Stereotactic Ablative Body Radiotherapy Research Articles

Single-Fraction Stereotactic Ablative Body Radiotherapy for Primary and Extracranial Oligometastatic Cancers

Stereotactic ablative body radiotherapy (SABR) consists of delivering high doses of ionising radiation, typically across three to eight fractions with high precision and conformity. SABR has become increasingly commonplace throughout the last quarter of a century and is offered for the treatment of various primary and metastatic tumour types. Delivering SABR in a single fraction has arisen as an appealing possibility for several reasons. These include fewer hospital visits, greater patient convenience, improved sustainability and lower costs. However, these factors must be balanced against considerations such as toxicity, side-effects and, most importantly, progression-free and overall survival. In this review we seek to analyse the results of studies looking at the efficacy of single-fraction SABR for lung, prostate, renal and pancreas primary tumours, as well as oligometastases. The tumour type to be most widely treated with single-fraction SABR is lung, but its remit continues to expand. We also look at the biological rationale underpinning SABR and how this can be extended to single-fraction regimens. Finally, we turn our attention towards the future directions of SABR and specifically single-fraction regimens. These include the possibility of combining SABR with immunotherapy and technological advances in the field, which could serve to expand the scope of SABR. We conclude by summarising the current clinical studies of single-fraction SABR.

18F]NaF PET/CT imaging of response to single fraction SABR to bone metastases from breast cancer.

Breast cancer commonly metastasises to the skeleton, and stereotactic ablative body radiation therapy (SABR) is an emerging treatment for oligometastatic disease. Accurately imaging bone metastases and their response to treatment is challenging. [18F]NaF-PET has a higher sensitivity and specificity than conventional bone scans for detecting breast cancer bone metastases. In this pre-defined secondary analysis of a prospective trial, we evaluated the change in [18F]NaF uptake after SABR. Patients with oligometastatic breast cancer received a single fraction of 20 Gy to up to three bone metastases. [18F]NaF-PET was acquired before and 12 months after SABR. Pre- and post-treatment [18F]NaF-PET images were registered to the treatment planning CT. The relative change in tumour SUVmax and SUVmean was quantified. The intersection of each of the radiation therapy isodose contours with a non-tumour bone was created. The change in SUVmean in sub-volumes of non-tumour bone receiving doses of 0-20 Gy was quantified. In total, 14 patients, with 17 bone metastases, were available for analysis. A total of 15 metastases exhibited a reduction in SUVmax; the median reduction was 42% and the maximum reduction 82%. An increased absolute reduction in SUVmax was observed with higher pre-treatment SUVmax. One patient exhibited increased SUVmax after treatment, which was attributed to normal peri-tumoural bone regeneration in the context of a bone metastasis. There was a median reduction of 15%-34% for non-tumour bone in each dose level.

Outcomes of Targeted Therapy Plus Immunotherapy and High-Dose Stereotactic Ablative Body Radiotherapy (SABR) for Metastatic Renal Cell Cancer Patients.

Stereotactic ablative body radiotherapy (SABR) is one of the treatment options for metastatic renal cell carcinoma (mRCC) but is limited by a lack of data to evaluate targeted therapy plus immunotherapy concurrently with high-dose SABR to multiple sites. We evaluated the safety and disease control for mRCC patients who concurrently received the above tri-modality treatment. Patients were treated with SABR (40-70 Gy/5-10 fractions) for small lesions or partial-SABR (tumor center boosted with 6-8 Gy/3-5 fractions with 50-60 Gy/20-25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs. When SABR/partial-SABR was not feasible, a moderate fractionated radiotherapy plan, usually 60Gy/20 fractions were applied. of Targeted therapy plus immunotherapy (PD-1 inhibitor) was not interrupted during or after radiotherapy (RT). Adverse events (AEs) were evaluated. Disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were calculated. The PFS1 was defined as the first progression since the start of RT. The PFS2 was defined as the second progression after the second RT course, if new metastases occurred after first RT were all re-irradiated, and the systemic therapy was not changed. The Kaplan-Meier method was used for time-to-event endpoints. A total of 51 patients, with a median age of 57 yr, were enrolled. The median follow-up was 12 months. There were 75% of patients with intermediate-risk and 18% with favorable-risk disease. 61% of the patients were oligometastatic. 71% had clear cell renal cancer. There were 241 metastases while 161 (67%) were irradiated. 80% of the lesions received SABRP/partial SABR. 1 patient with 14 lesions irradiated received proton therapy. All the surviving patients are continuing using targeted therapy while 81% patients complete at least 1-year PD-1 therapy. 10 patients (20%) had grade 3 drug-related AEs: pneumonitis (n = 2), elevated alanine transaminase (n = 4), myositis (n = 1), hand-foot syndrome myositis (n = 1), enteritis (n = 1), fatigue (n = 1). There were 1 grade 4 AEs of upper gastrointestinal bleeding. No grade 3-5 RT-related AEs was found. ORR and DCR for irradiated lesion were 51% and 98%. Median OS and PFS2 was not reached. Median PFS1 was 14(6-22) months. Estimated 1- and 2-yr OS, PFS1 and PFS2 were 90% and 90%, 56% and 38%, 74% and 51% respectively. Univariate analysis showed that an PFS1 benefit was found in patients who received radiation before systemic therapy failure (p = 0.038). We investigated the high-dose RT in combination of concurrent targeted and immunotherapy in patients with metastatic RCC. We found that this treatment regimen was well tolerated, with good cancer control. Early use of high-dose RT to multi-lesions may improve PFS. Partial-SABR for bulky lesions close to critical organs could be safely and effectively applied under certain circumstances. These encouraging findings warrant further investigation.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the FASTR/FASTR-2 Trials.

There has been emerging interest in the role of ultra-hypofractionated radiotherapy for high-risk prostate cancer, especially given its low α/β ratio. However, there is limited data on the long-term outcomes of this treatment strategy. The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer. FASTR was discontinued early due to unacceptable acute toxicity, whereas the acute toxicities in FASTR-2 were minimal. Herein, the long-term results from these trials are reported. Eligible patients had at least 1 high-risk feature as per the National Comprehensive Cancer Network criteria for high-risk prostate cancer, no evidence of metastatic disease, and either a score of 3+ on the Vulnerable Elderly Scale or declined standard therapy. A total of 19 patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 fractions delivered once weekly for 5 weeks, along with 1 year of androgen deprivation therapy (ADT). The excessive acute toxicity in FASTR prompted several modifications in FASTR-2, including the omission of nodal irradiation. A total of 30 patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 fractions delivered once weekly for 5 weeks, along with 18 months of ADT. A total of 44 patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Most patients were >70 years old (77%). High-risk features included Gleason score ≥8 (46%), T3-T4 disease (27%) and baseline PSA >20 (50%). With a median follow-up of 6.4 years, the cumulative incidence of grade ≥3 genitourinary/gastrointestinal toxicity was 50% among FASTR patients and 7% among FASTR-2 patients. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival and overall survival were 72%, 90%, 92% and 83%, respectively. A total of 12 patients (27%) required further treatment. No significant differences in clinical outcomes were noted between the FASTR and FASTR-2 cohorts. SABR for high-risk prostate cancer is an attractive option for reducing treatment burden. Clinical outcomes and toxicity with the FASTR-2 protocol were comparable to conventionally-fractionated radiotherapy plus ADT. Larger prospective, randomized trials exploring the role of SABR with ADT in high-risk disease are necessary to better understand the efficacy and tolerability of this approach.

Implementation Science in Radiation Oncology: Case Study for Liver SBRT.

The translation of research into clinical practice is challenging and implementation science is becoming as important as the trial design and development. Implementation science methodologies have been shown to reduce research-to-practice gap in other clinical settings. This is especially true for the field of Radiation Oncology where modern hypofractionated techniques, like Stereotactic Ablative Body Radiotherapy for Liver are at a high risk of over enthusiastic implementation as well as underutilization. We present the results of a multicomponent implementation methodology utilized to develop our Liver SBRT program as a model to safely translate a complex technology into clinical practice. After review of literature and market research a setup was created with focus on machine requirements, immobilization devices, motion management techniques and QA techniques. Clinical tools in the form of checklists were developed for patient selection, simulation along with image fusion, target delineation, planning (conformity indices, dose constraint criteria) and treatment delivery. All patients were treated on Truebeam® after Bodyfix® immobilization with plastic wrap. Planning was completed on Eclipse TPS with dose constraints and conformity guidelines defined per the RTOG 1112 and TG 101. Clinical outcomes including clinical and imaging follow-up for tumor control and toxicity were recorded. For this report, all patients treated were reviewed and compared to published data to assess the success of the implementation methodology. A total of 64 consecutive Patients treated with liver SBRT at Dignity Health Cancer Institute (DHCI) were eligible for the study. 58 patients treated for primary liver malignancies were included in this analysis to assess outcomes including control of disease and toxicity to compare to the published literature. Median follow up for these patients 6.5 months (4-46mnths). Median GTV volume was 38.7cc (0.1cc-2056.1 cc), median PTV volume was 159.35 cc (21.5cc-2673.5cc). Median SBRT prescription dose was 50 Gy/5 fractions (35-50 Gy). Median Liver- GTV was 1595.8 cc(770.7cc-2983.0cc). Following toxicities were noted- Grade 1- 10.3%, Grade 2 - 1.72%, Grade 3- 3.44%. No Grade 4 toxicity was noted. 1 year LC rate was 96.6%. 8.6% showed out of field liver failure and 6.9% developed distant metastasis. These results were compared to the current published literature and are shown to be comparable. Strong and well thought out Implementation methodologies can ensure reproducing results in clinical practice, comparable to the controlled environment of trials. These are crucial in translation of clinical trials utilizing advanced technologies to promote the culture of safety in clinical practice of Radiation Oncology. Regular assessment and tracking of clinical outcomes can be used as Quality markers for directing care and reimbursements for future.

SABRSeq: A Randomized Phase Ib Trial of SABR Sequencing with Pembrolizumab in Metastatic Non-Small Cell Lung Cancer (NSCLC)

The optimal sequencing of stereotactic ablative body radiotherapy (SABR) with anti-PD1 checkpoint blockade is unknown. The purpose of SABRseq was to assess the toxicity of the combination of SABR delivered either before or after the commencement of pembrolizumab. The central hypothesis is that the treatment combination will have a safety profile that is clinically acceptable and demonstrate anti-tumor efficacy. Furthermore, we hypothesize that differences in systemic immune activation will be observed between treatment arms. This was a single institutional phase Ib randomized clinical trial (Trial ID NCT03307759). Eligible patients had metastatic NSCLC, ECOG performance 0-1, and had not received prior checkpoint immunotherapy, high-dose radiation (>36 Gy) within 6 months, or either systemic or radiation therapy within 4 weeks of randomization. Eligible patients had either TPS≥50% PD-L1 expression in the first-line or TPS≥1% PD-L1 expression with prior chemotherapy exposure. Patients were randomized to SABR before the commencement of pembrolizumab [ARM1] or SABR commencing after pembrolizumab [ARM2]. SABR was delivered in a single fraction of 18-20 Gy to 1-3 lesions. The primary endpoint was treatment-related adverse events (AE's) related to SABR and/or pembrolizumab. Secondary endpoints included best overall response (BOR), overall survival (OS), and progression-free survival (PFS). Translational objectives included the evaluation of longitudinal changes in immunological cellular subsets within peripheral blood to explore changes in systemic immunity and circulating tumor DNA (ctDNA) dynamics. Between December 2017 and December 2019, 13 patients were randomized. The median follow-up was 37 months. The study was closed early due to poor accrual. Median age was 66 years, with 11 patients (84%) having adenocarcinoma. Nine (69%) were enrolled in the first-line setting. The median [range] number of lesions was 6 [3-11]. The median [range] cycles of pembrolizumab delivered in ARM 1 was 13 [12-32] and ARM 2 was 9 [3-34]. Grade 3 treatment-related AEs were experienced in 0 of 5 patients in ARM1 and in 1 of 8 patients in ARM 2 (hyperglycemia). There were no grade 4 or 5 adverse events reported. The BOR by both RECIST and iRECIST criteria was CR in one patient, PR in seven patients, SD in five patients. Median (95% Cis) PFS was 12.4 months (6.3-21.0), and median (95% Cis) OS was 47.1 months (12.6-not reached; 2-year point estimate 62% [31-82]). Mass cytometry was used on serial peripheral blood samples to examine changes in the frequency of immune cells, changes in T cell activation, differentiation and functional polarization state. Targeted sequencing was performed to assess ctDNA. Translational outcomes will be presented. There was no evidence of a concerning safety signal from either SABR before or after start of pembrolizumab. The combination demonstrated activity with promising PFS and OS and is worthy of evaluation in larger randomized trials.

Adaptive Dose-Staged Stereotactic Ablative Body Radiotherapy for Treatment of Large Central NSCLC Lung Tumors: A Dosimetric Simulation Study

Adaptive dose-staged Stereotactic Radiosurgery (SRS) treatment of cranial AVM and personalized ultrafractionated stereotactic ablative radiotherapy (PULSAR) proposed by Timmerman et al. for lung cancer has been shown to be an effective technique with lower toxicities in the management of large lesions. The PULSAR technique requires periodic functional PET imaging or tumor biopsy more than one week apart post stereotactic ablative body radiotherapy (SABR) PULSE to utilize the tumor biological response feedback to delineate the residual active disease for subsequent (SABR) PULSES' adaptive treatment planning. The purpose of this study is to explore dosimetrically the benefit of SABR PULSES for the treatment of large central lungs tumors. A retrospective simulation study of five anonymized patients with large NSCLC was performed. Tumors were located centrally in left (N = 3) and right (N = 2) lungs. The PTVs generated by 5mm symmetric margin to the ITV, the ITV and PTV volumes were 30.0±21.4cc (10.6-64.5cc) and 65.4±35.2cc (30.7-121.0cc), respectively. Depending on the total PTV volume, 4 other adaptive PTVs were simulated by generating a symmetric reduction of the PTV volumes by 2 or 3mm assuming given enough time shrinking the original volume after each PULSE due to biological response during the time between the initial and subsequent SABR PULSES. The organs-at-risk (OARs) were contoured and 3 VMAT arcs plans were generated and optimized for each PTV with the same VMAT objective functions. The original PTV plan with 50 Gy in 5 consecutive fractions was compared with the sum of the 5 PULSES in 10 Gy per PULSE with adaptive volumes. A statistical analysis and a paired t-test of the 50 Gy plan in 5 consecutive fractions were compared with the 5 PULSES summed dose for the ITV, PTV, and the OARs. The t-test showed the 5 PULSES plans significantly lowered the doses to the ipsilateral, and contralateral lungs and heart when compared to 5 consecutive 10 Gy/fraction plans (p-Values, 0.031, 0.01, 0.02, respectively). The 11 Gy ipsilateral lung volume, a precursor for developing normal lung tissue fibrosis about one-year post SABR was significantly lower for the 5 PULSES (136±44cc Vs. 241±83cc) (p-Value, 0.01). The mean and maximum dose to the original PTV was significantly lower in 5 PULSES technique (p-Value, 0.0001, 0.046). The dose to the spinal canal was not statistically different between the two techniques (p-Value, 0.12). The current management of large central lung tumors is conventional fractionation with chemotherapy or delivering lower fractional SABR dose to meet the OAR dose constraints that may hinder the successful radioablation and local control. The PULSAR treatments using SABR dosimetrically provides significant sparing of normal tissue. Dose escalation for larger central lung tumors may be possible using this technique for effective local control and better overall survivorship.

5-Year Renal Function Outcomes after SABR for Primary Renal Cell Carcinoma: A Report from the International Radiosurgery Oncology Consortium of the Kidney (IROCK)

Renal cell carcinoma (RCC) presents uncommonly in patients with a congenital solitary kidney or prior contralateral nephrectomy. The objective of this study was to compare renal function outcomes of stereotactic ablative body radiotherapy (SABR) in patients with solitary vs. bilateral kidneys. Patients with primary RCC with ≥2 years of follow-up at 12 participating International Radiosurgery Consortium for Kidney (IROCK) institutions were included. Patients with upper tract urothelial carcinoma or metastatic disease were excluded. Renal function was measured by estimated glomerular filtration rate (eGFR). For patients where eGFR was not recorded, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate eGFR based on known creatinine. Baseline characteristics and renal function outcomes were compared between solitary vs. bilateral kidneys. Multivariable logistic regression was used to identify factors predictive of eGFR decline ≥ 15 mL/min and any eGFR increase evaluated at 1-year post-SABR. One hundred and ninety patients with solitary (n = 56) or bilateral kidneys (n = 134) underwent SABR and were followed for a median of 5.0 years (IQR: 3.4-6.8). Pre-SABR eGFR (mean ± SD) was similar in patients with solitary (61.1 ± 23.2 mL/min) vs. bilateral kidneys (58.0 ± 22.3 mL/min, p = 0.324). Mean tumor size was 3.70 ± 1.40 cm in solitary and 4.35 ± 2.50 cm in bilateral kidneys (p = 0.026). After SABR, an initial compensatory increase in eGFR was observed in both cohorts (22.7% solitary and 17.7% bilateral at 1 year). This compensatory increase persisted in patients with bilateral but not a solitary kidney (10.3% vs. 0% at 3-years and 21.1% vs. 0% at 5-years, respectively). At 5-years post-SABR, eGFR decreased by -14.5 ± 7.6 in solitary and -13.3 ± 15.9 mL/min in bilateral kidneys (p = 0.665). At all timepoints assessed, there were no significant differences in eGFR decline between solitary vs. bilateral cohorts (all p > 0.05). There were also no significant differences in post-SABR end-stage renal disease (7.1% vs. 6.7%) or dialysis (3.6% vs. 3.7%) in solitary vs. bilateral, respectively. Multivariable analysis demonstrated that increasing tumor size (OR per 1 cm: 1.57; 95% CI: 1.14-2.16, p = 0.006) and baseline eGFR (OR per 10 mL/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) was more likely to be associated with eGFR decline ≥ 15 mL/min. There was no significant association between solitary vs. bilateral kidney and eGFR decline (OR: 1.22; 95% CI: 0.45-3.34, p = 0.693). There was no observed difference between renal function outcomes in patients with a solitary vs. bilateral kidneys. While larger tumor size may increase the risk of eGFR decline post-SABR, treatment of a solitary kidney does not appear to increase the risk of renal dysfunction long-term.

MR-Guided Stereotactic Ablative Body Radiotherapy for Pancreatic Oligometastases from Renal Cell Carcinoma

Patients with pancreatic metastases from renal cell carcinoma (RCC) have been reported to have an unusually favorable prognosis. Traditionally, treatment for these pancreatic oligometastases comprises either surgical resection or systemic therapy. However, stereotactic ablative body radiotherapy (SAbR) may be an effective, non-invasive alternative strategy, provided that it shows acceptable toxicity and high local control rates among treated patients. We reviewed all patients treated with MR-guided SABR for pancreatic oligometastases from renal cell carcinoma at a single institute. We explored adverse events (AE), freedom from local progression (FFLP), progression-free survival (PFS), and freedom from start of systemic therapy (FFST) among treated patients. The Kaplan-Meier method was used to describe the time-to-event endpoints. From June 2019 to September 2022, we identified 11 patients treated with MR-guided SAbR to 31 pancreatic oligometastases from RCC. Patients had a mean age of 65.6 years (±6.8) and had a median of 3 irradiated pancreatic metastases (range 1-7). Metastases were treated with 5 fractions of 7 Gy (n = 1 metastasis) or 8 Gy (n = 30 metastases) per fraction. One grade 3 adverse event (bleeding) was observed. At a median follow-up of 10.5 months (range 5-46 months), estimated FFLP at 1 year was 100%. 1y-PFS was 83% (95% CI 58-100%), and 1y-FFST was 91% (95% CI 75-100%). First exploration of MR-guided SAbR to pancreatic oligometastases from RCC indicates that it can be an effective and safe treatment option. Moreover, MR-guided SAbR may facilitate deferral of systemic therapy initiation in this select group of patients with favorable prognosis.

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

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

Five-Day Spacing of Two Fractionated Ablative Radiotherapies Enhances Antitumor Immunity

This study aimed to enhance tumor control and abscopal effects by applying diverse stereotactic ablative radiation therapy (SABR) schedules. FSaII, CT-26, and 4T1 cells were used for tumor growth delay and lung metastases analysis after 1- or 5-day intervals radiation therapy (RT) with 40, 20, and 20 Gy, respectively. Immunodeficient BALB/c-nude, immunocompetent C3H, and BALB/c mouse models were used. For immune monitoring, FSaII tumors were analyzed using flow cytometry, immunofluorescence staining, and real-time quantitative reverse transcription polymerase chain reaction. The spleens were used for the ELISpot assay and flow cytometry to determine effector CD8 T cells. For abscopal effect analysis in CT-26 tumors, the volume of the nonirradiated secondary tumors was measured after primary tumors were irradiated with 1-day or 5-day intervals. Contrary to the high-dose 1-day interval RT, the 5-day interval RT significantly delayed tumor growth in immunocompetent mice, which was not observed in immunodeficient mice. In addition, the 5-day interval RT significantly reduced the number of lung metastases in FSaII and CT-26 tumors. Five-day spacing was more effective than 1-day interval in enhancing the antitumor immunity via increasing the secretion of tumor-specific IFN-γ, activating the CD8 T cells, and suppressing the monocytic myeloid-derived suppressor cells. The 5-day spacing inhibited nonirradiated secondary tumor growth more effectively than did the 1-day interval. Compared with the 1-day interval RT, the 5-day interval RT scheme demonstrated enhanced antitumor immunity of CD8 T cells associated with inhibition of myeloid-derived suppressor cells. Enhancing antitumor immunity leads to significant improvements in both primary tumor control and the abscopal effect.

The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer

AimsThe forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. Materials and methodsThe survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. ResultsFrom 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. ConclusionThere is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

Stereotactic body radiation therapy for stage I medically operable non-small cell lung cancer

Stereotactic ablative body radiation therapy (SBRT) has emerged as the standard treatment for inoperable patients with stage I non-small cell lung cancer (NSCLC). In the current study, we retrospectively analyzed a medically operable patient cohort with stage I NSCLC who refused surgery and subsequently underwent SBRT. Overall survival (OS) and progression-free survival (PFS) were calculated. Between April 2014 and July 2020, 55 patients were enrolled to the study. Forty (72.7%) patients were male, with a mean age of 69.85 ± 4.65 years (range 59–78 years). ECOG performance status were 0 and 1, except for one case. At the time of analysis, 8 deaths were observed. Of these, 25% (n = 2) died due to cardiac events, 12.5% (n = 1) due to pulmonary causes, 12.5% (n = 1) due to lung cancer-related causes, and the cause of death was unknown for 50% (n = 4). The pulmonary causes and cardiac events were not associated with radiation-induced toxicity. The median survival time was 34 months, with a range of 12 to 44 months. 2-year OS and PFS were 97% and 98%, 3-year OS and PFS were 82% and 77%, respectively. Treatment with SBRT was well tolerated and no grade 3 and 4 treatment-related adverse events were observed. SBRT seems to be a well- tolerated and effective alternative for patients with operable early-stage NSCLC.

Stereotactic Body Radiotherapy for Lung Oligo-metastases: Systematic Review and International Stereotactic Radiosurgery Society Practice Guidelines

PurposeA systematic review of treatment characteristics, outcomes, and treatment-related toxicities of stereotactic body radiation therapy (SBRT) for pulmonary oligometastases served as the basis for development of this International Stereotactic Radiosurgery Society (ISRS) practice guideline. MethodsIn accordance with PRISMA guidelines, a systematic review was performed of retrospective series with ≥50 patients/lung metastases, prospective trials with ≥25 patients/lung metastases, analyses of specific high-risk situations, and all randomized trials published between 2012 and July 2022 in the MEDLINE or Embase database using the key words “lung oligometastases”, “lung metastases”, “pulmonary metastases”, “pulmonary oligometastases”, “stereotactic body radiation therapy (SBRT)” and “stereotactic ablative body radiotherapy (SBRT)”. Weighted random effects models were used to calculate pooled outcomes estimates. ResultsOf the 1884 articles screened, 35 analyses (27 retrospective-, 5 prospective, and 3 randomized trials) reporting on treatment of >3600 patients and >4650 metastases were included. The median local control was 90 % (Range: 57–100 %) at 1 year and 79 % (R: 70–96 %) at 5 years. Acute toxicity ≥3 was reported for 0.5 % and late toxicity ≥3 for 1.8 % of patients. A total of 21 practice recommendations covering the areas of staging & patient selection (n = 10), SBRT treatment (n = 10), and follow-up (n = 1) were developed, with agreements rates of 100 %, except for recommendation 13 (83 %). ConclusionSBRT represents an effective definitive local treatment modality combining high local control rates with low risk of radiation-induced toxicities.

Stereotactic ablative body radiation therapy for isolated pulmonary metastases from pancreatic cancer after metastectomy with positive margins: a case report

BackgroundIsolated pulmonary oligometastases as the first site of dissemination after initial resection of pancreatic ductal adenocarcinoma (PC) is a rare event, and the treatment in this subgroup is challenging. Recurrence in the lung after initial primary tumour resection is associated with the most long-term survivors of patients with metastatic PC. Stereotactic ablative body radiation therapy (SABR) or metastectomy for pulmonary oligometastases from PC is becoming more common. However, patients with close or positive margins after metastectomy for isolated pulmonary metastatic PC are at high risk for recurrence. This requires a treatment capable of achieving high rates of local control and improved quality of life by delaying the need for systemic chemotherapy. In other settings, SABR has been shown to achieve these goals, allowing safe dose escalation with excellent conformity and short duration of treatment.Case presentationWe report the case of a 48-year old Caucasian man with a history of locally advanced PC initially treated with neoadjuvant chemotherapy followed by Whipple’s resection in August 2016. After a disease-free interval of 3 years, he developed three isolated pulmonary metastases which were treated with local resection. In the setting of microscopically positive resection margins (R1), adjuvant lung SABR was delivered to all three sites. His treated lung disease remained radiologically stable for up to twenty months after SABR. Treatment was well tolerated. In January 2021, he developed a malignant pre-tracheal node which was treated with conventionally fractionated radiotherapy and remained controlled for the duration of follow-up. A year later, he developed widespread metastatic disease including pleura, bone and adrenal gland, together with presumed progression in one of the original lung lesions, receiving palliative radiotherapy for right chest wall pain. He was later found to have an intracranial metastasis and died in February 2022, 5½ years after initial treatment.ConclusionWe present the case of a patient treated with SABR after R1 resection of 3 isolated pulmonary metastases from PC, with no treatment toxicities and durable local control. For well-selected patients in this setting, adjuvant lung SABR may be a safe and effective treatment option.

A phase I/II study of durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer.

4164 Background: Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB) in genomically unselected patients (pts). Synergistic effects of combined ICB and radiotherapy have been suggested in varied solid tumors. Few studies have evaluated this approach in pts with PC. We sought to evaluate the safety and efficacy of PD-L1 inhibitor durvalumab (D) and SABR after induction chemotherapy, in LA and BR PC. Herein, we present phase II data from two cohorts. Methods: A multi-institutional, non-randomized phase 1/2 trial of SABR and D was conducted at Cedars-Sinai Medical Center (CS) and Memorial Sloan Kettering (MSK). Key eligibility: ECOG 0-1; unresectable PC, with stable/responding disease following 2-3 cycles gemcitabine and nab-paclitaxel (GnP) or 4-6 months (m) FOLFIRINOX (FFX). CS enrolled pts with BR and LA PC; MSK enrolled pts with LA PC only. All pts received SABR between dose 1 and 2 of D, with slight variation in ablative radiation techniques (CS: 33Gy/5#; MSK: MRI adaptive ablative radiation, 50Gy/5#). D dosed on day 1: 750mg x 4 doses Q14 days, and subsequently Q2 or Q4 weeks x 1 year total, or until resection, progression of disease (POD), or limiting toxicity. Primary endpoint: 6-month progression free survival (6 m PFS). Secondary endpoints: rate of downstaging to resectability, objective response by RECIST v1.1, duration of response, PFS, Overall Survival (OS). PFS and OS estimated from consent date using Kaplan-Meier method. Association between surgery and outcomes was analyzed as a time dependent covariate in univariate Cox regression models for OS and PFS. To assess immunogenomic biomarkers of response, pre- and on-treatment tissue, blood and microbiome samples were gathered. Results: Between 08/2017 and 05/2022, N= 36 enrolled. Median age 67.5 years (range 48-79), 39% (14/36) female. Performance Status: N=12 (33%) ECOG 0; N= 24 (67%) ECOG 1. Median duration chemotherapy: 3.5 m (range 1.4, 5.8). Staging: N=31 (86%) LA; N=5 (14%) BR. N = 9 (25%) underwent resection; all R0. Conversion to resection was not associated with PFS (HR 0.45; 95% CI 0.17, 1.17, p=0.1) or OS (HR 0.69; 95% CI 0.26, 1.84, p=0.5). Survival and response data summarized in table. Toxicities of special interest: Grade 3 treatment-related: in N= 7; diarrhea N= 2; elevated AST/ALT N= 2; lipase/amylase elevation, N=1; nausea N=1. Grade 4: amylase elevation N=1. Conclusions: D and SABR after induction chemotherapy in LA and BR PC is safe, had an encouraging 6-m PFS of 69% and favorable R0 resection rate, warranting further evaluation. Immuno-genomic biospecimen analyses underway. Clinical trial information: NCT03245541 . [Table: see text]

Efficacy of preoxygenation administration in volunteers, in extending the end-expiration breath-hold duration for application to abdominal radiotherapy

End expiration breath hold (EEBH) is the preferred motion management method for abdominal Stereotactic Ablative Body Radiotherapy (SABR) treatments. However, multiple short EEBHs are required to complete a single treatment session. The study aimed to determine the efficacy of preoxygenation with hyperventilation in extending an EEBH duration.We randomised 10 healthy participants into two arms, each included breathing room air and oxygen at a rate of 10 L per minute (l/min) without hyperventilation for four minutes, and normally for four minutes and with hyperventilation for one minute at a rate of 20 breaths/minute for hyperventilation. The type of gas was blinded from the participants for each test. EEBH durations were then recorded, as well as systolic blood pressure, SpO2 and heart rate. A discomfort rating was also recorded after each breath hold.A significant increase in duration of almost 50% was observed between normal breathing of room air and breathing oxygen normally followed by hyperventilation. Vital signs remained consistent between the 4 tests. The tests were well tolerated with 75% of participants recording none or minimal discomfort.Preoxygenation with hyperventilation could be used to increase the EEBH duration for abdominal SABR patients which would assist in the accuracy of these treatments and possibly resulting in a reduction of overall treatment times.

Local Therapies for Hepatocellular Carcinoma and Role of MRI-Guided Adaptive Radiation Therapy.

Hepatocellular carcinoma (HCC) is the most common liver tumor, with a continually rising incidence. The curative treatment for HCC is surgical resection or liver transplantation; however, only a small portion of patients are eligible due to local tumor burden or underlying liver dysfunction. Most HCC patients receive nonsurgical liver-directed therapies (LDTs), including thermal ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and external beam radiation therapy (EBRT). Stereotactic ablative body radiation (SABR) is a specific type of EBRT that can precisely deliver a high dose of radiation to ablate tumor cells using a small number of treatments (or fractions, typically 5 or less). With onboard MRI imaging, MRI-guided SABR can improve therapeutic dose while minimizing normal tissue exposure. In the current review, we discuss different LDTs and compare them with EBRT, specifically SABR. The emerging MRI-guided adaptive radiation therapy has been reviewed, highlighting its advantages and potential role in HCC management.

Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

PO-2318 Clinical outcomes following stereotactic ablative body radiotherapy to inoperable pancreatic cancer

PO-2318 Clinical outcomes following stereotactic ablative body radiotherapy to inoperable pancreatic cancer