Stereotactic Ablative Radiotherapy Dose Research Articles

What is the predictive value of RECIST criteria following stereotactic lung radiation?

PurposeResponse EvaluationCriteriain Solid Tumors (RECIST) is commonly used to assess response to anti-cancer therapies. However, its application after lung stereotactic ablative radiotherapy (SABR) is complicated by radiation-induced lung changes. This study assesses the frequency of progressive disease (PD) by RECIST following lung SABR and correlates this with actual treatment outcomes as determined by longitudinal follow-up. Methods and MaterialsWe reviewed patients treated with lung SABR for primary lung tumors or oligometastases between 2010 and 2015. Patients were treated with SABR doses of 54–60 Gy in 3–8 fractions. All follow-up scans were assessed and the treated lesion was serially measured over time, with the maximum diameter on axial CT slices used for RECIST calculations. Lesions demonstrating PD by RECIST criteria were identified and subsequently followed for long-term outcomes. The final ‘gold-standard’ assessment of response was based on size changes after PD and, as available, positron emission tomography scan and/or biopsy. ResultsEighty-eight lesions met inclusion criteria. Seventy-five were lung primaries and thirteen were lung metastases. Median follow-up was 52 months (interquartile range: 33–68). Two-thirds (66 %, 58/88) of treated lesions met RECIST criteria for PD; however, local recurrence was only confirmed in 16 % (9/58) of cases. Most lesions that triggered PD by RECIST (47/58, 81 %) were ultimately found not to represent recurrence, while a minority (2/58, 3 %) had an uncertain response. The positive predictive value [PPV] of a RECIST defined PD event was 0.16. If PD was triggered within 12-months post-treatment, PPV was 0.08, compared to 0.21 for lesions triggering PD after 12-months. ConclusionUsing RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, only a minority had recurrence, leading to a poor PPV of RECIST. This highlights the limitations of RECIST in this setting and provides context for physicians when interpreting post-lung SABR imaging.

Predicting Local Control with Dosimetric Parameters in Patients Receiving Individualized Stereotactic Ablative Radiotherapy for Lung Tumors

Stereotactic ablative radiotherapy (SABR) is an effective treatment option for lung tumors. The individualized lung tumor SABR (iSABR) trial was a phase II single-arm study that personalized lung tumor SABR dose and fractionation based on tumor size, location, and histology with very low rates of local recurrence (LR). A secondary analysis of this trial was conducted to assess for potential dosimetric predictors of LR, in order to help guide future clinical treatment planning. From 2011 to 2018, local, regional and distant recurrence data were prospectively collected from 204 patients (261 lung SABR treatments) enrolled in a prospective trial. Baseline characteristics and treatment details were evaluated. Dosimetric and treatment plan parameters were evaluated for their potential to predict LR, using logistic regression and chi-squared analyses. The majority of treated tumors were peripheral (71%, vs 29% central), primary lesions (76%, versus 24% metastatic), and of adenocarcinoma histology (67%, versus 13% squamous cell carcinoma and 19% other). The median follow-up was 24 months (range 2-95). Twenty-seven (10.3%) LRs occurred, with a median time to LR of 15 months (range 6-81 months). There were no significant associations between the overall cohort and the dosimetric parameters. However, for the multi-fraction cohort, an increased proportion of the PTV receiving 110% and 115% of the prescription dose were associated with lower LR (p = 0.01 and p = 0.01 respectively). Specifically for the 50 Gy in 4 fraction cohort, an increased D1cc, D0.03cc, as well as the proportion of the PTV receiving 110%, 115%, and 120% of the prescription dose were associated with lower LR (p < 0.001, p = 0.001, p = 0.003, p < 0.001, p = 0.004, respectively). There was no association of LR with prescription dose expressed as biologically effective dose using an alpha/beta of 10 Gy (BED10), D99%, or single- versus multi-fraction regimens. SABR for lung tumors using the individualized protocol on this trial showed excellent LR rates. We identified dosimetric parameters that were associated with LR, including V110% and V115% within the multi-fraction cohort, as well as the 50 Gy in 4 fraction cohort the D1cc, D0.03cc, and proportions of the PTV receiving 110%, 115%, and 120% of the prescription dose in the 50 Gy in 4 fraction cohort. Optimal thresholds for these parameters will be identified in further analyses. There did not appear to be an association with LR and BED10, D99%, or comparing single- vs multi-fraction regimens.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors

Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. ClinicalTrials.gov Identifier: NCT01463423.

T Stage and Pretreatment Standardized Uptake Values Predict Tumor Recurrence With 5-Fraction SABR in Early-Stage Non-Small Cell Lung Cancer

PurposeFive-fraction stereotactic ablative radiotherapy (SABR) regimens are frequently used to treat centrally located early-stage non-small cell lung cancer or disease in the proximity of the chest wall as a means of optimizing tumor control and reducing treatment toxicity. However, increasing these SABR regimens to 5 fractions may reduce tumor control outcomes. We sought to identify the clinical parameters predictive of treatment failures with these 5-fraction courses. MethodsNinety patients with T1-2 non-small cell lung cancer were treated with 50 or 60 Gy in 5 fractions. Failure over time was modeled using cumulative incidences of local, regional, or distant failure, with death as a competing risk. Cox proportional hazards analysis for incidences of failure was performed to control for patient variables. ResultsOf 90 patients, 24 of 53 patients with T1 tumors and 19 of 37 patients with T2 tumors received 50 Gy SABR, and the other 47 patients received 60 Gy. Two-year overall survival and progression-free survival for the whole cohort were 75.8% and 59.3%, respectively. Total SABR dose (50 vs 60 Gy) did not influence survival nor failure rates at 2 and 5 years. Within 2 years of treatment, 7.8% of all patients developed local failure. For all patient and tumor characteristics evaluated, only T stage and pretreatment positron emission tomography standardized uptake values served as predictors of local, regional, and distant failure at 2 and 5 years posttreatment on univariate and multivariable analysis. ConclusionsFive-fraction SABR provides excellent in-field control. T2 and high fluorodeoxyglucose uptake tumors have increased failure rates, suggesting the potential need for adjuvant therapies, which are being assessed in randomized phase 3 trials.

Two-fraction stereotactic ablative radiotherapy (SABR) versus two-fraction high dose rate (HDR) brachytherapy for localized prostate cancer: Does dose heterogeneity matter?

Background and purposeContemporary radiotherapy for localized prostate cancer (PCa) is deliverable via stereotactic ablative radiotherapy (SABR) and high dose rate (HDR) brachytherapy. Here we report on a parallel cohort analysis of two prospective, phase II clinical trials of two-fraction prostate SABR versus two-fraction HDR monotherapy. Materials and methodsEnrolled patients had histologically-confirmed PCa (clinical stage T1c-T2b; grade group 1, 2, or 3; and PSA < 20 ng/mL). SABR and HDR doses were 26 Gy and 27 Gy in 2 weekly fractions, respectively. Patient-level data from each cohort was analysed to assess prostate specific antigen (PSA) response kinetics, biochemical failure, toxicity, and quality of life (QOL). ResultsThirty patients receiving SABR and 83 receiving HDR were included. Fifty percent and 30% of patients had unfavourable-intermediate risk disease, respectively. SABR patients had higher mean baseline PSA (8.7 versus 6.8 ng/mL, p = 0.016). Median follow-up was 72.7 and 65.3 months, respectively. Mean dose delivered (Dmean) was 26.6–26.8 Gy for SABR versus 35.5–45.5 Gy for HDR. Both cohorts achieved a median nadir PSA of 0.16 ng/mL at a median of 57 months post-treatment. Cumulative biochemical failure probability (±SE) at 72 months was 3.5% (±3.5%) for SABR versus 12.8% (±4.8%) for HDR (p = 0.19). Low rates of CTCAE grade ≥2 toxicity were observed in both cohorts. No differences in EPIC scores over time were observed between cohorts. ConclusionsTwo-fraction SABR yields similar rates of biochemical failure, acute and late toxicities, and QOL as two-faction HDR brachytherapy. These data support the design of a randomized controlled trial comparing these treatments.

Organ at Risk Dose Constraints in Stereotactic Ablative Radiotherapy: A Systematic Review of Active Clinical Trials

Organ at risk (OAR) dose constraints are a critical aspect of stereotactic ablative radiotherapy (SABR) treatment planning. As clinicians must balance tumor control and potential toxicities, knowledge and application of optimal dose constraints are essential to the safe and effective delivery of SABR. While standardized dose constraints have been studied and reported upon for conventionally fractionated radiotherapy, SABR dose constraints have not been as extensively studied, with limited evidence supporting preferred dose constraints for most OARs. Our objective was to report on OAR dose constraints used in ongoing clinical trials involving SABR for oligometastatic disease to help inform institutional practices.Clinicaltrials.gov was searched from inception to February 2020 to capture actively accruing clinical trials using SABR in oligometastatic disease. Full protocols (or at minimum, a list of dose constraints utilized) were obtained by contacting principal investigators or from publicly available sources. OAR constraints were abstracted by two authors and synthesized to report in a standardized manner. Variability of OAR constraints was assessed by comparing the width of the interquartile range and the difference between the maximum and minimum dose to a volume.Fifty-three of 85 eligible clinical trials contributed OAR constraints used in analysis. Dose constraints for 1-8 fractions of SABR were collected for 33 OARs. Variability was found in the absolute allowable OAR doses, use of planning OAR volumes (PRV), and whether constraints were optional vs. mandatory. For many OARs, the most common dose constraints (i.e., the mode) often matched a pre-existing publication, but no single pre-existing publication matched the modes of all OAR dose constraints. Organs with the most variability were the rectum, penile bulb, and chest wall and ribs. The esophagus, stomach, duodenum, and small bowel also possessed high variability for at least one constraint. OARs previously evaluated by HyTEC (High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic), such as spinal cord and optic pathway, appeared to have less variability among study protocols.We found substantial variability in many OAR dose constraints used in ongoing clinical trials evaluating SABR in oligometastatic disease. Future research and recommendations for standardized OAR dose constraints, as well as consistency in implementing PRV margins, should be a priority for the field of radiation oncology.

The Influence of Neighborhood Socioeconomic Status and Follow-up on Survival in Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiotherapy

Cancer patients with lower socioeconomic status (SES) have been shown to have worse outcomes, but the influence of neighborhood-level SES has not been well-established. One widely used geographic measure of SES is via a publicly available, U.S. Census-based neighborhood disadvantage metric called the Area Deprivation Index (ADI). We hypothesized that residence in a lower SES neighborhood, as indicated by higher ADI, would be associated with worse progression-free (PFS) and overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).A retrospective review was conducted using an institutional database containing patient and disease characteristics including race, smoking status, and Charlson Comorbidity Index (CCI) scores. Neighborhood-level factors, such as ADI and rural-urban codes, were incorporated by applying clinical informatics to manage large-scale data. Loss to follow-up was defined as being alive but with no follow-up > 6 months after completing SABR. Kaplan-Meier with log-rank analysis and Cox regression were conducted for PFS and OS, and logistic regression was performed to evaluate for predictors of loss to follow-up. Statistical significance was set at P < 0.05.There were 513 patients treated from 2004-2018 with a median follow-up of 25 months (range: 0-190). Median PFS was 20 months, and median OS was 36 months. The median age was 73 years; 45% were male, 14% were Black, 30% were actively smoking, 74% were from an urban neighborhood. Median SABR dose was 54 Gray in 3 fractions. ADI scores ranged from 21.68 to 156.85 and were normally distributed; the first quintile mean ADI was 71.49 (least disadvantaged) and the fifth quintile mean ADI was 124.97 (most disadvantaged). On Kaplan-Meier (log-rank) analysis, loss to follow-up was associated with worse PFS and OS (P < 0.001). On multivariable analysis, loss to follow-up (HR 12.43, 95% CI: 6.40-24.18) and Black race (HR .59, 95% CI: .36-.98) were associated with improved PFS. For OS, after controlling for other variables, loss to follow-up (HR 5.41, 95% CI: 4.15-7.05), higher ADI (HR 1.01, 95% CI: 1.00-1.02), urban home location (HR 1.56, 95% CI: 1.18-2.05), higher CCI (HR 1.16, 95% CI: 1.08-1.24), and larger tumor size (HR 1.13, 95% CI: 1.01-1.27) were associated with worse OS, whereas female sex (HR .61, 95% CI: .49-.76) and Black race (HR .42, 95% CI: .28-.65) were associated with improved OS. ADI, urban home location, and race were not significant predictors of loss to follow-up.Loss to follow-up, urban home location, and lower socioeconomic status, as represented by higher ADI values, were found to be independently associated with worse OS, suggesting the importance of considering SES and potential barriers to follow-up in patient care.

A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR)

Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

CyberKnife Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Gynecological Cancers

Purpose Use of stereotactic ablative radiotherapy (SABR) in the treatment of recurrent or metastatic lesions from a primary gynecologic cancer is a relatively new concept. The present study aims to assess the safety, efficacy, and possible toxicity profile of CyberKnife SABR, recurrent or metastatic disease. Materials/Methods CyberKnife VSI-based SABR was offered to 20 oligometastatic/recurrent gynecological cancer patients between 2013 and 2019. Patient, tumor, and treatment characteristics including radiotherapy details, clinical outcome in terms of local control rates, and toxicities are reported in this study. Results Twenty-five recurrent or oligometastatic lesions for 20 primary gynecologic cancer patients including cervical ( n = 8), ovarian ( n = 6), endometrial ( n = 5), and vulvar ( n = 1) cancers were analyzed. Of these, 4 (16%) were intracranial lesions and remaining 21 (84%) were extracranial, consisting of 14 (67%) extrapelvic and 7 (33%) pelvic lesions. The median SABR dose delivered was 60 Gy biologically effective dose (range 42–133 Gy) in an average of four fractions (range 1–6). The mean follow-up was 18 (range 2–70) months. Local tumor control was achieved in 82% of patients. There was no grade ≥ 3 toxicity recorded. Conclusion Our study results suggest that CyberKnife SABR is an effective treatment modality with no major morbidity in patients with recurrent or oligometastatic gynecological cancers.

Long-term Outcomes of Six-Fraction Stereotactic Ablative Radiotherapy to Limited Lymph Node Metastases: An Institutional Case Series

Lymph node (LN) metastasis is one of the most common sites to develop disease recurrence or progression after initial cancer treatment. Aggressive local treatment such as surgery or radiotherapy might benefit selected patients with limited metastatic LN(s). Stereotactic ablative radiotherapy (SABR) has been shown to achieve high local control rates with limited toxicities, yet the efficacy and patterns of failure have not been well studied with long-term follow-up. Herein, we report institutional outcomes of patients receiving six-fraction-SABR to involved metastatic LN(s). Since 2012, patients with oligo-metastatic or oligo-progressive LN(s) referred for radical radiotherapy and underwent six-fraction SABR were enrolled for retrospective chart and image review. Response was assessed by RECIST 1.1. Failure patterns and toxicities were recorded. Progression-free survival and overall survival (OS) were estimated by Kaplan-Meier method and log-rank test was used for analysis of prognostic factors. Forty-two patients with forty-six irradiation nodal sites were treated with SABR in this retrospective study. The majority (23/42) were lung cancer patients and the most frequent treatment sites were mediastinum and hilum (26/46). The median SABR dose was 45 Gy (range 30-45 Gy). Only one patient experienced grade 3 gastrointestinal toxicity. With the median follow-up of 52.8 months, median OS is 26.7 months (range 3.3–73.9 months). In-field failure rate is less than 5% (n = 2), and five patients (10.9%) developed isolated recurrences at elective regional lymphatics. The One-year and two-year cumulative isolated regional failure rates are 8.7% and 10.9%, respectively. Patients received >40 Gy (BED10 66.6 Gy) had a significant superior OS compared to those treated with <40 Gy (median OS: 33.6 months versus 10.0 months, log-rank test p = 0.01). Radical treatment of oligo-metastatic or oligo-progressive involved LN(s) with SABR in six fractions seems to provide high local control rate with low-risk of treatment-related toxicities and is not associated with excessive recurrence rates at elective nodal regions after long-term follow-up. A prospective phase II trial to further evaluate the efficacy, safety and patterns of failure for SABR in limited LN metastases was ongoing. Table Failure Sites after LN(s) SABR (N = 46)Abstract 2418; TableVariableNumberWithin RT field2 (4.3%)Isolated elective field5 (10.9%)Distant field35 (76.1%) Open table in a new tab

Stereotactic Ablative Radiotherapy Fractionation for Hepatocellular Carcinoma in the United States.

IntroductionThis study aims to analyze the patterns of care, including fractionation and utilization, of hypofractionated stereotactic ablative radiotherapy (SABR) in the treatment of hepatocellular carcinoma (HCC).MethodsThe National Cancer Database was queried for patients diagnosed with HCC from 2004 to 2014 and treated with SABR in three, four, or five fractions in 15-20Gy, 10-13Gy, or 6-12Gy per fraction, respectively. Patients with stage IV and Charlson-Deyo Comorbidity Index > 0 were excluded in order to avoid bias resulting from the selection of poorer prognosis patients. The patients were then stratified based on several characteristics including biologically equivalent doses (BEDs) of =/> 100 Gy and <100 Gy to determine whether there was an association with overall survival (OS) and a multivariable analysis (MVA) was performed to assess for potential confounding factors. ResultsThere were 462 patients identified in whom the most common SABR fractionation regimen was 10Gy x five fractions (25.3%), followed by 8Gy x five fractions (17.7%), and 15-16Gy x three fractions (26.4%). A total of 152 patients were treated to a BED < 100Gy, which was associated with a median OS of 20.8 months (95% CI 14.55-27.11). Three hundred and ten patients were treated to a BED =/> 100Gy, which was associated with a median OS of 30.8 months (95% CI 5.25-32.08). On MVA, BED =/> 100Gy was not significantly associated with improved OS (HR 0.85, 95% CI 0.64-1.14, p = 0.28). Factors that were associated with significantly worse survival were tumor size in the largest quartile (HR 2.197 CI 1.440-3.354, p < 0.0001) and T3a disease (HR 2.474 CI 1.472-4.158, p = 0.001 compared to T1). ConclusionSABR fractionation schemes vary widely, but are most commonly 10Gy x five fractions followed by 8Gy x five fractions and 15Gy x three fractions. BED of at least 100Gy is not associated with improved OS. Further studies are needed to best identify the optimal SABR dose and fractionation.

IBS14.02 Best Management of Early Stage NSCLC in ILD Patients

IBS14.02 Best Management of Early Stage NSCLC in ILD Patients

Stereotactic Ablative Radiotherapy for Mediastinal and Hilar Lymphadenopathy: A Systematic Review

Stereotactic ablative radiotherapy (SABR) is a form of high dose hypofractionated radiotherapy typically delivered ≤ 5 fractions and a desired BED10 ≥ 100 Gy10. While established for parenchymal lung tumors, its safety and effectiveness for mediastinal and hilar lymphadenopathy (MHL), is not well established, given the potential for toxicity due to proximity of nearby organs at risk. Therefore, the objective of this study was to summarize reported outcomes following SABR for MHL. A systematic review, based on the PRISMA guidelines, was performed using MEDLINE® (PubMed®), EMBASE and Cochrane Library databases from inception until December 2018. Studies reporting outcomes from SABR specifically for MHL from all primary malignancies were included. Studies were not excluded based on SABR dosage and fractionation prescribed. Non-English studies, guidelines, reviews, non-peer reviewed correspondences, and studies with fewer than 5 patients were excluded. If multiple publications were found from the same institution, only the most recent publication and/or largest cohort were included for data abstraction. From the 223 studies initially identified, 4 studies totaling 196 unique patients met all inclusion criteria. All studies were retrospective in design, and from single institutions. The majority (65%) of patients (n=127) had a diagnosis of non-small cell lung cancer, and breast was the second most common with 16 patients (8%). Median follow-up periods ranged between 12.0-32.2 months. SABR dose and fractionation ranged from 21 Gy to 60 Gy in 3-11 fractions, which corresponded to a median BED10 ranging from 46-106 Gy10. Planning tumor volume (PTV) margins employed ranged from 3 to 5 mm. Three studies reported local control (LC) rates, which were: study I) 97% (1-year) and 77% (5-year); study II) 66% (16-month) and study III) 88% (2-year). Overall survival (OS) was calculated from time of treatment in 3 studies, with a weighted median OS of 24.3 (18.0-27.2) months. Weighted progression-free survival (PFS) calculated from 2 studies were 11.4 (9.0-13.1) months. Overall, SABR was well tolerated; with a weighted Grade 3-5 toxicity rate of 6% (n = 11). The weighted treatment-related mortality (i.e. Grade 5 toxicity) rate was 2% (n=4). Despite the potential for serious toxicity, SABR for MHL appears to be feasible and effective. Considering the inconsistency of reported patients, SABR prescriptions, treatments, and outcome variables, both multi-institutional and/or prospective data would be helpful to determine the relative therapeutic benefit of SABR in this high-risk treatment scenario.

Outcomes of Stereotactic Ablative Radiotherapy for Lymph Node Oligometastases

Stereotactic ablative radiotherapy (SABR) for the treatment of oligometastases is being investigated in ongoing prospective studies, with available phase II data suggesting favorable outcomes. However, there is little data regarding the use of SABR for oligometastatic lymph nodes (LNs). The objectives of the study are to report the demographics, toxicity and outcomes of all patients treated provincially with SABR to oligometastatic LNs. We conducted an analysis of all patients who underwent SABR to oligometastatic LNs in our provincial program, from 2013 to 2017. Some of the patients were treated on clinical trials, and data was prospectively collected. For the remaining majority of the patients, baseline patient, tumor, treatment and clinical outcome data were collected through retrospective review. Local control (LC), progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Cox regression analysis was used to identify predictors of outcomes. Twenty-four patients underwent SABR to 35 LNs (median 1 and mean 1.5 LNs per patient). The primary sites were colorectal 8 (22.9%), kidney 6 (17.1%), esophagus 4 (11.4%), gallbladder 4 (11.4%), stomach 3 (8.6%), lung 3 (8.6%), skin 2 (5.7%), pancreas 2 (5.7%), liver 1 (2.9%), duodenum 1 (2.9%), and unknown origin 1 (2.9%). Four (11.4%) LNs were in the neck / supraclavicular regions, 14 (40.0%) in the hilum / mediastinum and 17 (48.6%) in the abdomen / pelvis. All patients had treated and controlled primary sites at the time of SABR. The median follow-up post-SABR was 31.7 months. The SABR dose fractionation ranged between 30-60 Gy in 5-10 fractions, with median BED10 of 72 Gy (range 41.3-105 Gy). All patients were treated with VMAT technique, with 4DCT and respiratory gating used for motion management in 19 (54.3%) cases. The 1- and 3-year LC were 85.4% and 62.7%. The median PFS was 7.6 months, with 1-year PFS at 25.7% and 3-year at 18.4%. The median OS was 45.0 months, with 1-year OS at 91.3% and 3-year at 55.7%. Thirteen (54.2%) patients initiated systemic therapy after SABR, at a median time for these patients of 10.0 months following completion of SABR. The median systemic therapy-free survival (STFS) for all patients after SABR was 17.8 months. There was no grade 3-5 toxicity as per CTCAE V5 criteria. On multivariate analysis, younger age (p=0.019) and female gender (p=0.046) were found to be factors predictive of improved OS. SABR to oligometastatic LNs achieves meaningful STFS, without significant toxicity. While the treatment yields moderate rates of long-term LC, the PFS was limited in this cohort. Further evaluation of patient and tumor selection is warranted.

Stereotactic radiotherapy combined with immunotherapy is safe and effective: Results from a phase I clinical trial.

9557 Background: There is growing evidence to suggest synergism between stereotactic ablative radiotherapy (SABR) and immunotherapy (IO) against metastatic melanoma. The optimal timing and dosing of SABR for this purpose has not been established. Here, we report results from a Phase I trial, finding the best outcomes with low dose SABR delivered late. Methods: Metastatic melanoma pts with at least two metastases received SABR to a single metastatic site. All pts had standard dose IO with anti-PD1 and/or anti-CTLA4. Following a standard 3+3 design, pts were escalated through three SABR doses (10Gy, 15Gy and 20Gy) delivered at three different time points (Cycle 1, 2, or 3 of IO). Dose limiting toxicity (DLT) were defined as Grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or cox regressions were used to assess the impact of SABR dose, timing and use of combination IO on toxicity, progression-free (PFS) and overall survival (OS) while controlling age, gender and baseline performance status. Results: Between April 2016 and August 2018, 24 pts were enrolled. The median age was 66 years and most were ECOG 0-1 (92%). The median follow-up was 10 months. Three pts (12.5%) developed DLTs (enterocolitis, hepatitis and liver function derangement). None occurred at SABR treated sites and all were in pts receiving 15Gy. DLTs were not associated with SABR timing (p = 0.44) or use of combination IO (p = 0.72). On this basis the IDSMC recommended stopping the trial and maximum tolerated SABR dose was defined at 10 Gy. The median PFS and OS were respectively 5.4m (95% CI 2.1m-NR) and 16.9m (95% CI 7.1m-NR). The median PFS for those receiving 10Gy was numerically higher than those receiving 15Gy (11.8m vs 2.6 m, p = 0.42). The only treatment related factor associated with improved PFS (HR = 0.14, p = 0.02) and OS (HR = 0.09, p = 0.04) was receiving SABR with Cycle 3. SABR dose (PFS p = 0.75, OS p = 0.67) and IO type (PFS p = 0.13, OS p = 0.06) were not significant. Conclusions: SABR combined with IO is generally safe overall. We found the optimal therapeutic index may be achieved with 10Gy delivered with the third cycle of IO; a strategy that warrants further testing. Clinical trial information: ACTRN12616001064493.

Predictive Model of Progression in Early Stage Non Small Cell Lung Cancer Treated with Stereotactic Ablative Radiation Therapy

There is an emerging interest for combining stereotactic ablative radiotherapy (SABR) with immunotherapy in the management of early stage non small cell lung cancer (ES-NSCLC). To help best select which patients may benefit from immunotherapy in future trials, we aimed to determine the predictive factors of progression free survival (PFS) and time to progression (TTP) in a large cohort of ES-NSCLC patients treated with SABR. A retrospective analysis of patients with stage I–II NSCLC treated with SABR from 2004 to 2015 was conducted. SABR doses of 34-70 Gy in 1-10 fractions were delivered. Cox proportional hazard ratio models were used for analysis of potential predictive variables. The following variables were included in the model: patient age, gender, ECOG performance status, Charlson co-morbidity index, pre-treatment pulmonary function tests (percent forced expiratory volume in 1 second [%FEV1]) and percent diffusing lung capacity for carbon monoxide [%DLCO]), tumor stage, size, histology, location and maximum standardized uptake value (SUVmax) on FDG/PET. Variables with significant association with PFS and TTP in univariate analysis were used for subsequent recursive partitioning analysis (RPA) to identify appropriate cut-off points. A total of 912 patients with a median age of 72 years (range, 46-91) were included. Median follow-up was 59.3 months. Local recurrence, regional recurrence, distant metastasis and second primary lung cancer developed in 10.0%, 11.5%, 20.1% and 7.5% of patients, at a median time to recurrence of 14.9 months (range, 1.5–91.9), 10.5 months (range 1.4–70.7), 11.6 months (range, 0.2–91.9 months) and 23.6 months (range, 1.2–122.4), respectively. Actuarial 3- and 5-year PFS were 52.7% and 39.1%, and 3- and 5-year TTP were 72.2% and 66.7%, respectively. On univariate analysis, age (p=0.0009), ECOG (p<0.0001), Charlson score (p=0.0001), %DLCO (p<0.0001), %FEV1 (p=0.007), non-adenocarcinoma histology (p<0.0001), tumor size (p=0.01) and tumor SUVmax (p=0.0002) were associated with PFS, while %DLCO (p=0.002), tumor size (p=0.002) and tumor SUVmax (p=0.01) were associated with TTP. RPA identified age ≥ 78 years, Charlson score ≥ 5, %DLCO < 71%, %FEV1 < 65%, tumor size ≥ 3 cm and SUVmax ≥ 12 as significant cut-offs for adverse PFS outcome. RPA identified %DLCO < 71%, tumor size ≥ 3 cm and SUVmax ≥ 12 as significant cut-offs for adverse TTP. On multivariate analysis, age (p=0.05), Charlson score (p=0.03), %DLCO (p=0.00001), non-adenocarcinoma histology (p=0.02), and tumor size (p=0.002) remained predictive of PFS. Correlations with biological markers are currently on-going. Age ≥ 78 years, Charlson score≥ 5, %DLCO < 71%, tumor size ≥ 3 cm and non-adenocarcinoma histology were found to be independent predictors of PFS. Patients with %DLCO < 71%, tumor size ≥ 3 cm and SUVmax ≥ 12 had adverse TTP outcomes, suggesting that they may benefit from treatment intensification. A predictive model is being develop and will be presented.

Correlation of biologically effective dose and the tumor control in Stage I (

Stereotactic ablative radiotherapy (SABR) is one of the newly developed innovative radiotherapy and of which optimal dose prescription needs to be standardized. We aimed to investigate the dose-response relationship for patients with SABR. Fifty-three patients with Stage I non-small cell lung cancer patients, who underwent SABR between November 2006 and January 2015, were evaluated retrospectively. Thirteen patients (24.5%), who refused the surgery were included and 40 patients (75.5%) were medically inoperable at diagnosis. The median age was 74 years. The median SABR dose was 50 Gy in 3-8 fractions and the median biologically effective dose (BED;α/β = 10) was 105.6 Gy (range: 60-160.53 Gy). The median follow-up was 37.1 months. The 1 and 3 year local control rates were 91.7% and 85.1%. The 3 year overall and progression-free survival rate were 63.3% and 47.5%, respectively, and freedom from progression was 62.2%. Local control rate and 3-year overall survival according to tumor size was 100% and 79.4% in T1 tumors in a while 61.8% and 45% in T2a tumors. The 3-year local and regional control by BED10 was 79.4% and 69.4% in ≤100 Gy vs. 89.1% and 100% in >100 Gy (P = 0.526, 0.004). Dyspnea more than Grade 3 was reported in six (11.3%) patients and Grade 1 chest pain was shown in five (9.4%) patients. The excellent regional control was conferred with a prescription of more than BED10 of 100 Gy, which also might be needed to achieve better local tumor control in T2a patients with tolerable lung function.

Feasible Optimization of Stereotactic Ablative Radiotherapy Dose by Tumor Size for Stage I Non–small-cell Lung Cancer

IntroductionThe purpose of this study was to assess the effect of dose escalation of stereotactic ablative radiotherapy (SABR) by investigating the long-term clinical outcomes of SABR for stage I non–small-cell lung cancer (NSCLC). MethodsA retrospective analysis was performed on a total of 169 patients with 178 lesions of stage I NSCLC treated with SABR at a single institution from June 2000 to May 2015. The standard dose scheme for SABR was 48 Gy in 4 fractions during the early period of the analysis, but it was escalated to 60 Gy in 4 fractions from June 2009. All failures were recorded over the follow-up period. ResultsMedian follow-up time was 32 months. The 5-year overall survival rate was 46.7%, and the actuarial local control rate was 79.3%. Tumor size was an independent prognostic factor for survival. No relapse occurred in tumors ≤ 2 cm irrespective of SABR dose. Escalated doses of approximately 60 Gy in 4 fractions (biologically effective dose [BED] = 150 Gy10) achieved higher local control compared with 48 Gy in 4 fractions (BED = 106 Gy10) (76.2% vs. 60.6%) at 5-year follow-up (P = .022) in tumors > 2 cm. There were no differences in treatment-related toxicities between the dose groups. Major failures consisted of distant metastasis to another lung parenchyma. ConclusionSABR provides satisfactory long-term local control and high overall survival in medically inoperable stage I NSCLC. Tumors ≤ 2 cm had no local recurrence regardless of dose; whereas for tumors > 2 cm, an escalated BED of approximately 150 Gy10 provided significantly higher local tumor control.

Stereotactic ablative radiotherapy in the treatment of low and intermediate risk prostate cancer: Is there an optimal dose?

PurposeTo investigate if stereotactic ablative radiotherapy (SABR) dose is associated with PSA at 3years (PSA3y) in the treatment of localized prostate cancer and to explore predictors of late genitourinary (GU) toxicity. Materials and methodsThree prospective trials of SABR were undertaken at our institution: 1) 35Gy/5 fractions/29days; 2) 40Gy/5 fractions/29days; 3) 40Gy/5 fractions/11 or 29days. PSA3y was analyzed as a continuous variable. Toxicity was defined as the worst new toxicity and assessed using the radiation therapy oncology group (RTOG) late morbidity scheme. Univariate and multivariable regression analyses were conducted to assess the association between dose and PSA3y, and to explore predictors of late grade 2+ GU toxicity. ResultsMedian PSA3y was 0.64 (intraquartile range (IQR): 0.41–1.12) and 0.27 (IQR: 0.12–0.55) ng/mL for patients treated with 35 and 40Gy respectively. A dose of 40Gy was an independent predictor of lower PSA3y on multivariable analysis (p<0.001). Dose of 40Gy (odds ratio (OR): 16.69, 95%CI: 5.78, 48.20, p<0.001) and higher International Prostate Symptom Score (OR: 1.01, 95%CI: 1.04, 1.16, p=0.001) predicted for late grade 2+ GU toxicity on multivariable logistic regression. ConclusionsThis analysis suggests that higher SABR dose is associated with lower PSA3y. Strategies to allow safe SABR dose escalation should be further investigated.

Treatment-Related Toxicity in Patients with Early Stage Non–Small Cell Lung Cancer and Co-Existing Interstitial Lung Disease: A Systematic Review

Abstract Introduction Definitive treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC) is usually well-tolerated. Patients with ES-NSCLC and co-existing interstitial lung disease (ILD) are at increased risk of severe treatment-related toxicity following definitive therapy. The main objective of this systematic review is to provide a pooled estimation of treatment-related mortality and ILD-specific toxicity in this population of patients and identify trends for further study. Methods The MEDLINE and Embase databases were queried from respective dates of inception to January 2016. Studies that included patients who underwent definitive treatment for ES-NSCLC not combined with other treatments were included. Patients with oligometastases who were treated with aggressive palliation were included if it did not constitute the majority of patients in a specific study. Results were summarized with weighted proportions according to the sample size of individual studies. Results Overall, 3056 records were reviewed and 50 journal articles were included in the abstraction. Weighted proportion of treatment-related mortality (and ILD-specific toxicity) in primarily medically inoperable patients was as follows: stereotactic ablative radiotherapy (SABR) 15.5% (25%), particle beam therapy 4.3% (18.2%) and RFA 8.7% (25%). Data for medically operable patients who underwent surgery were extracted for reference. Treatment-related mortality and ILD-specific toxicity was 2.2% and 12%, respectively, in the surgical population. On analysis of reported SABR dose parameters, V20 Conclusion A consistently high level of treatment-related mortality and ILD-specific toxicity was observed in primarily medically-inoperable patients treated with SABR, particle beam therapy and RFA. For these patients, curative treatment should be considered in the context of the high toxicity rates and overall poor prognosis. Stringent radiation dosimetric parameters may result in reduced toxicity.