Stereotactic Body Radiation Therapy Dose Research Articles

Effects of stereotactic body radiotherapy for clinical outcomes of patients with liver metastasis and hepatocellular carcinoma: A retrospective study.

This retrospective clinical study described the treatment efficacy and safety of stereotactic body radiotherapy (SBRT) for patients of hepatocellular carcinoma (HCC) and liver metastasis tumors. The therapeutic effect and prognosis of patients with liver cancer treated with stereotactic body radiation therapy (SBRT) at the Fudan University Shanghai Cancer Center (Shanghai, China) between July 2011 and December 2020 were retrospectively analyzed. Overall survival (OS), local control (LC) rates and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis and the log-rank test. Local progression was defined as tumor growth after SBRT on dynamic computed tomography follow-up. Treatment-related toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 4. A total of 36 patients with liver cancer were enrolled in the present study. The prescribed dosages (14 Gy in 3 fractions or 16 Gy in 3 fractions) were applied for SBRT treatments. The median follow-up time was 21.4 months. The median OS time was 20.4 [95% confidence interval (CI): 6.6-34.2] months, and the 2-year OS rates for the total population, HCC group and liver metastasis group were 47.5, 73.3 and 34.2%, respectively. The median PFS time was 17.3 (95% CI: 11.8-22.8) months and the 2-year PFS rates for the total population, HCC group and liver metastasis group were 36.3, 44.0 and 31.4%, respectively. The 2-year LC rates for the total population, HCC group and liver metastasis group were 83.4, 85.7 and 81.6%, respectively. The most common grade IV toxicity for the HCC group was liver function impairment (15.4%), followed by thrombocytopenia (7.7%). There were no grade III/IV radiation pneumonia or digestive discomfort. The present study aimed to explore a safe, effective and non-invasive treatment method for liver tumors. At the same time, the innovation of the present study is to find a safe and effective prescription dose of SBRT in the absence of consensus on guidelines.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study

Background This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). Materials and methods This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. Conclusions An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.

Phase 1 Dose Escalation of Stereotactic Body Radiation Therapy and Concurrent Cisplatin for Reirradiation of Unresectable, Recurrent Squamous Cell Carcinoma of the Head and Neck

Patients with locoregional recurrence of squamous cell carcinoma of the head and neck (SCCHN) have relatively poor outcomes; therefore, stereotactic body radiation therapy (SBRT) has been investigated for this patient population. We performed a phase 1 clinical trial to establish a maximum tolerated dose of SBRT with concurrent cisplatin in previously irradiated locoregional SCCHN. Patients with recurrent SCCHN who had previously undergone radiation therapy to doses ≥45 Gy to the area of recurrence ≥6 months before enrollment and who were not surgical candidates or refused surgery were eligible. SBRT was delivered every other day for 5 fractions. Starting dose level was 6 Gy×5 fractions, followed by 7 Gy×5 fractions and 8 Gy×5 fractions. Chemotherapy consisted of cisplatin given before every SBRT fraction at a dose of 15 mg/m2. Patients were monitored for dose-limiting toxicities (DLT) that occurred within 3 months from the start of SBRT. Secondary endpoints included locoregional failure, distant metastasis, and overall survival. Twenty patients were enrolled, with 18 patients evaluable for endpoints. One patient at dose level 1 (30 Gy) died of unknown causes 2 weeks following completion of treatment. Therefore, an additional 3 patients were accrued to the 30-Gy dose level, with no further DLTs observed. Three patients were then accrued at dose level 2 (35 Gy) and 9 patients at dose level 3 (40 Gy) without DLTs. At a median follow-up of 9.5 months, cumulative incidence of locoregional failure at 2 years was 61% (95% confidence interval [CI], 12%-66%), cumulative incidence of distant metastasis was 11% (95% CI, 74%-100%) at 2 years, and overall survival was 22% (95% CI, 9%-53%) at 2 years. Concurrent cisplatin and reirradiation with an SBRT dose of ≤40 Gy was safe and feasible in patients with locoregionally recurrent or second primary SCCHN.

Abstract 4424: Immunoregulatory role of club cell secretory proteins in non-small cell lung cancer

Abstract Introduction. Immune checkpoint inhibitors (ICI) particularly those targeting the PD-1/PD-L1 axis are approved for NSCLC patients. However, most patients experience little clinical benefit due to immunosuppressive barriers in the tumor microenvironment. Our goal to identify immunomodulatory agents that may overcome these barriers, led to the finding that low dose stereotactic body radiation therapy (SBRT) in combination with ICI resulted in marked tumor regression and improved survival by generating durable anti-tumor immunity (Ban et al., Nature Cancer, 2021). Unexpectedly, we uncovered that the immune-modulating functions of SBRT was acutely dependent on the secretory function of lung resident Scgb1a1+ club cells that protect the bronchioles from xenobiotic agents. Blocking club cell secretome in vivo blunted the efficacy of the combination treatment and altered myeloid cell phenotypes. These findings led to the hypothesis that radiation-induced club cell factors may synergize with ICI to attenuate immunosuppressive barriers by reducing myeloid suppressive cells. Methods and Data. Expression of 8 highest expressed club cells secretory factors (CC10, SP-A, SP-B, SP-D, Hp, Secretoglobin 3A1, 3A 2, and 1C 1) in combination with PD-1 blockade elicited significant tumor control and improved survival of NSCLC mice. Mechanistically, the 8 club cell factors inhibit myeloid suppressor cell phenotypes as determined by reduced pSTAT3, pERK and concomitant inhibition of immunosuppressive mediators Arg1, iNOS, etc. Further screening of individual club cell factors showed that CC10 alone effectively blunted myeloid suppression activity as determined by flow cytometry for Arg1 and iNOS. Hence, CC10 can functionally alter the immunosuppressive nature of myeloid suppressor cells. The ability of CC10 in improving the efficacy of ICI in impairing tumor growth and improving survival is currently being examined. Conclusions. Myeloid suppressor cells inhibit immune cells like T cells or NK cells leading to poor prognosis in cancer treatment. Increase in their numbers has been linked to tumor aggressiveness and low efficacy of immunotherapy. Hence, there is an unmet clinical need to specifically target these cells. Agents targeting myeloid suppressor cell accumulation and differentiation (e.g., ATRA, Vitamin D, Sunitinib, Gemcitabine, Bevacizumab, Tadalafil), are being tested in human clinical trials. However, these agents lack specificity and selectivity for myeloid suppressor cells in vivo. Therefore, our work provides the rationale for the development of CC10 as selective inhibitor of myeloid suppressor cells and has the potential for achieving a robust and durable anti-tumor immunity in NSCLC. Citation Format: Aakanksha Rajiv Kapoor, Vivek Mittal. Immunoregulatory role of club cell secretory proteins in non-small cell lung cancer. [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 4424.

Stereotactic body irradiation for metastasis from renal carcinoma: A retrospective study

Background Renal cell carcinoma (RCC) has traditionally been considered to be radioresistant. Response rates are believed to be improved by a high dose of stereotactic body radiotherapy (SBRT). A retrospective analysis was conducted of patients treated with SBRT for metastatic disease from RCC. Material and methods We reviewed records from 20 patients who underwent SBRT for a total of 30 RCC metastases from 2015 to 2020. Patients were included who had a confirmed primary RCC and radiographic evidence of metastasis, either synchronous or metachronous. The most common SBRT fractionation was 30 Gy in 3 fractions. Results Median age was 60 years (range, 40–77 years) and 60% were male. After a median follow-up of 18 months (range, 3–36 months), overall survival was estimated to be 85% and 70%, at 1 and 2 years, respectively, and local control at 2 years was 83.33%. Only 5 patients had documented progression of disease, all of whom received biologically effective dose inferior to 100 Gy, and no patients treated with a higher biologically effective dose had disease, which progressed. The most common acute toxicity was grade 1 fatigue (20%). No grade 3 or higher acute toxicity occurred. Conclusions Treatment with SBRT in patients with RCC metastases yielded a high local control rate, promising survival rate, and low toxicity.

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats.

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT-drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)-methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f'x and RT9Gy×3 f'x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f'x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f'x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f'x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f'x sequential regimen. Compared to the RT9Gy×3 f'x concurrent regimen, the RT9Gy×3 f'x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f'x is more significant with the sequential regimen than with the concurrent regimen.

BOMB trial: First results of stereotactic radiotherapy to primary breast tumor in metastatic breast cancer patients.

A prospective dose escalation trial was developed to evaluate the maximum tolerated dose of stereotactic body radiotherapy (SABRT) to primary breast cancer in stage IV disease. The aim of the present report was to describe safety and outcome of the first dose level cohort of patients. Patients with histologically confirmed diagnosis of invasive breast carcinoma (biological immuno-histochemical profile: luminal and/or HER2 positive) and distant metastatic disease not progressing after 6 months of systemic therapy with a tumor CT or 5FDG-PET detectable were deemed eligible. The starting dose was 40 Gy in 5 fractions (level 1) because this dose proved to be safe in previous dose-escalation trial on adjuvant stereotactic body radiotherapy. The maximum dose level was chosen as 45 Gy in 5 fractions. Dose limiting toxicity was any grade 3 or worse toxicity according to CTCAE v.4. Time-to-event Keyboard (TITE-Keyboard) design (Lin and Yuan, Biostatistics 2019) was used to find the maximum tolerated dose (MTD). MTD was the dose of radiotherapy associated with a ≤ 20% rate pre-specified treatment-related dose-limiting toxicity (DLT). To date 10 patients have been treated at the starting dose level. Median age was 80 years (range 50-89). 7 patients had a luminal disease, while 3 patients had an HER2 positive disease. No patient suspended ongoing systemic treatment. No protocol defined DLTs were observed. Grade 2 skin toxicity occurred in 4 patients with diseases located close to or involving the skin. Median follow-up was 13 months and all 10 patients were evaluable for response: 5 achieved a complete response, 3 achieved a partial response and 2 showed a stable disease, all with a clinical benefit (resolution of skin retraction, bleeding and pain). The mean reduction in the sum of the largest diameters of target lesions was of 61.4% (DS=17.0%). SABR to primary breast cancer seems feasible and is associated with symptoms reduction. Continued accrual to this study is needed to confirm the safety and assess the MTD. ClinicalTrials.gov, identifier NCT05229575.

Role of palliative SBRT in barcelona clinic liver cancer-stageC hepatocellular carcinoma patients.

To evaluate the role of palliative stereotactic body radiation therapy (SBRT) in Barcelona Clinic Liver Cancer stage‑C (BCLC-C) hepatocellular carcinoma (HCC) patients who are not suitable for other loco-regional therapies. It is an observational retrospective study done between May 2020 and September 2021. The data were collected from 35patients of advanced HCC who underwent SBRT. Patients of Child Pugh status (CPs) A5-B7 and with aliver reserve of ≥ 700cc were included. Local control (LC), overall survival (OS) and adverse events including decompensation were carefully recorded. In the cohort, Portal vein and IVC tumor thrombosis were present in 33(94.3%) and 8(22.85%) patients, respectively. Lung and nodal metastasis were found in 11(31.4%) and 21(60%) of patients, respectively. The median gross tumor volume (GTV) was 563cc (range 80-1925cc). The median SBRT dose prescription was 35 Gy (range 25-40 Gy) in 5-10 fractions. Post radiation therapy, there was improvement in pain and discomfort in24 out of29 (82.75%) and18 out of23 (78%) patients respectively. Also bone metastasis related pain was improved in all3 (100%) patients. One year LC, and OS were 80% and 30% respectively. On multivariate analysis, the GTV volume > 750cc and PIVKA-II > 8000 mAU/ml remained the predictor factor for poor OS. Post SBRT, change in child-pugh score by 1point was observed in 7patients (20%) which was managed conservatively. SBRT is asafe and feasible option for BCLC‑C HCC. It not only improves the quality of life by symptom control but also results in good LC and OS with acceptable toxicity. SBRT should be considered in amultidisciplinary fashion for patients presenting with advanced HCCs.

Phase 1 Dose Escalation Study of SBRT Using 3 Fractions for Locally Advanced Pancreatic Cancer

The optimal dose and fractionation of stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (LAPC) have not been defined. Single-fraction SBRT was associated with more gastrointestinal toxicity, so 5-fraction regimens have become more commonly employed. We aimed to determine the safety and maximally tolerated dose of 3-fraction SBRT for LAPC. Two parallel phase 1 dose escalation trials were conducted from 2016 to 2019 at Memorial Sloan Kettering Cancer Center and University of Colorado. Patients with histologically confirmed LAPC without distant progression after at least 2 months of induction chemotherapy were eligible. Patients received 3-fraction linear accelerator-based SBRT at 3 dose levels, 27, 30, and 33 Gy, following a modified 3+3 design. Dose-limiting toxicity, defined as grade ≥3 gastrointestinal toxicity within 90 days, was scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. The secondary endpoints included cumulative incidence of local failure (LF) and distant metastasis (DM), as well as progression-free and overall survival PFS and OS, respectively, toxicity, and quality of life (QoL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the pancreatic cancer-specific QLQ-PAN26 questionnaire. Twenty-four consecutive patients were enrolled (27 Gy: 9, 30 Gy: 8, 33 Gy: 7). The median (range) age was 67 (52-79) years, and 12 (50%) had a head/uncinate tumor location, with a median tumor size of 3.8 (1.1-11) cm and CA19-9 of 60 (1-4880) U/mL. All received chemotherapy for a median of 4 (1.4-10) months. There were no grade ≥3 toxicities. Two-year rates (95% confidence interval) of LF, DM, PFS, and OS were 31.7% (8.6%-54.8%), 70.2% (49.7%-90.8%), 20.8% (4.6%-37.1%), and 29.2% (11.0%-47.4%), respectively. Three- and 6-month QoL assessment showed no detriment. For select patients with LAPC, dose escalation to 33 Gy in 3 fractions resulted in no dose-limiting toxicities, no detriments to QoL, and disease outcomes comparable with conventional RT. Further exploration of SBRT schemes to maximize tumor control while enabling efficient integration with systemic therapy is warranted.

Abstract P1-10-05: Safety of stereotactic body radiation therapy, stereotactic radiosurgery, and other radiation therapy with use of CDK 4/6 inhibitors for hormone receptor positive (HR+), HER2- metastatic breast cancer: a retrospective cohort study

Abstract Objective Patients with hormone receptor positive (HR+), HER2- metastatic breast cancer frequently require radiation therapy (RT) in addition to systemic therapy for disease control and symptom management. CDK 4/6 inhibitors are increasingly used in the care of hormone positive breast cancers. Stereotactic body radiotherapy (SBRT), a form of very focused high dose radiation, is also increasingly used in the care of metastatic breast cancer. Limited data have reported on the safety of palliative RT with CDK4/6 inhibitors, with some reports demonstrating synergistic effects with potential for increased toxicity. The objective of our study is to assess toxicity among patients who received SBRT, stereotactic radiosurgery (SRS), or other high dose RT along with CDK 4/6 inhibitors for treatment of metastatic breast cancer. Methods Women with metastatic breast cancer who received SBRT, SRS, or other higher dose RT with CDK 4/6 inhibitors at any point in their treatment between 2013 and 2021 were retrospectively identified. Timing of radiation therapy, either before, during, or after CDK 4/6 inhibitor use was assessed, as well as the interval between the two treatments. Treatment sites for radiotherapy included lung/chest, spine, and brain metastases. Physician assessed adverse events were obtained through clinical follow up and graded using CTCAE v5. Local control and OS were reported. Results Twenty patients met study inclusion criteria. Patients received radiation therapy and CDK 4/6 inhibitors concurrently (within 7 days) [n=7, 35%], within 30 days (RT pre-CDK 4/6 inhibitor use) [n=3, 15%], and greater than 30 days (RT pre-CDK 4/6 inhibitor use [n=6, 30%] and RT post-CDK 4/6 inhibitor use [n=4, 20%]). Radiation treatment sites were spine [n=10, 55%], brain [n=6, 30%], and lung/chest wall [n=3, 15%]. Radiation doses were as follows: 60 Gy in 5 fractions [n=1, 5%], 50 Gy in 5 fractions [n=2, 10%], 55 Gy in 20 fractions (chest wall recurrence) [n=1, 5%], 35 Gy in 15 fractions [n=1, 5%], 30 Gy in 10 fractions [n=6, 30%], 30 Gy in 3 fractions [n= 4, 20%], 24 Gy in 1 fraction [n=3, 15%], 20 Gy in 5 fractions [n=2, 10%]. Palbociclib was used in 85% of patients [n=17] and abemaciclib in 15% [n=3]. Median follow up for surviving patients was 4.7 years [IQR: 2.5-6.8 years]. Local control was achieved in 85% of patients [n=17]. Median OS was 2.7 years [IQR: 0.1-6.8 years]. Grade 2 toxicity [n=9, 45%] and grade 3 toxicity [n=3, 15%] was reported across all three treatment areas, with grade 2 or 3 fatigue [n=7, 35%] being the most frequently reported toxicity. In the spine treatment group, 1 patient who had CDK 4/6 inhibitor use within 30 days of radiotherapy experienced a grade 3 vertebral compression fracture as well as grade 3 fatigue. In the lung/chest wall treatment group, the patient treated to 55 Gy in 20 fractions to the chest wall with concurrent use had grade 3 skin/wound toxicity requiring prolonged wound care before healing. In the intra-cranial SRS group, grade 3 fatigue was reported in 1 patient with concurrent use. Conclusion The use of CDK 4/6 inhibitors concurrently with or within 30 days of radiation therapy was generally well tolerated with limited grade 3 toxicity. Two of three reports of grade 3 toxicity occurred with concurrent treatment. Due to the potential radiosensitizing properties of CDK 4/6 inhibitors, it may be prudent to hold combined treatment when clinically feasible. Further study is needed to validate these results. Citation Format: Kiran Chauhan, Roman O. Kowalchuk, Allison E. Garda, Dean A. Shumway, Mark R. Waddle, Robert Mutter, Kimberly Corbin. Safety of stereotactic body radiation therapy, stereotactic radiosurgery, and other radiation therapy with use of CDK 4/6 inhibitors for hormone receptor positive (HR+), HER2- metastatic breast cancer: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-05.

Abstract PD3-04: Locoregional Stereotactic Body Radiotherapy in Breast Cancer Patients Unsuitable for Surgical Resection

Abstract Purpose: Breast cancer (BC) patients (pts) who are not surgical candidates or decline surgical resection are usually managed with palliative systemic therapy alone or palliative radiotherapy if clinically appropriate. Stereotactic body radiotherapy (SBRT) has shown excellent results for different primary malignancies, and we hypothesized it could improve outcomes in this context with acceptable toxicity. This study aims to assess the local control (LC) and toxicity rates of breast SBRT in pts unsuitable for surgical resection. Methods and Materials: We performed a retrospective analysis using an institutional registry of all BC pts unsuitable for resection who underwent breast and/or regional lymph node (LN) SBRT to a dose of 35-40 Gy in 5 fractions from 2014 to 2021. Patients were deemed unsuitable for resection if they were medically inoperable, declined surgery, had unresectable tumors, or where surgery was not appropriate, such as due to metastatic disease. The primary endpoint was LC (defined as no evidence of progression of the treated lesion as per RECIST 1.1 criteria) and toxicity grade ≥ 3 (as per CTCAE v5.0). Secondary endpoints included radiological response (RR) of the target tumor at the last follow-up, progression-free survival (PFS), and overall survival (OS). All endpoints were assessed per course of treatment, with death as a competing factor for LC. Results: This study included 61 treatment courses in 57 pts. The median age was 81 years (range 38-99), 74% being older than 70 years of age. Eighteen percent had stage I-II, 44% stage III, and 38% stage IV disease. Unresectable tumor (10%), patient refusal (18%), medically inoperability (34%), and metastatic disease (38%) were the main causes of not having surgery. The molecular subtypes were HER-2 in 3%, basal-like 23%, and luminal disease 74%. Previous systemic treatment consisted of endocrine therapy (ET) alone (49%), chemotherapy (CT) or target therapy (TT) alone (11%), both ET and CT/TT (18%), or none (21%). Seventy-two percent of tumors were progressing on ET (44%) or CT/TT (28%) at the time of SBRT. The median interval from cancer diagnosis to SBRT was 14.6 (range 0.5-180) months (mos). Fifty-four percent had breast SBRT, 15% LN SBRT, and 31% both. For LN treatment, axillary, internal mammary, and supraclavicular nodes were the target in 43%, 3%, and 2% of treatments, respectively. The median clinical and radiological follow-up was 16.8 (range 0.2-87) and 13.4 mos (range 1-81), respectively. The worst acute and late grade ≥ 3 toxicity was 16% and 4%, respectively, and all cases consisted of radiation dermatitis. No patient was unable to complete treatment due to acute toxicity. There was one case of grade 4 skin necrosis 6.3 mos after 35 Gy in 5 fractions to an axillary LN. The LC rate at 1 year was 100% and 2 years 88.6% (95% CI = 79-99%). The median time to local progression among those who progressed was 18.2 mos (95% CI = 12-not reached). At last FU, the RR of treated tumors was: complete response = 8%, partial response = 46%, stable disease = 38%, and progressive disease = 8%. The PFS and OS rates at 1 year was 69.8 % (95% CI = 58-82) and 74.6% (95% IC = 63-86), 2 years 39.1% (95% CI = 26—52) and 50.6% (95% IC = 36-65), 3 years 26.7 % (95% CI =14-39) and 38.7% (95% IC = 24-54), and 4 years 18.5 % (95% CI = 8-29) and 29.2% (95% CI = 14-44), respectively. The median PFS was 21.7 mos (95% CI = 17-28) and OS 31.1 mos (95% CI = 21- 38). Ongoing analysis intends to identify clinical and pathological predictors of LC, PFS, and OS. Conclusion: Our initial data suggest that breast SBRT safely provides excellent LC rates in non-operable BC pts. This approach may be a treatment option in pts who are not good surgical candidates, particularly in elderly pts with multiple comorbidities, which comprised 74% of our cohort. A clinical trial is underway to determine the optimal dose and side effect profile for primary breast SBRT with curative intent in pts not undergoing definitive surgery. Citation Format: Daniel Palhares, Hanbo Chen, Benazir Khan, Claire McCann, Sandi Bosnic, Ezra Hahn, Hany Soliman, Eileen Rakovitch, Justin Lee, Danny Vesprini. Locoregional Stereotactic Body Radiotherapy in Breast Cancer Patients Unsuitable for Surgical Resection [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-04.

PACE-A: An international phase 3 randomised controlled trial (RCT) comparing stereotactic body radiotherapy (SBRT) to surgery for localised prostate cancer (LPCa)—Primary endpoint analysis.

298 Background: People presenting with early-stage LPCa have several treatment options. There is therapeutic equipoise with lack of randomised evidence for superiority of radiotherapy or surgery. PACE-A aimed to determine if there is improved quality of life (QoL) following SBRT compared to surgery. Methods: PACE (NCT01584258) is a phase 3 open-label multiple-cohort RCT. In PACE-A, people with LPCa, T1-T2, Gleason≤3+4, PSA≤20ng/mL & suitable for surgery were randomised (1:1) to SBRT or surgery. SBRT dose was 36.25Gy/5 fractions in 1-2 weeks; surgery was laparoscopic or robotically assisted prostatectomy. Androgen deprivation was not permitted. Co-primary endpoints were patient reported outcomes (PROs) of Expanded Prostate Index Composite (EPIC-26) questionnaire number of absorbent pads per day & EPIC bowel subdomain score at 2 years. Target sample size was 234 participants (pts) to detect 9% difference in urinary incontinence (80% power, 5% 2-sided alpha) & 5-point difference in mean bowel subdomain score (90% power, 5% 2-sided alpha) with higher EPIC score (range 0-100) indicating better QoL. Secondary endpoints included clinician reported toxicity and additional PROs (1% significance level). Analysis is by treatment received. Results: From Aug 2012 to Feb 2022, 123 men from 10 UK centres were randomised. The IDMC advised stopping recruitment after a 2-year gap in during COVID. Pts had median age 66years (IQR: 61, 69), median PSA 8ng/ml (6, 11) with 52% tumours ≥T2b and 79% Gleason 3+4; 93% pts were of white race. 58/63 pts received SBRT as allocated (2 received surgery, 2 unknown, 1 withdrawn); 48/60 received surgery as allocated (1 received SBRT, 3 received CRT, 2 unknown, 6 withdrawn). 8 laparoscopic and 42 robotic assisted operations were performed. Median follow-up is 50 months (IQR 41, 74). At 2 years, fewer SBRT pts reported use of urinary pads: 2/43 (4.5%) vs 15/32 (46.9%), p<0.001. SBRT pts had significantly worse bowel subdomain score (mean (SD) 88.4 (12.7) vs 97.3 (5.5), p<0.001). 7/45 (15.6%) SBRT and 0/31 (0%) surgery pts reported moderate/big problem with bowel symptoms (p=0.04). SBRT pts reported less EPIC sexual subdomain score (58.0 (31.9) vs 29.3 (20.5), p<0.001); there was no evidence of a difference in urinary subdomain score (85.5 (19.8) vs 80.5 (20.8), p=0.29). At 2 years, CTCAE genitourinary grade 2 or higher(G2+) toxicity was seen in 5/54 (9.3%) SBRT vs 4/42 (9.5%) surgery pts (p=0.97); there was no G2+ gastrointestinal (GI) events seen in either group. Conclusions: PACE-A contributes the first randomised data to the comparison of SBRT with surgery in LPCa providing PRO data relevant to informed decision making. Compared to surgery, pts receiving SBRT had better urinary continence & sexual bother score; clinician reported GI toxicity was low but SBRT pts reported more bowel bother at 2 years. Clinical trial information: NCT01584258 .

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 .

The Association of Radiation Dose With Overall Survival for Patients Treated With Prostate Stereotactic Body Radiation Therapy.

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/β = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89], P=0.009) on MVA. On Kaplan-Meier analysis, 36.25 Gy was associated with improved survival (p=0.034), with a five-year OS of 92% and 88%, respectively. Conclusions In a multi-institutional retrospective database of 2,214 IR patients treated with prostate SBRT, a prescription dose of 36.25 Gy/5 fx was associated with improved OS vs. 35 Gy/5 fx. Results are hypothesis-generating but do lend support to the current National Comprehensive Cancer Network (NCCN) guidelines that the minimum recommended dose for prostate SBRT is 36.25 Gy/5 fx.

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial.

There are a lack of studies about whether radiation dose escalation synergizes with immunotherapy and targeted therapy in pancreatic cancer. In this study, we performed a secondary analysis to investigate whether a high radiation dose rather than a low dose plus pembrolizumab and trametinib provided improved survival compared with gemcitabine in post-operative locally recurrent pancreatic cancer. In this open-label, randomised, controlled, phase 2 trial, eligible patients with pancreatic ductal adenocarcinoma characterized by mutant KRAS and positive immunohistochemical staining of PD-L1 and documented post-operative local recurrence were randomly assigned using an interactive voice or web response system, without stratification, to receive stereotactic body radiation therapy (SBRT) with doses ranging from 35 to 40Gy in five fractions, pembrolizumab 200mg every three weeks and oral trametinib 2mg once daily (SBRT+K+M) or SBRT and gemcitabine (1000mg/m2) on day 1 and 8 of each 21-day cycle (SBRT+G) until disease progression in our hospital in China. Those had radiotherapy, immunotherapy or targeted therapy were excluded. Patients and investigators were not masked to the assignment. In each arm, patients were stratified based on biologically effective dose (BED10; α/β=10) of 60-65Gy and BED10 ≥65Gy. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). All patients received their assigned treatment and were included in the efficacy and safety analyses. This study is registered with ClinicalTrials.gov, NCT02704156. Between Oct 10, 2016, and Oct 28, 2017, 147 of 170 randomly assigned participants were eligible for inclusion in this analysis. In BED10 of 60-65Gy group, 34 and 29 patients had SBRT+G and SBRT+K+M, respectively. While there were 42 and 42 patients with SBRT+G and SBRT+K+M in BED10 ≥65Gy group. Patients in the SBRT+K+M group had longer OS compared with the SBRT+G group, but this did not reach statistical significance (median: 15.1 vs. 12.4 months, HR 0.67 [95%CI 0.43-1.04]; p=0.071). For BED10 of 60-65Gy, OS was similar between patients in the SBRT+K+M and SBRT+G groups (median, 13.6 vs. 12.4 months; HR 0.69 [95% CI 0.41-1.16]; p=0.16). For BED10 of ≥65Gy, PFS was prolonged with SBRT+K+M versus SBRT+G (median: 8.6 vs. 5.0 months, HR 0.48 [95% CI 0.31-0.77]; p=0.0021). For BED10 of 60-65Gy, there was no significant difference in PFS between the two groups (PFS: median, 7.9 vs. 4.3 months; HR 0.69 [95% CI 0.42-1.15]; p=0.16). In BED10 of 60-65Gy group, 7 (20.6%) and 8 patients (27.6%) with SBRT+G and SBRT+K+M had grade 3 or 4 adverse events (p=0.52). In BED10 ≥65Gy group, 8 (19.0%) and 12 patients (28.6%) with SBRT+G and SBRT+K+M had grade 3 or 4 adverse events (p=0.31). No treatment-related death occurred. Dose escalation of SBRT may improve PFS with pembrolizumab and trametnib versus gemcitabine for patients with post-operative locally recurrent pancreatic cancer. However, benefits of PFS did not translate into longer OS. This may be ascribed to small sample size and post-hoc analysis that was not powered to determine the significance. Therefore, synergy of high dose of SBRT with immunotherapy and targeted therapy required further investigations in phase 3 trials. Shanghai Shenkang Centre and Changhai Hospital.

Induction FOLFIRINOX followed by stereotactic body radiation therapy in locally advanced pancreatic cancer.

FOLFIRINOX (the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is the preferred systemic regimen for locally advanced pancreatic cancer (LAPC). Furthermore, stereotactic body radiation therapy (SBRT) is a promising treatment option for achieving local control in these patients. However, clinical outcomes in patients with LAPC treated using FOLFIRINOX followed by SBRT have not been clarified. Therefore, we aimed to evaluate clinical outcomes of induction FOLFIRINOX treatment followed by SBRT in patients with LAPC. To this end, we retrospectively reviewed the medical records of patients with LAPC treated with induction FOLFIRINOX followed by SBRT in a single tertiary hospital. We evaluated overall survival (OS), progression-free survival (PFS), resection rate, SBRT-related adverse events, and prognostic factors affecting survival. Fifty patients were treated with induction FOLFIRINOX for a median of 8 cycles (range: 3-28), which was followed by SBRT. The median OS and PFS were 26.4 (95% confidence interval [CI]: 22.4-30.3) and 16.7 months (95% CI: 13.0-20.3), respectively. Nine patients underwent conversion surgery (eight achieved R0) and showed better OS than those who did not (not reached vs. 24.1 months, p = 0.022). During a follow-up period of 23.6 months, three cases of grade 3 gastrointestinal bleeding at the pseudoaneurysm site were noted, which were managed successfully. Analysis of the factors affecting clinical outcomes revealed that a high radiation dose (≥ 35 Gy) resulted in a higher rate of conversion surgery (25% [8/32] vs. 5.6% [1/18], respectively) and was an independent favorable prognostic factor for OS in the adjusted analysis (hazard ratio: 2.024, 95% CI: 1.042-3.930, p = 0.037). Our findings suggest that induction FOLFIRINOX followed by SBRT in patients with LAPC results in better survival with manageable toxicities. A high total SBRT dose was associated with a high rate of conversion surgery and could afford better survival.

Quantifying the changes in the tumour vascular micro-environment in spinal metastases treated with stereotactic body radiotherapy - a single arm prospective study.

The primary objective was to quantify changes in vascular micro-environment in spinal metastases (SM) patients treated with stereotactic body radiotherapy (SBRT) with multi-parametric dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The secondary objective was to study plasma biomarkers related to endothelial apoptosis. Patients were imaged with DCE-MRI at baseline/1-week/12-weeks post-SBRT. Metrics including normalised time-dependent leakage (Ktrans), permeability surface product (PS), fractional plasma volume (Vp), extracellular volume (Ve) and perfusion (F) were estimated using distributed parameter model. Serum acid sphingomyelinase (ASM) and sphingosine-1-phosphate (S1P) were quantified using ELISA. Clinical outcomes including physician-scored and patient-reported toxicity were collected. Twelve patients (with varying primary histology) were recruited, of whom 10 underwent SBRT. Nine patients (with 10 lesions) completed all 3 imaging assessment timepoints. One patient died due to pneumonia (unrelated) before follow-up scans were performed. Median SBRT dose was 27 Gy (range: 24-27) over 3 fractions (range: 2-3). Median follow-up for alive patients was 42-months (range: 22.3-54.3), with local control rate of 90% and one grade 2 or higher toxicity (vertebral compression fracture). In general, we found an overall trend of reduction at 12-weeks in all parameters (Ktrans/PS/Vp/Ve/F). Ktrans and PS showed a reduction as early as 1-week. Ve/Vp/F exhibited a slight rise 1-week post-SBRT before reducing below the baseline value. There were no significant changes, post-SBRT, in plasma biomarkers (ASM/S1P). Tumour vascular micro-environment (measured by various metrics) showed a general trend towards downregulation post-SBRT. It is likely that vascular-mediated cell killing contributes to excellent local control rates seen with SBRT. Future studies should evaluate the effect of SBRT on primary-specific spinal metastases (e.g., renal cell carcinoma).

Preliminary Analysis of a Phase II Trial of Stereotactic Body Radiation Therapy for Prostate Cancer With High-Risk Features After Radical Prostatectomy

PurposeThere are limited data regarding using stereotactic body radiation therapy (SBRT) in the postprostatectomy setting. Here, we present a preliminary analysis of a prospective phase II trial that aimed to evaluate the safety and efficacy of postprostatectomy SBRT for adjuvant or early salvage therapy. Materials and MethodsBetween May 2018 and May 2020, 41 patients fulfilled inclusion criteria and were stratified into 3 groups: group I (adjuvant), prostate-specific antigen (PSA) < 0.2 ng/mL with high-risk features including positive surgical margins, seminal vesicle invasion, or extracapsular extension; group II (salvage), with PSA ≥ 0.2 ng/mL but < 2 ng/mL; or group III (oligometastatic), with PSA ≥ 0.2 ng/mL but < 2 ng/mL and up to 3 sites of nodal or bone metastases. Androgen deprivation therapy was not offered to group I. Androgen deprivation therapy was offered for 6 months for group II and 18 months for group III patients. SBRT dose to the prostate bed was 30 to 32 Gy in 5 fractions. Baseline-adjusted physician reported toxicities (Common Terminology Criteria for Adverse Events), patient reported quality-of-life (Expanded Prostate Index Composite, Patient-Reported Outcome Measurement Information System), and American Urologic Association scores were evaluated for all patients. ResultsThe median follow-up was 23 months (range, 10-37). SBRT was adjuvant in 8 (20%) patients, salvage in 28 (68%), and salvage with the presence of oligometastases in 5 (12%) patients. Urinary, bowel, and sexual quality of life domains remained high after SBRT. Patients tolerated SBRT with no grade 3 or higher (3+) gastrointestinal or genitourinary toxicities. The baseline adjusted acute and late toxicity grade 2 genitourinary (urinary incontinence) rate was 2.4% (1/41) and 12.2% (5/41). At 2 years, clinical disease control was 95%, and biochemical control was 73%. Among the 2 clinical failures, 1 was a regional node and the other a bone metastasis. Oligometastatic sites were salvaged successfully with SBRT. There were no in-target failures. ConclusionsPostprostatectomy SBRT was very well tolerated in this prospective cohort, with no significant effect on quality of life metrics postirradiation, while providing excellent clinical disease control.

Consolidatory ablative stereotactic body radiation therapy after induction chemotherapy for unresectable pancreatic cancer: A single center experience.

Consolidatory radiotherapy in form of stereotactic body radiation therapy (SBRT) with an ablative dose following induction chemotherapy is emerging as a promising treatment scheme for unresectable pancreatic cancer. Outcomes of given treatment at a single center for contiguous patients with unresectable pancreatic cancer were evaluated to build the optimal treatment strategy. In this retrospective study, a total of 50 patients with unresectable pancreatic cancer who underwent induction chemotherapy and ablative dose SBRT were included. SBRT dose was 40-50 Gy in five fractions. Two strategies were adopted to adhere to the organs at risk (OAR) dose constraints: simultaneous integrated protection (SIP) technique and magnetic resonance (MR)-guided adaptive technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated from the start date of SBRT. The median follow-up period for survivors was 21.1 months (range, 6.2-61.0 months). Eleven (22.0%) patients underwent resection after SBRT, which were all R0 resection. In patients with non-metastatic disease, the median OS was 26.5 months (range, 4.1-61.0 months), and the 1- and 3-year LPFS were 90.0% (95% confidence interval [CI], 72.0-96.7%) and 57.4% (95% CI, 31.7-76.4%), respectively. Patients with oligometastatic disease had inferior survival outcomes, but there was no survival difference among responders to induction chemotherapy. In the multivariable analysis, tumor size ≤4 cm, non-metastatic status, and good response to induction chemotherapy were associated with improved LPFS. In dosimetric analysis, GTV Dmin ≥50.5 Gy was the strongest prognosticator against local progression. Grade ≥3 adverse events occurred in two (4.0%) patients with non-adaptive RT, but none in patients with MR-guided adaptive RT. Ablative dose SBRT following induction chemotherapy is an effective strategy for selected patients with unresectable pancreatic cancer. The SIP technique and MR-guided adaptive RT were attributed to minimizing the risk of adverse events. Further studies are needed to identify the best candidates for consolidatory SBRT in unresectable pancreatic cancer.

Stereotactic body radiotherapy using helical tomotherapy for hepatocellular carcinoma: clinical outcome and dosimetric comparison of Hi-ART vs. Radixact.

Helical tomotherapy (HT), a unique rotational dose delivery machine, has been updated from Hi-ART to Radixact. We retrospectively evaluated the treatment outcomes of stereotactic body radiotherapy (SBRT) using HT for hepatocellular carcinoma (HCC) and compared the dosimetric details of Hi-ART and Radixact. Between April 2014 and November 2020, 28 patients with HCC were treated with SBRT using HT for a cure at Soonchunhyang University College of Medicine, Bucheon. According to the Barcelona Clinic Liver Cancer classification, 9 patients had stage 0 disease, 12 had stage A, 4 had stage B, and 3 had stage C. The tumor size ranged from 1 cm to 8 cm (median, 2 cm). The SBRT dose ranged from 40 to 60 Gy (median, 48 Gy) with 4 fractions. Twenty-three patients were treated with Hi-ART and 5 patients were treated with Radixact. To compare the dosimetric parameters between Hi-ART and Radixact, we created treatment plans with the same constraints, pitch, modulation factor, and field width for the same patient in pairs. The median follow-up time from the date of SBRT administration was 24 months (range, 3-67 months). The local failure-free survival and intrahepatic failure-free survival rates were 96% and 58% at 1 year, 84% and 36% at 2 years, and 76% and 18% at 3 years, respectively. The overall survival rate was 93% at 1 year, 93% at 2 years, and 53% at 3 years, respectively. When the paired treatment plans were reviewed, the beam-on time and intermediate dose-spillage were found to be significantly reduced in Radixact than Hi-ART (P<0.001). With regard to normal organ sparing, the irradiated dose to the total liver, normal liver, heart, and kidney was significantly lower with Radixact (P<0.001). SBRT using HT for HCC showed favorable treatment outcomes. Radixact, the latest version, physically improved treatment efficiency by reducing treatment time and provided better organ sparing than Hi-ART.