SBRT Dose Research Articles

STRILL: Phase I Trial Evaluating Stereotactic Body Radiotherapy (SBRT) Dose Escalation for Re-Irradiation of Inoperable Peripheral Lung Lesions.

Few data are available on the role of SBRT re-irradiation for isolated recurrences. We designed a prospective phase I study to evaluate the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation, for peripheral lung lesions. RT was delivered with a dose escalation design from 30 Gy in five fractions up to 50 Gy in five fractions. The primary end point was the definition of the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation. The dose-limiting toxicity was pneumonia ≥G3. Fifteen patients were enrolled. No cases of pneumonia ≥G3 occurred in any of our cohorts. Only one patient developed pneumonia G1 during treatment. Three patients developed acute toxicities that included dyspnea G1, cardiac failure G3, and chest wall pain. One patient developed G3 late toxicity with acute coronary syndrome. After a median follow-up of 21 months (range 3.6-29.1 months), six patients (40%) had a local relapse. Distant relapse occurred in five patients (33.3%). At the last follow-up, six patients died, all but two due to progressive disease. SBRT dose escalation for thoracic re-irradiation is an effective and well-tolerated option for patients with inoperable lung lesions after a first thoracic RT with acceptable acute and late toxicities.

Early signs of efficacy in patients with anti-PD-1 naïve and anti-PD-1 resistant HNSCC treated with NBTXR3/SBRT in combination with nivolumab or pembrolizumab in the phase I trial Study 1100.

6035 Background: Overcoming resistance to immune checkpoint inhibitors (ICIs) is a major clinical challenge. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles administered by a single intratumoral injection, locally amplifies radiotherapy (RT) dose without adding toxicity to surrounding healthy tissue. NBTXR3/RT enhances tumor cell death, tumor antigen release, and effectively expands T-cell repertoire in preclinical models, thus potentially triggering local and systemic immune responses to help improve ICI treatment. NBTXR3 has demonstrated favorable local control in pts with LA-HNSCC. Here we report early outcomes from the ongoing Study 1100 trial in pts with locoregionally recurrent (LRR) or metastatic (M+) head & neck squamous cell carcinoma (HNSCC) who were either naïve to or who continued anti-PD-1 therapy combined with NBTRX3/RT after primary or secondary resistance to anti-PD-1 alone. Methods: A phase I dose escalation/expansion trial [NCT03589339] evaluating NBTXR3/Stereotactic Body RT (SBRT) followed by nivolumab or pembrolizumab in 3 cohorts of pts with advanced solid tumors. Pts have H&N lesions either resistant to prior ICI or naïve, or lung, liver, or soft tissue metastases from ICI-resistant advanced solid tumors. SBRT doses were: HN 35 Gy/ 5 fxns; lung 45 Gy/ 5 fxns; liver 45 Gy/ 3 fxns; soft tissue as per investigator. Primary objective is safety of NBTXR3/RT/anti-PD-1 combination and its RP2D. Secondary objectives include efficacy. Results: The RP2D was 33%. There were 55 pts with HNSCC treated in the dose escalation/expansion parts. NBTXR3 injection was feasible and safe. There were 11pts (20%) who experienced G≥3 treatment related AEs, of which 3 pts experienced G≥3 AEs (5.5%) related to NBTXR3. Preliminary results of 33 pts, who were evaluable for efficacy: are reported. 6 pts with LRR disease: (2 ICI resistant, 4 naïve);. 27 pts with M+ disease (18 ICI resistant, 9 naïve). In ICI-resistant pts, objective tumor responses were observed in 25% (5/20), and the disease control rate (DCR) was 75% (15/20). In the ICI-naïve population, objective tumor responses were observed in 54% (7/13) of pts and DCR was 77% (10/13). There were observed improvements in injected lesions as well as in some noninjected target lesions. Updated efficacy data including OS in resistant and naïve pts will be presented. Conclusions: NBTXR3/RT/anti-PD-1 combination was feasible and well tolerated. Early data suggest the addition of NBTXR3/RT to ICI showed evidence of efficacy, including in patients who failed prior ICI, opening up an opportunity to further explore the ability of NBTXR3/RT to mitigate primary or secondary resistance to ICI. Clinical trial information: NCT03589339 .

A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases

PurposeStereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone due to its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Materials and MethodsIn this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at XXXX between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol-mandated. Local progression-free survival (LPFS), progression-free survival (PFS), prostatic specific antigen (PSA) progression, and overall survival (OS) were reported. Treatment-related toxicity was also reported. ResultsA total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume (CTV) and higher dose to the gross tumor volume (GTV). Four patients (4.1%, 4/98) experienced local progression at one site for each patient (3.2%, 4/126). Among the entire cohort, 2-year LPFS (including death without local progression) was 84.8%, 2-year PFS (including deaths as well as local, distant, and PSA progression) was 47.5%, and 2-year OS was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. ConclusionsOur study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Planning Considerations for the Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Radiotherapy for Locally-Advanced Non-Small Cell Lung Cancer

Phase III prospective randomized trial of primary lung tumor stereotactic body radiation therapy followed by concurrent mediastinal chemoradiation for locally-advanced non-small cell lung cancer (NRG LU-008), designed to lower the rates of radiation pneumonitis and improve the progression-free survival, is expected to become active nationally in July 2023. Due to the specific nature of the cases selected for this trial, a new approach to treatment planning had to be developed to satisfy the conditions of the trial. Levice Cancer Institute (Atrium Health, North Carolina) ran the initial Phase II trial and investigated several approaches, providing recommendations for the future dosimetry planning approach. A total of 60 patients were selected for the initial trial and treated with a combination of SBRT treatment to the primary tumor (50-54 Gy in 3-5 fractions) and conventional IMRT treatment to 60 Gy to the involved lymph nodes for patients with stage 3 or unresectable stage II NSCLC, combined with chemotherapy. Depending on the location of the primary tumor, all cases could be subdivided into no overlap between the SBRT and IMRT targets, adjacent targets, and overlapping targets. All SBRT plans were done with a 6X-FFF beam, advanced dose calculation algorithm, and 0.1 cm grid size. IMRT targets were primarily treated with VMAT plans, though a minority of cases were planned with the DMLC technique, with a 6X beam, advanced dose calculation algorithm, and 0.25 cm grid size. Various approaches to the planning included target cropping, avoidance via adjusting optimization objectives and utilizing the base dose of the SBRT plan to optimize the dose for the IMRT nodal plan. Various geometries utilized in the plan included a variation in the number of arcs, covered arc angles, and the number of beams. A significant reduction in the side effects was achieved throughout the trial, with only three patients experiencing grade 3 or higher pneumonitis, 3 patients experiencing grade 3 or higher cardiotoxicity, and 1 patient experiencing grade 3 esophagitis. For targets with no significant overlap between the primary tumor and nodal target, standard planning techniques proved to be sufficient. For the overlapping targets, the planning approach of utilizing 2 arcs, >180-degree coverage, for the SBRT plan, and using ¼ of the base SBRT dose to plan the IMRT nodal plan provided the best target coverage while achieving sufficient OAR sparing. Planning the joint SBRT-IMRT plan in the cases of a significant target overlap requires a careful approach, but is feasible with the proposed guideline and should be achievable for any center electing to participate in the NRG LU-008 trial.

Escalating SBRT Dose to Hypoxic Centers of Large Pulmonary Tumors via Simultaneous Integrated Boost Confers Effective Local Control with Minimal Toxicity

Hypoxia confers radio-resistance to tumor cells and drives malignant disease progression. SBRT treatment of large (>5.0 cm) pulmonary tumors pose significant dosimetric challenges in minimizing dose to adjacent organs at risk (OARs). Here, we detail the use of SBRT with simultaneous integrated boost (SIB) to the hypoxic centers of large pulmonary masses with effective local control and minimal normal tissue toxicity. Highly conformal treatment plans utilized 3-4 non-coplanar VMAT arcs with 6MV-FFF (1400 MU/min) and 4D-CT on TrueBeam to deliver 50 Gy in 5 fractions to the planning target volume (PTV). SIB dose of 60 Gy was delivered to a 1-cm internal margin from the gross tumor volume (GTV). Dose was calculated using Acuros-based engine. Pre-treatment Conebeam CT imaging was used for patient setup and verification. Treatments were delivered in < 15 minutes. Patients underwent post-treatment clinical evaluation and CT imaging in 3-month intervals to assess changes in tumor size and post-radiation sequelae. Clinical outcomes reported include treatment response and toxicity. Twenty-six patients with large, centrally (n = 13) or peripherally (n = 13) located tumors were evaluated; this included 16 NSCLC patients with T2-T3N0 disease and 5 with pulmonary metastases from distant sites. One patient had declined surgery, while 25/26 (96.1%) were deemed medically inoperable. All plans met RTOG-0813 requirements for target coverage and dose to OARs. Median follow-up interval was 11 months (0 to 23 months). Twenty-one of 26 (80.7%) patients received post-treatment CT imaging within 6 months of SBRT. Local control was achieved in 20/21 (95.2%) patients; one patient with a peripherally located tumor progressed outside the treatment field. Acute toxicity profile amongst the 25 patients assessed included grade 1 fatigue (n = 2), grade 1 rib pain (n = 1), and grade 2 pulmonary fibrosis (n = 1). Otherwise, 22/25 (88%) patients reported no radiation induced toxicities. Subgroup analysis was performed on patients with centrally located tumors, defined as located <2 cm from the hilum, heart, or bronchial trees. One of 13 (7.6%) patients with central tumors reported grade 1 rib pain; otherwise, no radiation induced adverse effects were observed. All patients with centrally located lung tumors experienced local control on surveillance imaging. SBRT with SIB to the hypoxic centers of large pulmonary masses is a safe, efficacious treatment that confers improved local control while maintaining dose to adjacent OARs. This study demonstrates the feasibility of delivering doses up to 60 Gy to the hypoxic centers of large lung tumors, while decreasing local tumor burden, minimizing treatment mobility, and improving clinic workflow. SBRT with SIB shortens treatment course to 5 fractions (in contrast to the traditional daily 30 fractions), thus improving patient comfort and compliance.

Phase I/II trial of durvalumab plus tremelimumab and stereotactic body radiotherapy for metastatic head and neck carcinoma: Final results.

6050 Background: Anti-PD-1/PD-L1 is now part of first line therapy in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic radiotherapy (SBRT) to metastatic lesions can reduce tumor burden and could be immune-stimulatory. The combination of SBRT with dual-checkpoint blockade with Durvalumab (D, anti-PD-L1) and Tremelimumab (T, anti-CTLA-4) has not previously been tested in HNSCC. We report on the safety and efficacy of this triple treatment combination (TTC) consisting of SBRT sandwiched between cycles of D and T in oligometastatic HNSCC. Methods: This is a phase I/II single arm multi-institutional study powered for 35 patients with oligometatastatic HNSCC (2-10 lesions) (NCT03283605). D (1500 mg) and T (75 mg) were given for 4 monthly cycles, followed by monthly D for 8 monthly cycles. SBRT to 2-5 lesions was administered during cycle 2. The safety of the TTC was the primary endpoint of the phase I and was evaluated through assessment of Grade 3-5 TTC-related adverse events (AE), based on CTCAE (v 4.03). The primary endpoint of the phase II portion was 6-month progression free survival (PFS), with a predetermined 6-month PFS (6moPFS) rate greater than 27% considered as a positive signal to conduct further research on this combination. Results: A total of 33 evaluable patients were recruited (study accrual was interrupted by the COVID pandemic). The table describes patients’ characteristics. Patients had received 1, 2 and 3 prior systemic therapy lines in 48%, 21% and 9% of the cases, including 6 (18%) patients who had received prior anti-PD-1/L1 or anti-CTLA-4 therapies. The median prescribed and maximum SBRT doses were 45 Gy (range: 18-50) and 52.3 Gy (range: 28.1-69) in 3-5 fractions, respectively Fourteen patients (42%) had Grade ≥ 3 AE attributable to D and T. Only 1 patient developed Grade ≥ 3 AE attributable to SBRT. This patient, who had mucosal radionecrosis after re-irradiation and refused surgical debridement and flap reconstruction, specifically developed 2 Grade 3, 1 Grade 4 and 1 Grade 5 AE. Our primary efficacy endpoint, 6moPFS, was 69.7% (95% CI: 55.6-87.3). Median PFS was 11.9 months (6.94-14.5) and median OS was 25.1 months (17.9-28.4). Rates of complete response, partial response, stable disease and progressive disease were 9%, 21%, 33% and 12%, respectively, with 8 (24%) patients with no evaluable non-SBRT treated lesion. Conclusions: The addition of SBRT to dual-checkpoint inhibition led to 1 (3%) additional patient developing severe AE. Best response rates were encouraging. Our primary efficacy outcome, 6mo PFS was attained and was higher than what was expected in this patient population. Clinical trial information: NCT03283605 . [Table: see text]

Liver SBRT dose accumulation to assess the impact of anatomic variations on normal tissue doses and toxicity in patients treated with concurrent sorafenib

Background and PurposeUnexpected liver volume reductions occurred during trials of liver SBRT and concurrent sorafenib. The aims were to accumulate liver SBRT doses to assess the impact of these anatomic variations on normal tissue dose parameters and toxicity. Materials and MethodsThirty-two patients with hepatocellular carcinoma (HCC) or metastases treated on trials of liver SBRT (30–57 Gy, 6 fractions) and concurrent sorafenib were analyzed. SBRT doses were accumulated using biomechanical deformable registration of daily cone-beam CT. Dose deviations (accumulated-planned) for normal tissues were compared for patients with liver volume reductions > 100 cc versus stable volumes, and accumulated doses were reported for three patients with grade 3–5 luminal gastrointestinal toxicities. ResultsPatients with reduced (N = 12) liver volumes had larger mean deviations of 0.4–1.3 Gy in normal tissues, versus −0.2–0.4 Gy for stable cases (N = 20), P > 0.05. Deviations > 5% of the prescribed dose occurred in both groups. Two HCC patients with toxicities to small and large bowel had liver volume reductions and deviations to the maximum dose of 4% (accumulated 36.9 Gy) and 3% (accumulated 33.4 Gy) to these organs respectively. Another HCC patient with a toxicity of unknown location plus tumor rupture, had stable liver volumes and deviations to luminal organs of −6% to 4.5% (accumulated < 30.5 Gy). ConclusionLiver volume reductions during SBRT and concurrent sorafenib were associated with larger increases in accumulated dose to normal tissues versus stable liver volumes. These dosimetric changes may have further contributed to toxicities in HCC patients who have higher baseline risks.

Dose prescription and reporting in stereotactic body radiotherapy: A multi-institutional study

Background and purposeRadiation dose prescriptions are foundational for optimizing treatment efficacy and limiting treatment-related toxicity. We sought to assess the lack of standardization of SBRT dose prescriptions across institutions. Materials & MethodsDosimetric data from 1298 patients from 9 academic institutions treated with IMRT and VMAT were collected. Dose parameters D100, D98, D95, D50, and D2 were used to assess dosimetric variability. ResultsDisease sites included lung (48.3 %) followed by liver (29.7 %), prostate (7.5 %), spine (6.8 %), brain (4.1 %), and pancreas (2.5 %). The PTV volume in lung varied widely with bimodality into two main groups (22.0–28.7 cm3) and (48.0–67.1 cm3). A hot spot ranging from 120-150 % was noted in nearly half of the patients, with significant variation across institutions. A D50 ≥ 110 % was found in nearly half of the institutions. There was significant dosimetric variation across institutions. ConclusionsThe SBRT prescriptions in the literature or in treatment guidelines currently lack nuance and hence there is significant variation in dose prescriptions across academic institutions. These findings add greater importance to the identification of dose parameters associated with improved clinical outcome comparisons as we move towards more hypofractionated treatments. There is a need for standardized reporting to help institutions in adapting treatment protocols based on the outcome of clinical trials. Dosimetric parameters are subsequently needed for uniformity and thereby standardizing planning guidelines to maximize efficacy, mitigate toxicity, and reduce treatment disparities are urgently needed.

Reducción tumoral en pacientes con tumores intraabdominales tratados con CyberKnife: la experiencia de un centro

Introduction: to estimate tumoral reduction and overall survival at one year in a series of patients with abdominal tumors treated with body fractionated stereotactic radiotherapy (SBRT). Methods: retrospective descriptive study of a series of patients with abdominal tumors (solid or hollow viscus), treated with image-guided SBRT using a CyberKnife system and who had post-treatment follow-up and control images. The study was completed at the XXXXXXX in a five-year period from January 2013 to January 2018, in XXXXXXX. Results: 16 patients were included. 75% of the cases were under 65 years of age. The treated lesions were located in the pancreas (37.5%), abdomino-pelvic lymph nodes (25%), liver (25%) and retroperitoneum (12.5%). Most of the treated patients required up to two fiduciary markers (93.7%). The SBRT dose applied ranged from 24 to 60 Gy, mostly in 3 fractions (81.3%). Mean tumoral reduction after treatment was of 15.6 mm (SD ±13.5), being statistically significant (p &lt;0.0003). According to RECIST 1.1 criteria, a complete response was achieved in 6.2% (n=1) of the cases, a partial response in 56.3% (n=9), and stable disease in 37.5% (n=6). No disease progression was documented in any patient during the follow-up period. The one-year overall survival rate was 93.7%. Conclusion: experience at this center shows that Cyberknife radiosurgery in both primary and metastatic abdominal tumors provides, in the short term, an adequate local control rate and improved one-year overall survival.

Optimizing Lung SBRT Dose while Accounting for Histology Ensures Optimal Local Control for Inoperable Stage I Non-Small Cell Lung Cancer: Can Higher Biologically Equivalent Dose Overcome Size and SUV?

<h3>Purpose/Objective(s)</h3> Retrospective studies suggest that increasing tumor size, PET avidity and squamous histology unfavorably impact local failure (LF) after lung SBRT. We sought to characterize the interaction of SBRT dose with these variables known to be associated with LF. <h3>Materials/Methods</h3> We identified 1,573 consecutive patients treated with definitive intent SBRT for stage I NSCLC from 2003-2020 from an IRB-approved institutional prospective registry. We utilized competing risk regression, with death as a competing event, to identify patient, tumor and treatment factors associated with the endpoints LFand any failure (AF), and Cox proportional hazards regression for overall survival (OS). <h3>Results</h3> Median tumor size was 2.2 cm and PET SUV 7.5. Histology was adenocarcinoma in 30.6%, squamous cell in 27.8%, NSCLC NOS in 7.3%, non-diagnostic in 9.7% and unbiopsied in 24.3%. 52.3% of patients were female; 5% never smokers, 72.7% former smokers, and 22.3% active smokers. 64% completed mediastinal staging and 93.9% were medically inoperable. Median Charlson score was 6, and median age 74.7 years. SBRT regimen was 30/1 in 5%, 34/1 in 21%, 48-50 Gy/4-5 in 46%, 54-60/3 in 24% and 50-60 Gy/8-10fx in 3%. With a median follow-up of 22.9 months 7.9% of patients had LF and 31.2% had AF 31.2%. Median OS was 35.4 months. On univariate analysis, squamous histology had a higher risk for LF vs. adenocarcinoma (HR=2.15, p=0.001). There was no difference in LF for NSCLC NOS (HR= 0.85, p=0.71) and un-biopsied patients (HR= 1.23, p=0.40) vs. adenocarcinoma. Other factors associated with increased risk of LF were tumor size (p<0.0001), metabolic activity (p<0.0001), and lower BED radiation dose (48-50 Gy/4-5 fx, BED 100-105, HR=3.56, p<0.0001). Single fraction radiation (BED 149.6) had similar LF compared to 54-60 Gy/3 fx (BED 150-180). On multivariable analysis, tumor size and metabolic activity were no longer statistically significant, leaving squamous histology (HR=1.92, p=0.0086) and lower BED radiation (48-50 Gy/4-5 fx, HR=3.07, p=0.002) as significant correlates. On multivariable analysis for AF, tumor size and metabolic activity were significantly associated with AF, while SBRT dose and squamous histology were not statistically significant. A broad range of correlates with OS were identified (age, gender, ethnicity, KPS, Charlson score, hemoglobin level, tumor size, PET SUV, histology, and SBRT dose). <h3>Conclusion</h3> While tumor size, PET avidity, squamous histology and SBRT dose were univariate correlates for LF, only squamous histology and SBRT dose remained significant on multivariate analysis. Squamous histology appears to be an independent driver of LF. Higher SBRT dose (54-60 Gy/3fx, 34 Gy/1 fx, BED >149) may overcome other correlates to LF (size, SUV), though these remain as the strongest correlates to distant recurrence.

Efficacy and Toxicity of Stereotactic Body Radiation Therapy Treatment of Multiple Lung Lesions

<h3>Purpose/Objective(s)</h3> As the role of SBRT in caring for patients with complex cancer presentations continues to expand, it is paramount to elucidate how many courses of lung SBRT are safe and what factors predict toxicity. Our study seeks to evaluate the dose-volume factors and associated toxicities for treatment of multiple lung tumors with SBRT. <h3>Materials/Methods</h3> This retrospective IRB approved study was conducted using our institutional database of patients who underwent SBRT for multiple lung lesions between 2012 to 2020. 64 patients underwent SBRT for multiple tumors for a total of 137 tumors treated. We compared dosimetry and clinical outcome parameters of these patients to a paired set of 50 randomly selected patients who received SBRT for a solitary lung lesion. Variables collected include patient age, gender, cancer stage, tumor histology, SBRT dose, dosimetric parameters, toxicities from SBRT, and progression-free survival (PFS). Acute toxicity was defined as any toxicity related to lung SBRT occurring <90 days from the start of SBRT and late toxicity was beyond 90 days from the end of SBRT. Statistical analysis was performed using statistical software. <h3>Results</h3> 137 pulmonary lesions in 64 patients (2+ lesions in every patient) were treated using SBRT at our institution. Of these 137 lesions, 122/137 (89.1%) were primary lung tumors and 15/137 (10.9%) were metastatic lesions. Out of the 137 lesions, 9.5% were classified as SCLC, 43.1% as adenocarcinoma, 36.5% as squamous cell carcinoma, and 10.9% as distant metastases. The mean prescription dose for multi-lesion patients was 50 Gy delivered in 3-5 fractions versus 50 Gy in 5 fractions in the single lesion group. The mean V5 (47.3% vs. 25.7%, p<0.05), V10 (26.8.3% vs. 15.4%, p<0.05), V20 (10.2% vs. 4.5%, p<0.05), and mean lung dose (10.05 Gy vs. 5.29 Gy, p<0.05) were significantly greater in multi-lesion patients compared to single lesion patients, respectively. Fatigue and dyspnea were the most commonly reported acute toxicities; 56.2% multi-lesion patients experienced fatigue and 18.8% experienced dyspnea while 22.0% of single lesion patients experienced fatigue and 12.0% experienced dyspnea (p=0.315). No late toxicities were documented. 126/137 (92.0%) of the lung lesions treated with multiple SBRT treatments demonstrated local control, while 11/137 (8.0%) had local recurrence. 1-year PFS was 92.2% in the multi-lesion group versus 84.0% in the single lesion group. There was no significant correlation between pulmonary toxicity and histology in the single lesion and multi-lesion groups. <h3>Conclusion</h3> Our results suggest that SBRT treatment of multiple pulmonary tumors is safe and feasible without increasing in acute or late pulmonary toxicity. While there is significant difference in all lung parameters between these two groups, it did not translate into increasing toxicity. Further studies are needed to understand the relation between radiation dose parameters and incidence of pulmonary toxicity.

Acute and Late Toxicity of Prostate-Only or Pelvic SBRT in Prostate Cancer: A Comparative Study

<h3>Purpose/Objective(s)</h3> To compare the urinary and gastrointestinal toxicity with or without the inclusion of pelvic nodal regions in patients treated with extreme hypofractionated stereotactic radiotherapy (SBRT) for prostate cancer. <h3>Materials/Methods</h3> Patients treated with definitive SBRT for non-metastatic adenocarcinoma prostate were identified from a prospectively maintained institutional database and details of radiotherapy volume, dose, acute and late adverse effects were analyzed. Symptoms of acute (within 90 days of completing SBRT) and late gastrointestinal and urinary toxicities were graded using CTCAE version 5.0. Each symptom was scored according to the worst reported grading during treatment and follow-up period. ‘Non-infective cystitis' was considered as ‘urinary toxicity' because it encompasses all other urinary symptoms. Cumulative toxicity rates between prostate-only SBRT (PO-SBRT) and whole pelvic SBRT (WP-SBRT) were compared using chi-square test. <h3>Results</h3> Total 220 patients were analyzed (PO-SBRT=118, WP-SBRT=102), with most having locally advanced disease (PO-SBRT 60% high risk, 40% intermediate risk; WP-SBRT 79% node positive, 21% high risk). Median SBRT dose was 36.25Gy (IQR 35-36.25) to the prostate (EQD2=90.6Gy, a/b=1.5Gy) and simultaneous integrated 25Gy to the pelvis (EQD2=46.3Gy) in five fractions on alternate days. No grade 3-4 acute toxicities were observed except one grade 3 urinary obstruction (PO-SBRT). WP-SBRT was associated with significantly higher grade 2 acute GI toxicity (29.4% vs 14.7%, p=0.008), acute proctitis (23.5% vs 11.2%, p=0.016) and acute diarrhea (13.7% vs 1.7%, p=0.001). At a median follow-up of 28 months, grade 2 late urinary toxicity was significantly higher with WP-SBRT (45.6% vs 25.0%, p=0.003), while gastrointestinal toxicity was similar in both the groups (18.9% vs 13.4% p=0.1). Grade 3 late toxicities were low in both the groups (urinary 2.5%, gastrointestinal 1%). <h3>Conclusion</h3> WP-SBRT is associated with significant increase in acute GI and late urinary toxicities compared to PO-SBRT. Prospective validation of these findings is ongoing.

Acute and Late Adverse Effects of Prostate-Only or Pelvic Stereotactic Radiation Therapy in Prostate Cancer: A Comparative Study

To compare the urinary and gastrointestinal adverse effects with or without the inclusion of pelvic nodal regions in patients treated with extreme hypofractionated stereotactic radiation therapy (SBRT) for prostate cancer. Patients treated with definitive SBRT for nonmetastatic adenocarcinoma prostate were identified from prospectively maintained institutional database, and details of radiation therapy volume, dose, acute, and late adverse effects were analyzed. Symptoms of acute (within 90 days of completing SBRT) and late gastrointestinal and urinary toxic effects were graded using Common Terminology Criteria for Adverse Effects version 5.0. Each symptom was scored according to the worst reported grading during treatment and the follow-up period. Cumulative rates of adverse effects between prostate-only SBRT (PO-SBRT) and whole pelvic SBRT (WP-SBRT) were compared using the χ2 test. Univariable and multivariable analysis was performed for possible factors affecting acute gastrointestinal and late urinary toxic effects. A total of 220 patients were analyzed (PO-SBRT = 118, WP-SBRT = 102), with a median follow-up of 28 months (interquartile range, 14-40). Most patients had locally advanced disease (PO-SBRT 60% high risk and 40% intermediate risk, WP-SBRT 79% node positive, and 21% high risk). The median SBRT dose was 36.25Gy (interquartile range, 35-36.25) to the prostate (2-Gy equivalent, EQD2 = 90.6Gy, a/b = 1.5Gy) and simultaneous integrated 25Gy to the pelvis (EQD2 = 46.3Gy) in 5 fractions on alternate days. No grade 3 to 4 acute adverse effects were observed except 1 grade 3 urinary obstruction (PO-SBRT). WP-SBRT was associated with a significantly higher rate of acute grade 2 gastrointestinal toxic effects (29.4% vs 14.7%, P = .008) and late grade 2 urinary adverse effects (45.6% vs 25.0%, P = .003). Both groups had low incidence of late grade 3 adverse effects (urinary 2.5%, gastrointestinal 1%). WP-SBRT was associated with significantly higher acute gastrointestinal and late urinary adverse effects compared with PO-SBRT, although overall incidence of severe adverse effects was low.

OC-0599 Factors associated with SBRT doses in oligometastatic disease: an EORTC/ESTRO OligoCare analysis

OC-0599 Factors associated with SBRT doses in oligometastatic disease: an EORTC/ESTRO OligoCare analysis

Intermittent Androgen Deprivation Therapy Plus Comprehensive Stereotactic Radiotherapy for Oligometastatic Prostate Cancer (CROP)

<h3>Purpose/Objective(s)</h3> The standard treatment for metastatic prostate cancer is systemic therapy. This prospective phase I/II study assessed the utility of SBRT to all tumor sites plus intermittent androgen deprivation therapy (ADT) in patients with hormone sensitive oligometastatic prostate cancer. Endpoints included incidence of SBRT induced late toxicities and clinical outcomes including cumulative incidences of developing biochemical progression, new metastases, restarting ADT, castration resistant prostate cancer (CRPC), and overall survival (OS). <h3>Materials/Methods</h3> Synchronous and metachronous metastatic disease presentations were eligible if there were ≤ 5 metastases, with ≤ 3 metastases in any one organ system. Conventional scans (CT/bonescan +/- MRI) were used to stage patients at baseline, although novel PET imaging was optional. SBRT was delivered to all sites of disease, including the prostate if not previously treated. SBRT dose was site dependent but was generally 30-35 Gy in 5 fractions for lymph nodes and non-spine bone lesions, 24-28 Gy in 2 fractions for spine, and 35 Gy in 5 fractions to the prostate. ADT was started prior to or immediately after SBRT and was continued for 1 year before moving to an intermittent approach. ADT was to be restarted when the PSA reached ≥ 10 ng/mL or earlier if clinically indicated (development of new metastases or rapidly rising PSA). Toxicity (CTCAE v4.0) and PSA measurements were collected every 4 months during follow-up. Conventional scans were performed at a minimum of once per year, but more frequent imaging was allowed at the discretion of the physician. Time zero was start of ADT or SBRT, whichever was earlier. <h3>Results</h3> 92 patients with 158 metastases were accrued with a median age of 74 years. Median follow-up time was 37 months. Median baseline PSA was 8.5 ng/mL (range 0.78 – 179.8). 39 (42%) patients had Gleason score of 8-10. 32 (35%) patients had synchronous disease presentation. 14 (15%) patients were staged with PET imaging. 5 (5%) patients developed late grade 3 GU toxicity and 6 (7%) patients developed a late SBRT induced bone fracture. There were no grade 4/5 toxicities. Median PSA nadir was 0.02 ng/mL. 50% of patients reached a PSA nadir of ≤ 0.02 ng/mL, while 92% of patients reached a PSA nadir of < 1 ng/mL. The cumulative incidence (CI) of biochemical progression (PSA nadir + 2 ng/mL) was 54% at 4 years. The 4-year CI of developing new metastases and local failure of irradiated sites was 42.8% and 7%, respectively. The 4-year CI of restarting ADT and developing CRPC was 62% and 25%, respectively. OS was 79% at 4 years. <h3>Conclusion</h3> The incidence of grade ≥ 3 toxicity was low when combining SBRT with intermittent ADT for hormone sensitive oligometastatic prostate cancer. With > 3 years of median follow-up, outcomes are promising compared to historical results of using ADT alone, particularly with regards to the development of CRPC. Further work will be done to identify potential predictors of clinical outcomes.

Outcomes for Oligometastatic Head and Neck Cancer Undergoing SBRT: Results From an International Multi-Institutional Consortium

Treatment of oligometastatic disease with SBRT has shown the potential to improve disease control and survival in trials largely focused on lung and prostate cancer. Outcomes in other sites, such as head and neck cancers (HNC) are poorly defined. Here we report the results of a multi-institutional cohort of oligometastatic HNC patients receiving SBRT.Data on HNC patients treated between 2008 and 2016 was extracted from an international consortium of six high volume SBRT centers. Patients were considered oligometastatic if they had 5 or fewer extracranial metastases. The risk of local recurrence (LR) and widespread progression (WSP, defined as 6 or more metastatic sites) was estimated with competing risks analysis. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method. Univariable and multivariable regression analysis (MVA) was used to determine the relationship between covariates and the main endpoints.Forty-two patients harboring 84 metastases from mucosal head and neck cancer were included. The median age was 64 and most patients were male (83%). The median follow up was 18.2 months. The most common primary site was the oropharynx (43%). Most patients had 1 or 2 metastases (78.6%). Metastatic sites treated with SBRT were mostly lung (50%) and bone (35.7%). Presentation was synchronous in 11 patients (26.2%), early metachronous (within 24 months of diagnosis, 57%) and late metachronous in 7 patients (> 24 months from diagnosis, 16.7%). The majority of patients (88%) had no systemic therapy prior to SBRT. SBRT dose and fractionation ranged from 20-28 Gy/1fx to 50 Gy in 5-10fx. The median biologic equivalent dose (BED10) was 100 Gy. The local control rate was 80% at 1 year and 66% at 2 years. The median PFS was 4.7 months. The median overall survival (OS) was 23.3 months. Improved local control on MVA was seen with patients who had a maximum point BED greater than the median (HR = 0.31; 95% CI: 0.10-0.91, P = 0.03). Disease burden significantly correlated with PFS, with larger combined PTV volumes for all metastases greater than the median of 48cc having worse PFS on MVA (HR = 2.99; 95% CI: 1.58-5.66, P < 0.001). The risk of WSP at 12 and 24 months was 31.7% and 48.3%, respectively. There was a trend towards lower rates of WSP for patients who presented with late metachronous disease versus all others (HR = 0.22; 95% CI: 0.03-1.82, P = 0.16). Severe toxicity was rare, with one patient developing a grade 3 brachial plexus injury after spine SBRT and one patient with grade 3 pneumonitis after lung SBRT.Patients undergoing SBRT for oligometastatic head and neck cancer have favorable local control and overall survival, however, PFS remains short. Patients with a late metachronous presentation may have more favorable biology. Future study should focus on whether subsets of patients such as those with synchronous or early metachronous disease may benefit from pre-SBRT systemic therapy.

Survival and Toxicity in Patients With Unresectable/Inoperable Biliary Cancers Treated with SBRT vs. Conventionally Fractionated Chemoradiation.

<h3>Purpose/Objective(s)</h3> The mainstay of treatment for unresectable/inoperable biliary cancers (UIBC) is chemotherapy (CHT) and radiotherapy (RT). We report our single institution clinical efficacy and safety in patients with UIBC treated with SBRT versus conventionally fractionated radiation (CRT). <h3>Materials/Methods</h3> Patients with UIBC treated with SBRT (n = 18) or CRT (n = 23) between 2006 and 2020 were identified. Additional management included neoadjuvant, adjuvant and/or concurrent CHT. Kaplan-Meier estimates of progression free survival (PFS), overall survival (OS) and locoregional control (LRC) were compared with log rank tests. Toxicities during treatment and follow up were based on the CTCAE v5.0. Acute toxicity was defined as adverse events < 6 months from initiation of RT. Differences by RT in patient and treatment characteristics and toxicities were assessed with Chi-square and Fisher's exact tests. Given the small sample, differences with significance of <i>P</i> < 0.10 were considered of potential clinical relevance. <h3>Results</h3> Of the 41 patients analyzed 54% were male, and 20% were non-white. CRT patients were younger than SBRT (median age 64 vs 76 yrs., <i>P</i> < 0.001). Tumor sites included 58% intrahepatic, 27% extrahepatic and 15% gallbladder. There were more > 5 cm tumors in the SBRT (51%) group than CRT (22%). The median SBRT dose was 60 Gy in 5 fractions and the median dose for CRT was 50 Gy in 25 fractions. SBRT dose was dichotomized into BED₁₀ ≥ 100 Gy and < 100 Gy. Of all patients, 29% did not receive any CHT, 24% received neoadjuvant CHT, 44% received adjuvant CHT and 51% received concurrent CHT. Overall, 26 patients died. Median follow-up of those alive was 8.2 months with no difference by RT type. The 1-yr PFS was 31.5% (95% CI 8.5-58.1) for SBRT and 18.8% (95% CI 5.9-37.3) for CRT (<i>P</i> = 0.042). Gallbladder and intrahepatic locations were associated with higher PFS compared to extrahepatic disease (<i>P</i> = 0.002). The 1-yr OS was 68.4% (95% CI 33.9-87.5) for SBRT and 67.0% (95% CI 42.7-82.8) for CRT (<i>P</i> = 0.151). BED₁₀ ≥ 100 Gy had higher OS than CRT or low dose SBRT (<i>P</i> = 0.014). Improved ECOG status was associated with higher OS (<i>P</i> = 0.044). LRC was 42.0% (95 CI 11.3-70.8) for SBRT and 26.1% (95% CI: 7.1-50.6) for CRT (<i>P</i> = 0.149). There was a trend towards improved LRC in tumors > 5 cm (<i>P</i> = 0.097). For acute toxicity, both treatments were well tolerated overall with only 1 patient with grade 3+ toxicity. 74% of CRT patients had an acute toxicity compared to 39% of SBRT patients (<i>P</i> = 0.024). There was no difference in late toxicity between the two groups. There was no grade 3+ late toxicity. <h3>Conclusion</h3> In this single-institution retrospective study, there was improved PFS in UIBC treated with SBRT. There was a trend towards improved LRC in larger tumors. Dose escalation to BED₁₀ ≥ 100 Gy in this series improved OS. SBRT was also better tolerated than CRT.

Single Institution Experience of Stereotactic Body Radiation Therapy in Non-small Cell Lung Cancer: Comparison of Two Dose Regimes and a Perspective on Ideal Dose Regimens.

IntroductionStereotactic body radiation therapy (SBRT) is an effective treatment for early-stage non-small cell lung cancer (NSCLC) patients who are either medically inoperable or who decline surgery. SBRT improves tumor control and overall survival (OS) in medically inoperable, early-stage, NSCLC patients. In this study, we investigated the effectiveness of two different SBRT doses commonly used and present our institutional experience.PurposeTo determine the clinical outcomes between two treatment regiments (50 Gray [Gy] vs. 55 Gy in five fractions) among Stage I NSCLC patients treated with SBRT at a state academic medical center.MethodsWe performed a retrospective analysis of 114 patients with Stage I (T1-2 N0 M0) NSCLC treated at a state academic medical center between October 2009 and April 2019. Survival analyses with treatment regimens of 50 Gy and 55 Gy in five fractions were conducted to detect any improvement in outcomes associated with the higher dose. The primary endpoints of this study included OS, local control (LC), and disease-free survival (DFS). Log-rank test and the Kaplan-Meier method were used to analyze the survival curves of the two treatment doses. The SPSS v.24.0 (IBM Corp., Armonk, NY, USA) was used for statistical analyses.ResultsThe 114 early-stage NSCLC patients (median age, 68 years; range 12 to 87 years) had a median follow-up of 25 months (range two to 86 months). The number of males (n = 72; 63.2 %) exceeded the number of females (n = 42; 36.8 %). The majority of patients in this study were Caucasians (n = 68; 59.6 %) and 46 patients were African Americans (40.4 %). Two-thirds of the patients (n = 76; 66.7 %) were treated with 50 Gy in five fractions, and 38 patients (33.3 %) with 55 Gy in five fractions. The one-, two-, and three-year OS and DFS rates were improved in the patients treated with 55 Gy [OS, 81.7 % vs. 72.8 %; 81.7 % vs. 58.9 %; 81.7 % vs. 46.7 % (p = 0.049)], [DFS, 69.7 % vs. 69.7 %; 61.9 % vs. 55.7 %; 61.9 % vs. 52.0 % (p = 0.842)], compared to those treated with 50 Gy. Adenocarcinoma was the most common histology in both groups (51.3 % and 68.4 %). Failure rates were elevated for the 50 Gy regimen [39 (34.2 %) vs. 12 (8.5 %)]. Three year control rates were (66.3 % vs. 96.6 %; p = 0.002) local control; (63.3 % vs. 94.4 %; p = 0.000) regional control; and (65.7 % vs. 97.1 %; p = 0.000) distant control, compared to those treated with 55 Gy.ConclusionEarly-stage NSCLC patients treated with SBRT 55 Gy in five fractions did better in terms of local control, overall survival, and disease-free survival rates compared to the 50 Gy in five fractions group.

Radiation treatment planning study to investigate feasibility of delivering Immunotherapy in Combination with Ablative Radiosurgery to Ultra-High DoSes (ICARUS).

PurposeImmune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95–120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra‐high doses of radiation (BED10 > 300) to be used in future clinical trials.Methods and MaterialsThe radiation plans from 15 patients enrolled on a phase I trial of SBRT + pembro were reanalyzed. Metastatic disease sites included liver (8/15), inguinal region (1/15), pelvis (2/15), lung (1/15), abdomen (1/15), spleen (1/15), and groin (1/15). Gross tumor volumes (GTVs) ranged from 80 to 708 cc. Following the same methodology used in the Phase I trial on which these patients were treated, GTVs > 65 cc were contracted to a 65 cc subvolume (SubGTV) resulting in only a portion of the GTV receiving prescription dose. Volumetric modulated arc therapy (VMAT) was used to plan treatments BED10 = 360 Gy. Plans utilizing both 6FFF and 10FFF beams were compared to clinical plans delivering BED10 = 112.50 Gy. The target primary goal was V100% > 95% with a secondary goal of V70% > 99% and OAR objectives per the trial. To demonstrate feasibility, plans were delivered to a diode array phantom and evaluated for fidelity using gamma analysis.ResultsAll 30 plans met the secondary coverage goal and satisfied all OAR constraints. The primary goal was achieved in 12/15 of the 6FFF plans and 13/15 of the 10FFF plans. Average gamma analysis passing rate using criteria of 3% dose difference and 3, 2, and 1 mm were 99.1 ± 1.0%, 98.5 ± 1.6%, and 95.1 ± 3.8%, respectively.ConclusionNovel VMAT planning approaches with clinical treatment planning software and linear accelerators prove capable of delivering radiation doses in excess of 360 Gy BED10 to tumor subvolumes, while maintaining safe OAR doses.

The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.