Trial Of Stereotactic Body Radiation Therapy Research Articles

An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer

BackgroundImmuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.MethodsEligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.ResultsSixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses.ConclusionsThis study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy.Trial registrationEudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

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.

TROG 15.03/ANZUP International Multicenter Phase II Trial of Focal Ablative STereotactic RAdiotherapy for Cancers of the Kidney (FASTRACK II)

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive alternative for primary renal cell cancer (RCC) in patients unsuitable for surgery. The objective of the FASTRACK II clinical trial was to investigate the efficacy of SBRT for primary RCC. This non-randomized, intergroup multi-institutional phase II study was activated in 7 Australian centers and 1 Dutch center, through the Trans Tasman Radiation Oncology Group (TROG) and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Eligible patients had biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, ECOG performance ≤2 and were medically inoperable, high risk or declined surgery. For tumors ≤4 cm a single fraction of 26 Gy was prescribed, for tumors > 4 cm, 42 Gy in three fractions was prescribed. The primary outcome of the study was to estimate the efficacy of SBRT for primary RCC, defined as local control based on RECIST criteria. The study was powered assuming that 1-year local control would be 90%, with the null hypothesis of ≤80% considered undesirable and not worthy of proceeding to a future randomized controlled trial. Between July 2016 and February 2020, 70 patients were enrolled with a median follow-up of 42 months. Median age was 77 years. Forty-nine patients were male (70%), median BMI was 32 and median Charlson comorbidity score was 7. The median [IQR] RENAL complexity score was 8 [7-10]. Biopsy confirmation was 100%. Twenty-three patients (33%) had T1a disease. The median (interquartile range [IQR]) tumor size was 4.6cm [3.7-5.5]; it was 3.3cm [3.0-3.6] in those receiving single fraction (n = 23), and 5.3cm [4.6-6.0] in those receiving 3-fraction SBRT (n = 47). During real-time pre-treatment quality assurance review, 10 cases (14.3%) required resubmission for protocol deviation, 2119 variables were assessed at final review, and final protocol compliance was 99.3%. Seven (10%) patients experienced grade 3 treatment-related adverse events, with no grade 4 or 5 events observed. Eleven (16%) patients reported no adverse events. Local control was 100% throughout the lifetime of the trial (p<0.001). Cancer-specific survival was also 100% throughout the lifetime of the trial. Freedom from distant failure (95% CIs) at 1 and 3 years was 99% (90-100%). Overall survival (95% CIs) at 1 and 3 years was 99% (90-100%) and 82% (70-89%), respectively. Baseline mean eGFR (95% CI) was 61.1 mLs/min (56.6; 65.6) and reduced by -10.8 mLs/min (-13.0; -8.6) by 1-year, by -14.6 mLs/min (-17.0; -12.2) by 2-years and plateaued thereafter. In the first multicenter prospective trial of a non-surgical primary RCC cohort, enrolling mostly T1b+ disease, SBRT was an effective treatment strategy with no observed local failures. We observed an acceptable side effect profile and renal function after SBRT. These outcomes support the design of a future randomized clinical trial of SBRT versus surgery for primary RCC. The trial was registered with ID: NCT02613819.

Long-Term Toxicity in Patients Receiving Radiotherapy for Ultracentral Stage I Non-Small Cell Lung Cancer – A Secondary Analysis of the LUSTRE Randomized Trial

Hypofractionated and stereotactic body radiotherapy (SBRT) are increasingly used in the treatment of centrally located, early-stage non-small cell lung cancer (NSCLC), though there are concerns of increased morbidity and mortality in patients with ultracentral tumors (UC). We report on the long-term toxicity of patients with UC lung cancer treated on a prospective randomized clinical trial of SBRT versus conventionally hypofractionated radiotherapy (CRT) for stage I NSCLC (NCT01968941). Patients with UC tumors, defined as those where the planning target volume directly overlaps with the proximal bronchial tree (PBT), were identified from the larger cohort of patients treated on the trial. These patients received either SBRT with 60 Gy in 8 fractions or CRT with 60 Gy in 15 fractions. The primary endpoint of this secondary analysis was development of any grade 3 or higher toxicity defined using CTCAE version 3.0. Secondary endpoints included local control, as well as dosimetric analysis of the PBT, using EQD2 with α/β ratio of 3 to assess the relationship between dose to the PBT and toxicity. Twenty-nine patients were identified with UC tumors; 21 received SBRT and 8 received CRT. Median age was 72 years (range 55-88 years) and 59% were female. Median FEV1 was 1.46L (range 0.64-2.37L). Patients had either T1 (59%) or T2 (41%) lesions, with median tumor size 2.5cm (range 1.1-4.9cm). Most patients had histologically confirmed disease (squamous cell, n = 10; adenocarcinoma, n = 8; radiographically suspicious, n = 11). The median follow-up was 2.9 years (range 0.7-5.2 years). The 3-year local control rate of all patients was 88.3% (95% confidence interval: 75.7-100%). There were 3 patients with late (>3 months) grade 3 toxicity (bronchial stricture, chest pain, and atelectasis) and 1 patient with late grade 5 toxicity (bleeding/hemorrhage), all treated in the SBRT arm. Median EQD2 dose to PBT in patients with grade ≥3 late toxicity compared to the rest of the cohort was: Dmax, 132 vs 129 Gy; D0.1cc, 129 vs 119 Gy; D1cc, 124 vs 80 Gy; and D5cc, 83 vs 41 Gy. Median EQD2 volumetric doses in grade ≥3 patients (compared to the rest) to PBT were: V65 Gy, 9.7 vs 2.2cc; V80 Gy, 7.9 vs 1.1cc; V90 Gy, 6.2 vs 0.4cc; and V100 Gy, 4.8 vs 0.3cc. The single patient with grade 5 toxicity had the highest D5cc (116 Gy) and V100 Gy (7cc) among all patients. Stereotactic radiation with 60 Gy in 8 fractions for UC lung cancer provides good local control but carries an approximately 15-20% rate of late grade ≥3 toxicity. There appears to be a dosimetric association between toxicity and dose to the PBT. It may be more important to minimize volumetric PBT dose rather than maximum point dose to reduce risk of severe late toxicity.

Neoadjuvant SBRT combined with immunotherapy in NSCLC: from mechanisms to therapy.

The utilisation of neoadjuvant immunotherapy has demonstrated promising preliminary clinical outcomes for early-stage resectable non-small-cell lung cancer (NSCLC). Nevertheless, it is imperative to develop novel neoadjuvant combination therapy regimens incorporating immunotherapy to further enhance the proportion of patients who derive benefit. Recent studies have revealed that stereotactic body radiotherapy (SBRT) not only induces direct tumour cell death but also stimulates local and systemic antitumour immune responses. Numerous clinical trials have incorporated SBRT into immunotherapy for advanced NSCLC, revealing that this combination therapy effectively inhibits local tumour growth while simultaneously activating systemic antitumour immune responses. Consequently, the integration of SBRT with neoadjuvant immunotherapy has emerged as a promising strategy for treating resectable NSCLC, as it can enhance the systemic immune response to eradicate micrometastases and recurrent foci post-resection. This review aims to elucidate the potential mechanism of combination of SBRT and immunotherapy followed by surgery and identify optimal clinical treatment strategies. Initially, we delineate the interplay between SBRT and the local tumour immune microenvironment, as well as the systemic antitumour immune response. We subsequently introduce the preclinical foundation and preliminary clinical trials of neoadjuvant SBRT combined with immunotherapy for treating resectable NSCLC. Finally, we discussed the optimal dosage, schedule, and biomarkers for neoadjuvant combination therapy in its clinical application. In conclusion, the elucidation of potential mechanism of neoadjuvant SBRT combined immunotherapy not only offers a theoretical basis for ongoing clinical trials but also contributes to determining the most efficacious therapy scheme for future clinical application.

Abstract 1096: Single cell transcriptomic sequencing of pancreatic ductal adenocarcinoma reveals an enrichment of immunosuppressive pathways in patients at high risk for early local progression following stereotactic body radiation therapy

Abstract Patients with locally advanced pancreatic ductal adenocarcinoma (PDAC) have limited therapeutic options with their disease being defined as neither metastatic nor amenable to surgical resection. Although stereotactic body radiation therapy (SBRT) is a viable treatment option in this context, disease progression remains far too common in PDAC. Understanding the interaction between radiation, cancer cells, and the tumor microenvironment (TME) may lead to an understanding of novel resistance pathways that can be exploited. In order to identify these potential nodes of therapeutic actionability, we leveraged a phase I/II dose escalation clinical trial of SBRT with a radiomodulating agent, GC4419, undertaken in patients with locally advanced PDAC. In this trial, core biopsies were obtained following neoadjuvant chemotherapy, but before and after SBRT with 50-60Gy in 5 fractions. A total of 16 biopsies underwent single cell RNA sequencing with 7 patients with matched samples before and after radiation. Of the 7 matched patients, a total of 3 experienced early local progression following SBRT, and were deemed to be nonresponders. We observed a significant increase in NK-like cells and a decrease in B-cells and Mast cells following SBRT in nonresponders. On the other hand, we also observed a significant enrichment in pathways related to downregulation of innate immunity within macrophage populations following SBRT suggesting that an immunosuppressive microenvironment may prevail in these patients. Subsequently, we observed functionally distinct cancer-associated fibroblasts (CAFs) subtypes, including myofibroblastic, inflammatory, and antigen presenting CAFs (apCAF). ApCAFs are believed to be involved in antigen presentation to CD4 T cells, but lack the costimulatory molecules to activate immune response, and are thus presumed to contribute to an immunosuppressive microenvironment through anergy. Interestingly, the population of apCAFs decreased significantly following SBRT in non-responders, and increased in those patients deemed to be responders. Thus whether apCAFs have an additional inflammatory role in the setting of patients receiving radiation remains to be further understood. We have shown how single cell RNA sequencing can be used to profile the kinetics of cell populations following SBRT. This has revealed an interplay between members of the tumor microenvironment whereby immunosuppressive pathways appear to prevail over immunostimulatory signals in nonresponders. Understanding which pathways are enriched in those patients at highest risk for local recurrence may provide insight into novel therapeutic strategies that can be implemented concurrently with radiation therapy. Citation Format: Vincent Bernard, Adnan Elhammali, Daniel Lin, Ching-Wei Tzeng, Manoop S. Bhutani, Cullen Taniguchi. Single cell transcriptomic sequencing of pancreatic ductal adenocarcinoma reveals an enrichment of immunosuppressive pathways in patients at high risk for early local progression following stereotactic body radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1096.

Genitourinary Quality-of-Life Comparison Between Urethral Sparing Prostate Stereotactic Body Radiation Therapy Monotherapy and Virtual High-Dose-Rate Brachytherapy Boost

Although radiation dose escalation improves prostate cancer disease control, it can cause increased toxicity. Genitourinary (GU) symptoms after prostate radiation therapy affect patient health-related quality of life (QoL). We compared patient-reported GU QoL outcomes following 2 alternative urethral sparing stereotactic body radiation therapy regimens. Expanded Prostate Cancer Index Composite (EPIC)-26 GU scores were compared between 2 urethral sparing stereotactic body radiation therapy trials. The SPARK trial prescribed a "Monotherapy" dose of 36.25 Gy in 5 fractions to the prostate. The PROMETHEUS trial prescribed 2 phases: a 19- to 21-Gy in 2 fractions "Boost" to the prostate, followed by 46 Gy in 23 fractions or 36 Gy in 12 fractions. The biological effective dose (BED) for urethral toxicity was 123.9 Gy for Monotherapy and 155.8 to 171.2 Gy for Boost. Mixed effects logistic regression models were utilized to estimate the difference in the odds of a minimal clinically important change from baseline EPIC-26 GU score between regimens at each follow-up. 46 Monotherapy and 149 Boost patients completed baseline EPIC-26 scoring. Mean EPIC-26 GU scores revealed statistically superior urinary incontinence outcomes for Monotherapy at 12 months (mean difference, 6.9; 95% confidence interval [CI], 1.6-12.1; P=.01) and 36 months (mean difference, 9.6; 95% CI, 4.1-15.1; P < .01). Monotherapy also revealed superior mean urinary irritative/obstructive outcomes at 12 months (mean difference, 6.9; 95% CI, 2.0-12.9; P < .01) and 36 months (mean difference, 6.3; 95% CI, 1.9-10.8; P < .01). For both domains and at all time points, the absolute differences were <10%. There were no significant differences in the odds of reporting a minimal clinically important change between regimens at any time point. Even in the presence of urethral sparing, the higher BED delivered in the Boost schedule may have a small adverse effect on GU QoL compared with Monotherapy. However, this did not translate to statistically significant differences in minimal clinically important changes. Whether the higher BED of the boost arm offers an efficacy advantage is being investigated in the Trans Tasman Radiation Oncology Group 18.01 NINJA randomized trial.

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

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

Randomised phase II trial of stereotactic body radiotherapy in combination with checkpoint inhibitors in metastatic castration-resistant prostate cancer (CheckPRO): a study protocol

IntroductionImmunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and...

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

Adverse Events Following Treatment with Combination Ablative Radiotherapy and Immunotherapy: A Pooled Analysis of Phase I Trials

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial disease but concerns over safety when combined with immunotherapy (IO) limit its use in patients on IO who might otherwise benefit. Here we report adverse events (AEs) associated with combined SBRT and IO using prospectively-collected data on patients pooled from three trials investigating multi-site SBRT and IO. <h3>Materials/Methods</h3> Patients were included from three trials of SBRT to 1-4 sites with sequential or concurrent IO: (1) nivolumab/urelumab or nivolumab/cabiralizumab given within 7 days of starting SBRT (concurrent); (2) pembrolizumab given 1-7 days after completing SBRT (sequential); and (3) nivolumab/ipilimumab given within 14 days prior (concurrent) or 1-7 days after SBRT (sequential). SBRT was performed per NRG BR001. All evaluable trial patients were included. AEs were recorded prospectively per CTCAE v4.0 in weekly monitoring meetings and were included if rated at least possibly related to treatment. Survival was analyzed using Kaplan-Meier method with 90-day landmark analysis. Association with AEs was assessed using logistic regression. <h3>Results</h3> 207 patients were included. Median age was 61, 42% were male, a median of 2 sites were treated, and 62% of patients received sequential IO. Over 30 histologies were treated with the most common being NSCLC (21%) and colorectal (14%). Median follow-up was 10 months. 50% and 27% of patients experienced at least 1 grade ≥2 or grade ≥3 AE, respectively. Table 1 shows rates of grade ≥3 AEs experienced by >1 patient. Grade ≥3 AEs were least common with pembrolizumab (14%) and most common with nivolumab/ipilimumab (57%). There were 3 grade 5 AEs: 2 respiratory failures and 1 pulmonary hemorrhage that were rated possibly treatment related. 58% of grade ≥3 toxicities occurred within 90 days of beginning therapy. A 90-day landmark survival analysis of patients with or without grade ≥3 AEs showed no significant difference in PFS or OS among 127 and 171 evaluable patients, respectively. On univariate analysis age, sex, smoking history, number of sites treated, sequencing of IO, and IO agent were not significantly associated with development of one or more grade ≥3 AEs. <h3>Conclusion</h3> This analysis presents the largest prospectively evaluated cohort of patients treated with combination SBRT and IO to date. AE rates were similar to those seen with IO or SBRT alone. We observed no significant association between AEs and survival in our cohort, possibly due to heterogeneity in histologies and IO agents. We conclude that multi-site SBRT and IO can be safely co-administered. We provide a robust toxicity characterization to serve as comparison for future RT/IO trial design.

Single Cell Sequencing of Pancreatic Ductal Adenocarcinoma Reveals a Paradoxical Immunosuppressive Microenvironment Following Stereotactic Body Radiation Therapy

<h3>Purpose/Objective(s)</h3> Patients with locally advanced pancreatic ductal adenocarcinoma (PDAC) have limited therapeutic options with their disease being defined as neither metastatic nor amenable to surgical resection. With stereotactic body radiation therapy (SBRT) emerging as a viable treatment option in this context, disease progression remains far too common in PDAC. Understanding the interaction between radiation, malignant cells, and the tumor microenvironment (TME) may lead to an understanding of novel biological mechanisms that can be exploited. We hypothesized that a detailed itemization of the tumor components through single cell RNA (scRNA) sequencing may allow us to understand emerging immunosuppressive pathways following SBRT than can function as potential nodes of therapeutic actionability. <h3>Materials/Methods</h3> To do this we leveraged an institutional IRB approved protocol. Tumor biopsies were obtained under a phase I/II dose escalation trial of SBRT with a radiomodulating agent, GC4419, undertaken in patients with locally advanced PDAC. Core biopsies were obtained following neoadjuvant chemotherapy, but before and after SBRT with 50-60Gy in 5 fractions. A total of 16 biopsies from patients on trial were suitable for single cell sequencing with 7 patients with matched samples before and after radiation. ScRNA sequencing was performed using the 10x-genomics Chromium droplet-based platform. <h3>Results</h3> A total of ∼27,000 cells across 16 biopsy samples were analyzed. Subtypes of functionally distinct subtypes of cancer-associated fibroblasts (CAFs) were detected including myofibroblastic (myCAF), inflammatory CAFs (iCAF), and antigen presenting CAFs (apCAF). Specifically, following SBRT, there was an enrichment of apCAFs, which are involved in antigen presentation to CD4 T cells, but lack the costimulatory molecules to activate immune response, thus possibly leading to an immunosuppressive environment through anergy. Within the immune microenvironment, there was a shift to M1 macrophage (proinflammatory) polarization, following SBRT. Inversely, there was also an enrichment of regulatory T cells following SBRT, with no significant differences in populations of cytotoxic or memory T cells. <h3>Conclusion</h3> We have shown how single cell RNA sequencing can be used to profile the kinetics of cell populations following radiation therapy. This has revealed a paradoxical immunosuppressive effect following SBRT, whereby immunostimulatory signals are negated by an immunosuppressive microenvironment, providing potential therapeutic targets to be used concurrently with radiation therapy.

Atezolizumab and Stereotactic Body Radiation Therapy in Metastatic, Recurrent or Persistent Cervical Cancer: Interim Results from a Non-Randomized, Open-Label Phase II Multi-Institutional Study

<h3>Purpose/Objective(s)</h3> Inhibition of the anti-PD-1/PD-L1 axis has been approved in the metastatic, recurrent, or persistent settings for cervical cancer. Stereotactic body radiation therapy (SBRT) has a well-defined role in the management of oligometastatic disease. There may be potential synergy between stereotactic radiation and anti-PD-1/PD-L1 checkpoint inhibition in advanced cervical cancer. We hypothesize treatment with atezolizumab and SBRT will be well tolerated and may improve tumor control rates compared to atezolizumab alone in the management of metastatic, recurrent, or persistent cervical cancer. <h3>Materials/Methods</h3> The study is designed as a prospective, single arm, nonrandomized, open-label, phase II multi-institutional trial of SBRT with 24 Gy in 3 fractions to patients with ≥ 2 metastatic sites followed 1 week later by atezolizumab (1200 mg IV every 3 weeks) for patients with recurrent, persistent, or metastatic cervical cancer. The primary objective of the study is to evaluate the objective response rate by immune-related response evaluation criteria in solid tumors (irRECIST) criteria following SBRT and atezolizumab at the unirradiated target lesion. Secondary endpoints include progression free survival (PFS), overall survival (OS), and adverse events. Results of the pre-planned interim analysis are reported. Clinical trial information: NCT03614949. <h3>Results</h3> Between January 2019 and September 2021, a total of 13 patients were enrolled. The majority of patients had adenocarcinoma (n=9; 69%) with a median age of 50 (range: 36-69). Median number of lines of prior therapy was 2 (range: 1-5). Median follow-up is 18 months (range: 2.7-35.8 months). The median PFS was 4.5 months (95% CI: 3.87- Not reached) with a 6-month PFS of 46%. The median OS was 11 months (95% CI 7.77 – Not reached) with a 6-month OS of 84%. The overall response (irRECIST) was a partial response in 3 (23%) and stable disease in 4 (31%) patients. An objective response was observed in 2 patients meeting criteria to move to the stage II portion of the trial. Study therapy was well tolerated with no patients discontinuing therapy due to side effects. The most common grade ≥2 toxicities at least possibly attributed to study therapy included lymphopenia (n=4; 31%), fatigue (n=3; 23%), and hypothyroidism (n=2; 15%). <h3>Conclusion</h3> Atezolizumab and SBRT was well tolerated in the first stage of the phase II trial. Objective responses were noted in two patients meeting the pre-planned criteria to warrant opening of the second stage of the study.

Bone Only Oligometastatic Renal Cell Carcinoma Patients Treated with Stereotactic Body Radiotherapy: A MULTI-Institutional Study

<h3>Purpose/Objective(s)</h3> Previous studies demonstrated the efficacy of stereotactic-body radiotherapy (SBRT) for oligometastatic renal cell carcinoma (RCC) patients. However, it has not been well-studied in patients with bone-only metastatic RCC. This study aimed to analyze the prognostic factors associated with overall survival (OS) and progression-free survival (PFS) in patients with bone-only metastatic RCC who have five or fewer lesions treated with SBRT. <h3>Materials/Methods</h3> The clinical data of 54 patients with 70 bone metastases undergoing SBRT treated between 2013 and 2020 with a fraction dose of at least 6 Gy per fraction, and a biologically effective dose (BED) of at least 90 Gy was retrospectively evaluated. The prognostic factors associated with OS and PFS were assessed. <h3>Results</h3> The majority of lesions were located in the spine (57.4%), and had only one metastasis (64.8%). The median SBRT fraction and total doses were 10 Gy (range: 6–18 Gy) and 20 Gy (range: 12–40 Gy), and SBRT was administered with a median fraction of 3 (range, 1–5). The median BED of SBRT was 108.4 Gy (range: 90.0–202.2 Gy). After a median follow-up of 22.4 months, the 1- and 2-year OS rates were 84.6% and 67.3%, respectively, and median OS was 43.1 months. The 1- and 2-year PFS rate, and median PFS were 63.0%, 38.9%, and 15.3 months, respectively. After completion of metastasis-directed treatment (MDT), disease progression occurred in 26 patients (48.1%) at a median of 12.7 months (IQR 7.1–29.9 months). There were 22 (84.6%) with distant metastasis, one (3.8%) with in-field local recurrence, and three (11.6%) with both distant metastasis and local recurrence. In SBRT-treated lesions, only 4 patients (7.4%) experienced local recurrence, and the 1- and 2-year LC rates per lesion were 94.9% and 92.0% per lesion. Age, metastasis localization, and number of fractions for SBRT were significant prognostic factors for OS in univariate analysis. In multivariate analysis, patients with spine metastasis had a better OS [HR=3.1 (95% CI, 1.3–7.7; p = 0.001)] compared to their counterparts, and patients who received single fraction SBRT [HR=2.2 (95%, 1.2–4.2; p = 0.01)] had a better PFS than those who did not. No patient experienced acute or late toxicities of grade 3 or greater. <h3>Conclusion</h3> To the best of our knowledge, this is the first multicenter study of bone-only oligometastatic RCC patients treated with SBRT. Despite excellent LC at the oligometastatic site treated with SBRT, disease progression was observed in nearly half of patients 13 months after MDT, particularly as distant disease progression other than treated lesion, necessitating an effective systemic treatment to improve treatment outcomes. Prospective trials of SBRT for oligometastatic bone sites are warranted because they may shed light on disease control, survival, and quality of life after such therapy.

Protocol of notable-HCC: a phase Ib study of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with resectable hepatocellular carcinoma

IntroductionLiver resection is the mainstay of curative-intent treatment for hepatocellular carcinoma (HCC), but the postoperative 5-year recurrence rate reaches 70%, and there are no adjuvant or neoadjuvant therapies recommended by...

Predictors of Pneumonitis in Combined Thoracic Stereotactic Body Radiation Therapy and Immunotherapy

Thoracic stereotactic body radiation therapy (SBRT) is associated with high rates of local control but carries a risk of pneumonitis. Immunotherapy is a standard treatment for patients with metastatic disease but can also cause pneumonitis. To evaluate the feasibility and safety of thoracic SBRT with systemic immunotherapy, clinical outcomes of patients treated with immune checkpoint blockade (ICB) and SBRT on prospective trials were reviewed. Three consecutive phase 1 trials of combination SBRT and ICB conducted between 2016 to 2020 for widely metastatic solid tumors were reviewed. The protocols mandated adherence to NRG BR001/BR002 organs at risk constraints, resulting in <100% coverage of some target volumes. ICB was administered either sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT), depending on protocol. End points included pneumonitis, dose-volume constraints, local failure, and overall survival. The cumulative incidence estimator and Kaplan-Meier method were used. In the study, 123 patients met eligibility with 311 metastases irradiated. The most common histologies included non-small cell lung cancer (33%) and colorectal cancer (12%). Median follow-up was 12 months. The overall rate of grade 3+ pneumonitis was 8.1%; 1-year local failure was 3.6%. Established dosimetric parameters were significantly associated with the development of pneumonitis (P < .05). In most patients, the lungs were not challenged with high doses of radiation, defined as receiving ≥75% of the maximum for a given lung dose-volume constraint. Patients who were challenged were not found to have a significantly higher risk of pneumonitis. In the largest series of thoracic SBRT and immunotherapy, local control was excellent with acceptable toxicity and support the conclusion that established dose-volume constraints for the lung are safe. However, these results highlight the potential value in reporting of organs at risk being challenged with doses approaching protocol specified limits.

A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer

Purpose/objective(s)To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer.Materials/methodsWe enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54–86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3–46 months (median, 31 months). Median duration of follow-up was 36 months (range 1–54 months). We used Radiation Therapy Oncology Group and National Cancer Institute—Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC).ResultsProtocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment.ConclusionOur phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Discordance of patient- and physician-reported toxicities in two prospective trials of stereotactic body radiotherapy (SBRT) for localized prostate cancer.

245 Background: SBRT for localized prostate cancer (PCa) is the focus of several ongoing and reported high-impact trials, which often focus on physician-reported toxicity (P-Tox) when comparing regimens. Patient-reported quality of life (PR-QoL) may differ and provide a more sensitive comparative metric of treatment burden, especially with fewer provider interactions during SBRT than during protracted RT courses. We evaluated the concordance of prospective genitourinary (GU) and gastrointestinal (GI) P-Tox and PR-QOL in men receiving SBRT for PCa. Methods: Data from two concurrently-enrolled prospective trials of SBRT in high-risk (Phase I Safety Endpoint, NCT01896271) and low-intermediate risk (Phase II GI Toxicity Endpoint, NCT02353832) PCa were used. Matching standardized schedules of collected PR-QoL [Expanded Prostate Cancer Index Composite (EPIC)] and P-Tox (CTCAE v5.0) were analyzed over the first 18 months of follow up, where symptoms are most pronounced. We assessed concordance of Grade≥2 GU/GI physician reported toxicity with PR-QoL declines exceeding anchor based minimal clinically important difference (MCID) thresholds (-6 urinary and -5 bowel summary scores, respectively) for each patient at each time point. Patients without baseline PR-QoL data were excluded in full, while time points with missing PR-QoL or P-Tox were excluded individually without imputation. Concordance was evaluated by Cohen’s kappa statistic. Results: From 101 patients, there were 256 (64%) follow up observations through 18 months with both PR-QoL and P-Tox at the time point and baseline. Concordance of PR-QoL and P-Tox was low at all time points for both GU and GI toxicity domains (mean kappa 0.093; Table). MCID was more often reported by patients than Grade≥2 toxicity by physicians (38% vs 17% for GU and 44% vs 10% for GI). There was little overlap of PR-QoL and P-Tox reporting: Grade≥2 P-Tox reported in 17% of observations with MCID in PR-QoL, while MCID in PR-QoL reported in 54% of observations of Grade ≥2 P-Tox. Mean concordance was similarly low when analyzing sub-groups of trial, investigator, and an alternative 2xMCID threshold. Conclusions: P-Tox and PR-QoL differed dramatically in two prospective studies of SBRT despite toxicity primary endpoints. This may reflect subjective and varying intervention thresholds driving P-Tox reporting, rather than actual patient burden. These data strongly support use of PR-QoL rather than P-Tox for SBRT comparative study endpoints and guidelines in this rapidly evolving space. [Table: see text]

LITE SABR M1: Planning design and dosimetric endpoints for a phase I trial of lattice SBRT

PurposeLattice stereotactic body radiation therapy (SBRT) is a form of spatially fractionated radiation therapy (SFRT) using SBRT methods. This study reports clinical dosimetric endpoints achieved for Lattice SBRT plans delivering 20 Gy in 5 fractions to the periphery of a tumor with a simultaneous integrated boost (SIB) of 66.7 Gy, as part of a prospective Phase I clinical trial (NCT04133415). Additionally, it updates previously reported planning and delivery techniques based on extended experience with a broader patient population. MethodsPatients were enrolled on a single-arm phase I trial conducted between November 2019 and August 2020. Eligibility was restricted to tumors >4.5 cm in the largest dimension. Characteristic SFRT dose gradients were achieved using a lattice of 1.5 cm diameter spheres spaced within the GTV in a regular pattern, with peak-to-valley dose varying from 66.7 Gy to 20 Gy within 1.5 cm. Organ-at-risk (OAR) sparing followed AAPM TG101 recommendations for 5-fraction SBRT. ResultsTwenty patients (22 plans) were enrolled on study, with one additional plan treated off study. All OAR and target coverage planning objectives were achieved, with the exception of a single small bronchus. Conformity of the 20 Gy isodose line significantly improved over the course of the study. The majority (85.2%) of treatment fractions were delivered in a 30 minutes timeslot, with 4 (3.5%) exceeding a total treatment time of 40 minutes. ConclusionLattice SBRT planning techniques produce consistent and efficient treatment plans. Refined techniques described here further improve the quality of the planning technique.

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy (SBRT) Prior to Radical Prostatectomy (RP) in Locally Advanced Prostate Cancer

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy (SBRT) Prior to Radical Prostatectomy (RP) in Locally Advanced Prostate Cancer