had no evidence of residual RCC, whereas with SBRT 4/13 (31%) patients had no evidence of residual RCC, 2/13 (15%) had scant/minimal residual disease, and 7/13 (54%) had evidence of RCC. No patients developed distant failure or death from RCC during follow-up. Recruitment, randomization and follow-up of patients with SRMs was feasible in this study. More patients received SBRT compared to RFA, highlighting the need for thorough multidisciplinary evaluation prior to randomization. Both treatments have excellent safety profiles, with RFA demonstrating initial higher rates of pathological/radiologic response, however long-term follow-up is required. This trial supports the need for a large scale RCT with appropriate radiographic and pathological endpoints built in.

Single Cell Analysis of Macrophage Heterogeneity and NK-Cell Exhaustion in Lewis Lung Cancer Xenograft Tumor

Stereotactic body radiation therapy (SBRT) has attracted much attention because of its ability to stimulate anti-tumor immune response. However, the mechanism of SBRT reprogramming the tumor microenvironment remains to be elucidated. Using Lewis lung carcinoma (LLC) xenograft mice model treated with SBRT (8Gy x 3F), multiplex assay was performed to measure serum chemokine levels, and single-cell RNA sequencing was performed to assess tumor microenvironment. The differential expression genes of each cell subcluster were identified by the "Find-All markers" function with default parameters provided by Seurat. Intercellular communication analysis was explored by using CellPhone DB package. The majority of serum chemokines involved macrophage recruitment, including CCL3, CCL4, CCL8, and CCL20, were highly secreted at 7 days after SBRT. Single-cell RNA sequencing of 108,741 cells were contained from 6 mouse Lewis lung carcinoma samples (n = 3 tumors for SBRT, n = 3 tumors pooled for SHAM). Besides Lewis cancer cells, myeloid cells were 57.61% ,70.82% in Sham-irradiation (SHAM) and SBRT while NT and T cells were 20.50%, 7.81% in SHAM and SBRT, respectively. When compared with SHAM group, upregulation of Ccl3, Ccl4, Ccl8 chemokine genes were observed in cancer cells of SBRT group. Differential expression genes analysis showed high expression level of Ccl8 (Log2FC 2.54, p<0.01) in cluster of Mrc1+macrophage. The SBRT group consisted of more Ccl8+Mrc1+macrophages (proportion 36.28% for SBRT, 27.44% for SHAM) and exhausted NK cells (proportion 22.56% for SBRT, 13.70% for SHAM). More importantly, intercellular communication analysis revealed a potential communication network between Ccl8+Mrc1+macrophages and exhausted NK cells. Our results provide a potential therapeutic strategy by disrupting Ccl8+ Mrc1+macrophages and NK-cell interaction to facilitate the stimulation of the anti-tumor immune response by SBRT.

Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review.

Clinical studies published from 2012 to 2022 were systematically reviewed using PubMed, MEDLINE (via PubMed) and Cochrane databases. Different radiotherapy-related data were extracted and analyzed. A total of 31 studies matched the inclusion criteria. Acute toxicity was less remarkable in stereotactic body radiotherapy (SBRT) compared to conventionally fractionated radiotherapy (CFRT), while in proton beam therapy (PBT) grade 3 or higher acute toxicity was observed more commonly with doses of 67.5 Gy (RBE) or higher. Late toxicity was not reported in most studies; therefore, comparison between groups was not possible. The range of median overall survival (OS) for the CFRT and SBRT groups was 9.3-22.9 months and 8.5-20 months, respectively. For the PBT group, the range of median OS was 18.4-22.3 months. CFRT and SBRT showed comparable survival outcomes with a more favorable acute toxicity profile for SBRT. PBT is a promising new treatment modality; however, additional clinical studies are needed to support its efficacy and safety.

Comparative Analysis of Photon Stereotactic Radiotherapy and Carbon-Ion Radiotherapy for Elderly Patients with Stage I Non-Small-Cell Lung Cancer: A Multicenter Retrospective Study.

The emergence of an aging society and technological advances have made radiotherapy, especially stereotactic body radiotherapy (SBRT), a common alternative to surgery for elderly patients with early stage non-small-cell lung cancer (NSCLC). Carbon-ion radiotherapy (CIRT) is also an attractive treatment option with potentially lower toxicity for elderly patients with comorbidities. We compared the clinical outcomes of the two modalities using Japanese multicenter data. SBRT (n = 420) and single-fraction CIRT (n = 70) data for patients with stage I NSCLC from 20 centers were retrospectively analyzed. Contiguous patients ≥ 80 years of age were enrolled, and overall survival (OS), disease-specific survival (DSS), local control (LC), and adverse event rates were compared. The median age was 83 years in both groups and the median follow-up periods were 28.5 and 42.7 months for SBRT and CIRT, respectively. The 3-year OS, DSS, and LC rates were 76.0% vs. 72.3% (p = 0.21), 87.5% vs. 81.6% (p = 0.46), and 79.2% vs. 78.2% (p = 0.87), respectively, for the SBRT vs. CIRT groups. Regarding toxicity, 2.9% of the SBRT group developed grade ≥ 3 radiation pneumonitis, whereas none of the CIRT group developed grade ≥ 2 radiation pneumonitis. SBRT and CIRT in elderly patients showed similar survival and LC rates, although CIRT was associated with less severe radiation pneumonitis.

Stereotactic Body Radiation Therapy With or Without Transarterial Chemoembolization Versus Transarterial Chemoembolization Alone in Early-Stage Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

This study aims to review the current evidence on the utility of stereotactic body radiation therapy (SBRT), with or without transarterial chemoembolization (TACE), for early-stage hepatocellular carcinoma (ESHCC) patients not amenable to standard curative treatment options. Literature search was conducted using PubMed, ScienceDirect, and Google Scholar. Comparative studies reporting oncologic outcomes were included in the review. Five studies (one phase II randomized controlled trial, one prospective cohort, three retrospective studies) compared SBRT versus TACE. Pooled analysis showed an overall survival (OS) benefit after 3years (OR 1.65, 95% CI 1.17-2.34, p = 0.005) which persisted in the 5-year data (OR 1.53, 95% CI 1.06-2.22, p = 0.02) in favor of SBRT. RFS benefit with SBRT was also seen at 3years (OR 2.06, 95% CI 1.03-4.11, p = 0.04) which continued after 5years (OR 2.35, 95% CI 1.47-3.75, p = 0.0004). Pooled 2-year local control (LC) favored SBRT over TACE (OR 2.96, 95% CI 1.89-4.63, p < 0.00001). Two retrospective studies compared TACE + SBRT versus TACE alone. Pooled analysis showed significantly improved 3-year OS (OR 5.47; 95% CI 2.47-12.11, p < 0.0001) and LC (OR: 21.05; 95% CI 5.01-88.39, p ≤ 0.0001) in favor of the TACE + SBRT group. A phase III study showed significantly improved LC and PFS with SBRT after failed TACE/TAE versus further TACE/TAE. Taking into account the limitations of the included studies, our review suggests significantly improved clinical outcomes in all groups having SBRT as a component of treatment versus TACE alone or further TACE. Larger prospective studies are warranted to further define the role of SBRT and TACE for ESHCC.

The efficacy of radical hepatectomy versus stereotactic body radiotherapy for primary hepatocellular carcinoma: A propensity score matching analysis.

4130 Background: Recent international guidelines have included stereotactic body radiotherapy (SBRT) which outstanding tumor control as a treatment option for hepatocellular carcinoma (HCC) in several settings. However, data evaluating surgery and SBRT are limited, and results published were controversial. The retrospective study aims to compare the efficacy of hepatectomy and SBRT for HCC. Methods: The study population started with patients in databases of primary HCC, treated with curative hepatectomy or SBRT, regardless of tumor number, tumor size, cirrhosis and portal vein thrombosis. Patients with prior cancer treatment other than transarterial chemoembolization were excluded. In order to reduce the potential confounding effect of treatment and selection bias, 3-to-1 propensity score models were constructed based on each patient’s estimated propensity score. The variables significant for overall survival were considered for the match, including age, sex, Child-Pugh score, ECOG performance status score, maximum diameter, BCLC stage, prothrombin time, total bilirubin, albumin, and white blood cell. Overall survival and progression-free survival were compared. Results: A total of 174 patients, 154 in hepatectomy group and 20 in SBRT group, were analyzed. 125 men and 29 women, mean 56.2 years of age, in hepatectomy group. 12 men and 8 women, mean 70.5 years of age, in SBRT group. ECOG was a significant favorable factor for overall survival. Maximum diameter, portal vein embolization, aspartate transferase and albumin was significant favorable factors for disease-free survival of patients with primary hepatocellular carcinomas. Before PSM, patients in the hepatectomy group tended to be younger, had better performance status, less cirrhosis, less tumor number and had better hepatic function than those in the SBRT group ( P &lt; .05). The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 77.9% vs 35.4 (P = .003) and 30 vs 20 month (P = .486), respectively. After PSM, 80 patients, 60 in hepatectomy group and 20 in SBRT group, were analyzed. The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 71.9% vs 56.6 (P = .92) and 17 vs 26 month (P = .656), respectively. The patients of hepatectomy group had less cirrhosis, better liver function and less tumor number than those in 20 with SBRT. Conclusions: For primary HCC, regardless of tumor size and tumor number, stereotactic body radiotherapy can provide similar result on overall survival and tumor control compared to hepatectomy. Stereotactic body radiotherapy can also be less invasive and provide less inpatient time. So stereotactic body radiotherapy can be a effective treatment for patients with primary HCC.

A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.

4096 Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .

Association of circulating CD103+ T cells with major pathological response in a randomized phase 2 trial of neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small cell lung cancer.

8550 Background: We previously reported results of a randomized phase 2 study, demonstrating a higher rate of major pathological response to durvalumab in combination with stereotactic body radiotherapy (SBRT) compared to durvalumab alone in patients with localized (stage I-IIIA) non-small cell lung cancer (NSCLC). Biomarkers of response in NSCLC are poorly understood. To address this, we evaluated sequentially collected peripheral blood mononuclear cells (PBMCs) from study participants to identify easily accessible biomarkers associated with major pathological responses. Methods: PBMCs were obtained from study participants at defined pre-treatment, peri-operative, and post-operative timepoints. We performed 25-marker spectral flow cytometric analysis of the T cell compartment in these samples and used dimensionality reduction and clustering programs to identify populations of interest. Results: Our analysis of these samples revealed populations of both CD4+ and CD8+ T cells with hallmarks of prior antigen exposure and tissue residency (CD103+, CCR7-, CD45RA-), suggesting tumor-experienced T cells circulating into the blood. Greater pre-treatment frequency of these T cell populations was associated with major pathological responses to neoadjuvant therapy. This observation was consistent when evaluating patients with major pathological responses across both treatment arms, and within the durvalumab plus SBRT group, where we had enough patients with major pathological responses. Maturation of disease-free survival data from this trial will enable us to evaluate the association of these biomarkers with long-term survival. Conclusions: Together, these data reveal an unexpected population of T cells in the peripheral blood with features of tissue-residency, which are associated with major pathological responses, and suggest that re-circulation of tumor-experienced T cells may represent a predictive biomarker for neoadjuvant treatment of NSCLC.

EGFR-TKIs plus stereotactic body radiation therapy (SBRT) for stage IV Non-small cell lung cancer (NSCLC): A prospective, multicenter, randomized, controlled phase II study

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. However, the acquired resistance greatly limits the survival benefit of EGFR-TKIs for EGFR-mutant NSCLC patients. We aimed to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus EGFR-TKIs in these patients. MethodsIn this prospective, randomized, controlled, phase 2 study, participants were recruited from 4 different hospitals in Wuhan, China. Eligible patients were histologically confirmed to have NSCLC with an EGFR-sensitive mutation (19DEL or 21L858R) and diagnosed at stage IV. Patients who had received first-line EGFR-TKIs treatment including gefitinib, erlotinib, and icotinib and achieved stable disease or partial response were enrolled after three months. Eligible participants were randomly assigned (1:1) to receive SBRT plus EGFR-TKIs or EGFR-TKIs treatment alone. In the combination-group, different tumor sites were irradiated at doses ranging from 30–50 Gy in five fractions. Considering the short duration of SBRT, the TKIs were continued during the radiotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and safety. This study was registered at ClinicalTrials.gov, with the registration number of NCT03595644. ResultsBetween May 4, 2018 and Dec 20, 2019, 74 patients were screened, of whom 62 patients were enrolled and randomized. The study was closed early with 62/72 patients due to slow accrual. The enrolled patients were randomly assigned to receive SBRT plus EGFR-TKI(n = 31) or EGFR-TKI alone (n = 31). One patient who was randomized to the SBRT plus EGFR-TKI group refused to receive SBRT during the treatment, and, 61 patients were included the modified intention-to-treat (mITT) analysis, with 30 in the SBRT plus EGFR-TKI and 31 in the EGFR-TKI group. As of the clinical cutoff date (Feb 14, 2022), the median follow-up was 29.4 months (IQR 6.9–38.9). The median PFS of the EGFR-TKI group and SBRT combination group was 9.0 vs 17.6 months (hazard ratio [HR] = 0.52, 95% confidence interval [95%CI], 0.31–0.89, P = 0.016). Meanwhile, the median OS was 23.2 vs 33.6 months (HR [95%CI], 0.53(0.30–0.95); P = 0.026). There was no grade 3 or greater toxicity observed in either group, the grade 2 adverse events were 50% in the EGFR-TKIs + SBRT group while the percentage was 45.2% in the EGFR-TKIs group. ConclusionsThe addition of SBRT significantly delayed the onset of acquired resistance to EGFR-TKIs and prolonged the PFS and OS of patients. Radiotherapy of the primary lesion alone might be superior to metastatic sites. Further confirmatory studies are needed to confirm our findings.