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B A. A Alizadeh b Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties. B Conflicts of interests pertinent to the abstract b B D. M. Kurtz b Other remuneration: Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Genentech: Consultancy. B W. Wilson b Other remuneration: Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Syncopation: Current equity holder in private company, Patents & Royalties; Roche: Consultancy; Adaptive Biotechnologies: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties. [Extracted from the article]

Distinct molecular determinants of treatment-failure in elderly Hodgkin lymphoma identified by cell-free DNA profiling: A LYSA Study Interestingly, pre-treatment ctDNA levels did not differ between EBV+ and EBV- tumors ( I p i = 0.92), while specific genetic aberrations were significantly associated with respective EBV status (Figure C). Older HL pts, especially those with high baseline ctDNA levels and/or EBV+ tumors, have an exceedingly high risk of treatment failure with conventional chemotherapy, and likely require future risk-adapted strategies. [Extracted from the article]

We therefore developed a robust patient-derived lymphoma organoid (PDLO) system utilizing primary biopsies from FL patients and assessed response to bispecific T-cell mediated immunotherapy. Novel immunotherapies including bispecific T-cell engagers require an intact TME for immune effector function and cannot be modeled in traditional B-cell monocultures. B Conclusions: b FL PDLOs allow ex vivo modeling of T-cell mediated immunotherapies with B-cell killing, activated T-cell expansion, and T-cell exhaustion signatures. [Extracted from the article]

Atrial fibrillation (AF) has been associated with prior thoracic radiotherapy. However, AF risk after irradiation of specific cardiac substructures, namely the pulmonary veins (PVs), is still being characterized. We sought to investigate the relationship between PV irradiation and the development of clinically significant (grade≥3) AF (AFG≥3) and determine whether PV dose-volume cutoff values may predict for AFG≥3 risk. We conducted a retrospective study including serial patients who underwent definitive radiotherapy for localized cancers at a single academic institution from 2004-2022, with available dosimetric data. We calculated radiotherapy doses (mean, maximum dose [d max ], and absolute volume receiving ≥15 Gy [V15]) in 2 Gray (Gy) fraction equivalent dose to PVs and other cardiac substructures, including left atrium (LA), sinoatrial node (SAN), and left coronary arteries (LCA tot = left main+left anterior descending+left circumflex). AF incidence was calculated using Fine-Gray with univariable and multivariable analyses clustered by cancer type and adjusted for the competing risk of death to measure adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for AFG≥3 incidence. We used the validated "Mayo AF risk score" ([MAFRS] range, 0-12; greater risk with higher scores) to adjust for clinical factors known to predict for AF. We identified 539 patients with median follow-up time of 58.8 months (range, 0-120). Cancer types included 43% [ n = 230] non-small cell lung cancer, 32% [ n = 174] breast cancer, 22% [ n = 119] Hodgkin lymphoma, and 3% [ n = 16]) esophageal cancer. Baseline factors included a median age of 58 years, 40% male, 52% never-smokers, 59% MAFRS 0-1, 42% PV d max >20 Gy. 35 AFG≥3 events occurred at a median of 22.9 months (range, 0.3-120). AFG≥3 risk was greater among patients with higher PV d max (per Gy; aHR 1.02, 95% CI 1.01-1.03, P<0.001), higher V15 LCAtot (per cm3; aHR 1.14, 95% CI 1.06-1.23, P = 0.001), higher LA volume (per cm3; aHR 1.01, 95% CI 1.00-1.02, P = 0.02). Conversely, AFG≥3 risk was lower among patients with MAFRS 0-1 compared to ≥2 (aHR 0.47, 95% CI 0.23-0.96, P = 0.04) and greater LA d max (per Gy; aHR 0.99, 95% CI 0.98-0.99, P<0.001). The hazard ratio for PV d max remained comparably significant across baseline MAFRS groups (P interaction = 0.14). Higher SAN d max was not associated with AFG≥3 risk (HR 1.01, 95% CI 0.99-1.02, P = 0.36). Finally, in a spline analysis, patients with PV d max >20 Gy (among several potential local maxima identified) had significantly higher risk of AF even when stratified by MAFRS. Pulmonary vein d max , in addition to LCA tot dose, appear to be significant predictors of grade ≥3 AF — regardless of other underlying clinical risk factors. These findings provide new evidence to support the clinical relevance of these cardiac substructures with respect to radiation toxicity, and suggest that PV dose metrics may warrant further validation. [ABSTRACT FROM AUTHOR]

Several studies have noted an increase in the volume of lung tumors treated with stereotactic ablative radiotherapy (SABR) through the course of treatment. The prevalence of such changes and the effect on disease control have not been well studied. Tumor swelling could improve control through immune effects, or worsen it due to geographic miss of the radiotherapy. This is the first study investigating the association between inter-fraction volume changes during lung SABR and clinical outcomes. Patients with AJCC 7th ed. T1-2N0M0 non-small cell lung cancer (NSCLC), who had 4-5 fraction SABR from 4/2009-7/2019 were included in this retrospective study. A planning target volume (PTV) of 5mm was used with motion management as needed. Using cone-beam CT (CBCT) images obtained before each treatment, we contoured each tumor with a standardized procedure in commercially available software. Tumor volumes were assessed prior to initial, midway (third fraction), and last fraction. To explore the relationships between volumetric changes and baseline characteristics, univariable and multivariable linear regression was used. To assess relationship of volume change with outcomes, Fine-Gray models were used with outcomes of local, regional, and distant recurrence, with death as a competing risk. The analysis plan was specified prior to data collection. 121 patients were included. The median ratio of tumor volume at the middle of treatment to start of treatment (Start-Mid) was 1.18 (IQR 1.08, 1.27); the ratio of end of treatment to start (Start-End) was 1.15 (IQR 1.04, 1.28). There was a negative correlation between initial tumor volume and both Start-Mid and Start-End values (p = 0.004 and 0.005, respectively) on univariable analysis. Tumors treated with 50 Gy in 4 fractions (BED 10 112.5 Gy) exhibited larger Start-Mid values compared to those treated with 50 Gy in 5 fractions (BED 10 100 Gy, p = 0.038). Other examined characteristics had no significant correlation with inter-fraction tumor volume changes. Multivariable linear regression analysis reaffirmed a strong correlation between initial tumor volume and both Start-Mid and Start-End changes (p = 0.004 and 0.009, respectively). Fine-Gray models showed no significant correlation between tumor volume changes and local or regional recurrence but found a negative association between Start-Mid change and distant recurrence (p<0.001). Tumor volume often increases during lung SABR. This phenomenon did not appear to adversely affect locoregional control. Increased tumor volume was correlated with reduced distant recurrence, possibly representing an immune effect. Our findings suggest volume changes are likely a consequence of acute inflammatory reactions rather than tumor growth, and modest PTV expansions may be sufficient for tumor coverage. [ABSTRACT FROM AUTHOR]

Stereotactic ablative radiation therapy (SABR) leads to excellent local control in patients with primary or metastatic lung tumors. While there are multiple strategies for motion management in thoracic SABR, there is limited data to compare the efficacy of different approaches. We compared local tumor control by the extent of tumor motion and the motion management strategy for patients treated on the iSABR clinical trial. This is a secondary analysis of patients treated on the multicenter phase II iSABR clinical trial that utilized an individualized dosing strategy for patients with primary or metastatic lung tumors. We evaluated the extent of tumor motion on 4D CT and the motion management approach used during treatment (free breathing, breath hold [BH], or expiratory gating [EG]). For patients treated with free breathing or EG approaches, an internal target volume (ITV) was contoured based on tumor movement on the 4D CT. Patients were treated on a linear accelerator using Real-time Position Management (RPM) triggering. In-field local control rates were compared using the Kaplan-Meier method. In total, 62 patients with 63 tumors had available data on motion management. Fifteen patients (24.2%) underwent SABR with free breathing, 22 (35.5%) had BH (20 inspiratory, and 2 expiratory), and 26 (41.9%) had EG (24 amplitude based, and 2 phase based). 1-, and 2-year local control rates were 100% and 100% with free breathing, 94.7% and 83.2% with BH, and 90.7% and 78.6% with EG (p = 0.2), respectively. Overall, median maximal tumor motion was 10mm (3.5mm for tumors treated with free breathing vs 14.5mm for tumors treated with BH or EG). There was no association between local control and maximum extent of motion on 4D CT (HR = 1.01, p = 0.75). 1- and 2-year local control rates were 92.9% and 89.1% for tumors with maximal motion <10mm, and 96.3% and 82.5% for tumors with maximal motion >10mm (HR = 0.6, p = 0.53), respectively. Patients on the iSABR trial were treated with a range of motion management strategies including motion inclusive free breathing, BH and EG with no observed association between local control by treatment approach. The similar local control rates between mobile and non-mobile tumors suggests that the RPM approach used on the iSABR trial was effective. Our results will be further analyzed pending motion management data collection for the entire iSABR cohort. [ABSTRACT FROM AUTHOR]

For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects, or address the most threatening tumors while the immunotherapy provides benefit for the remaining disease. In the Radical RADiotherapy and Immunotherapy for metastatic Cancer of the Lung (RRADICAL) trial (NCT03176173), we posited that the addition of high-dose RT to ICI therapy could prolong progression-free survival (PFS). In this non-randomized single arm phase 2 trial, 45 patients with metastatic NSCLC who received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017 to May 2021. Imaging after initiation of ICI had to show partial response or stable disease (per RECIST version 1.1) or modest progression (per investigator). Patients received high-dose RT to 1-4 extracranial tumors and continued the ICI until disease progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks from enrollment, comparing to a historical control rate of 35%. Secondary endpoints included toxicity, overall survival (OS), and local control. The exact binomial and log-rank tests were used. Of 44 evaluable patients, median age was 71 years, 75% had adenocarcinoma, 64% were poly-metastatic, and 82% were on pembrolizumab. Of 81 treated tumors, the most common dose received was 40 Gray in 10 fractions (n = 41). Forty-six percent of patients had one tumor treated; the most common treatment site was lung. All visible tumors were treated in 21 (48%) patients. Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI = 44-75%), higher than the historical control rate (P < 0.001). Median time from enrollment to last dose of the same immunotherapy drug was 6.1 months (IQR = 2.7-12.8 mo). Median PFS was 6.9 months (95% CI = 4.0-13.5 mo) and median OS was 27.4 months (95% CI = 20.4-not reached). Several patients with pre-study disease progression on ICI treatment alone achieved durable responses with addition of radiotherapy, up to 56 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. Adding high-dose radiotherapy to immunotherapy in metastatic NSCLC improved 24-week PFS compared to historical controls receiving ICI therapy alone, indicating that this is a promising strategy for further study. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease in this setting. However, many patients progressed in other non-radiated sites soon after study RT, highlighting the need for better biomarkers for patient selection for aggressive local therapy. [ABSTRACT FROM AUTHOR]

Trimodality therapy with chemoradiation (CRT) followed by esophagectomy is the standard of care for locally advanced esophageal cancer. An unresolved question is whether pathologic complete response (pCR) can be assessed non-invasively for patients post-CRT. In this study, we assessed whether diffusion-weighted imaging (DWI) with MRI or PET can be used as predictors of pCR and other clinical outcomes after CRT. Patients were enrolled on a single-arm institutional trial (PA13-0380) assessing the role of imaging in predicting outcomes in potentially resectable esophageal patients undergoing trimodality therapy. All patients received neoadjuvant CRT, and 29 patients had subsequent surgery. DWI MRI and PET scans were obtained at baseline, 2 weeks after the start of CRT (interim) and 4 to 6 weeks after completion of CRT (follow up). Apparent diffusion coefficients (ADCs) were calculated based on DWI images. Circulating tumor DNA was obtained for 27 patients post-radiation using CAPP-Seq. Mann-Whitney tests compared imaging changes associated with pCR. Discrimination of pCR by imaging changes was quantified by received operating characteristics. Youden's index was applied to select optimal thresholds. Kaplan-Meier analysis was performed to assess differences in overall survival (OS) and progression-free survival (PFS) by changes in DWI, PET, and ctDNA parameters. Our cohort of 60 patients had a median follow up of 42.7 months, age of 65.4 yrs, and ECOG of 1 at completion of CRT. 90% were male, 58% had a history of smoking, and 85% were white. 83% had adenocarcinoma with the rest squamous cell carcinoma. Stages of the patients ranged from IIA to IIIB. All had moderately (47%) or poorly (53%) differentiated disease. All received 41.4-50.4 Gy in 1.8 Gy fractions with the majority receiving 50.4 Gy (95%). 29 patients underwent surgery after CRT of which 8 (27.6%) had pCR. Mean ΔADC from baseline to mid-treatment was most associated with pCR (AUC = 0.98, p<0.001) for patients undergoing surgery. Max ΔADC from baseline to first follow-up was most associated with OS (p = 0.002) and PFS (p<0.001) for the whole cohort. 27 patients had ctDNA analyzed after RT with the presence of ctDNA significantly associated with worse OS (HR = 0.12, p = 0.05) and PFS (HR = 0.10, p = 0.002). Combining ctDNA and max ΔADC generated a model that was more predictive of OS and PFS than either alone. We found that neither the PET parameters of TLG or SUV max at baseline or changes in these parameters from baseline to mid-treatment or first follow-up were as predictive as DWI. We show that changes in DWI is associated with pCR, OS, and PFS in resectable esophageal cancer patients undergoing CRT. DWI was more predictive than PET and a model combining DWI and ctDNA was the most predictive of clinical outcomes. This study shows the significant promise of using DWI in potentially guiding treatment decisions in esophageal cancer patients and will require validation in a larger cohort. [ABSTRACT FROM AUTHOR]

For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation. We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)—determined by treating physician and/or multidisciplinary tumor board—and overall survival (OS). Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations. Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients. [ABSTRACT FROM AUTHOR]

Over 500 clinical trials combining radiation (RT) and immune checkpoint blockade (ICB) have been initiated based on preclinical evidence that RT can augment local immunity and improve the efficacy of ICB. However, many recent clinical trials have not found a benefit of combining RT and ICB, raising questions about whether a synergy exists. We examined whether RT and ICB interact to beneficially stimulate the immune response in patients and identified biomarkers of response to RT and ICB. We performed a molecular analysis of 1,740 patients from 3 cohorts. The COSINR dataset is a randomized clinical trial of 22 non-small cell lung cancer (NSCLC) patients treated with concurrent or sequential SBRT and ipilimumab/nivolumab. Paired pre- and on-treatment biopsies of an irradiated metastasis underwent whole exome sequencing and RNA-seq. On-treatment biopsies were obtained after SBRT and prior to ICB (sequential) or after SBRT and one cycle of ICB (concurrent). The UC cohort consisted of targeted DNA sequencing of 58 NSCLC patients treated with ICB alone, sequential RT+ICB, or concurrent RT+ICB. The MSKCC dataset is a pan-cancer cohort of targeted DNA sequencing of 1,660 patients treated with ICB. Aneuploidy score (AS) was defined as the fraction of chromosome arms with arm-level copy number alterations. Survival analyses utilized the Kaplan-Meier method and multivariable Cox proportional hazards models. In the COSINR trial, SBRT+ICB increased, whereas SBRT alone decreased, expression of effector T cell IFN-gamma and adaptive immune signatures (P <0.05). Established biomarkers of ICB response, including IFN-gamma signature, tumor mutational burden (TMB), PD-L1 expression, and neoantigen burden were not associated with survival (P >0.05). However, patients whose tumors exhibited high (≥median) but not low, AS had improved survival when treated with concurrent vs. sequential SBRT+ICB (1-year overall survival [OS] 100% vs. 17%, P = 0.025). Our findings were corroborated in the UC cohort: high AS tumors treated with RT + ICB had superior 1-year OS compared to those treated with ICB alone (59% vs. 31%, P = 0.021). Among those who received RT + ICB, concurrent treatment improved OS relative to sequential (1-year OS 76% vs. 38%). RT did not improve OS in patients with low (

Minimizing cardiac toxicity after thoracic radiation therapy (RT) remains a clinical challenge. Mean heart dose is associated with major adverse cardiac events (MACE) and recent studies suggest RT dose to coronary arteries may better quantify risk after conformal RT. Prior studies have not evaluated RT dose to individual coronary arteries in risk modeling. We therefore sought to develop an integrated dosimetric model accounting for RT doses received by each coronary artery. We performed a retrospective study of a randomly selected representative cohort of patients with locally advanced non-small cell lung cancer. We scored cardiac events as (1) ischemic, (2) constrictive, (3) valvular, or (4) conductive. We contoured and measured doses received by the left circumflex (LCX), left anterior descending (LAD), left main coronary (LMCA), and right coronary arteries (RCA). RT doses were measured as equivalent dose in 2-Gray (Gy) fractions. Dosimetric parameters associated with cardiac toxicity were examined using cumulative incidence, competing risk regression models, receiver operator characteristic (ROC), and log-rank statistics with significance defined as two-tailed P <0.05. We identified 100 patients who received definitive RT (median=66 Gy, range=60-74 Gy) from 2006-2020. Median follow-up was 4.1 years (range, 0-11.0). Median age was 70 years (range, 38-84). Half the cohort was male (50%), a majority had smoking history (81%), and all received chemotherapy (100%). Thirty (30%) experienced MACE at a median of 13 months post-RT. Most events were ischemic (n=17, 57%) or conductive (n=13, 43%), with only 3 cases (10%) of valvular disease. Mean heart, LCX, LAD, and LMCA doses were predictive of cardiac toxicity (AUC=0.59, 0.58, 0.59, and 0.63, respectively) and were each significantly associated with MACE on univariable analysis (P <0.05). For patients with full labs available, 10-year atherosclerotic cardiovascular disease (ASCVD) risk was also associated with MACE (HR=1.31, P =0.04). Chemotherapy, age, diabetes, hypertension, prior cardiac event, and mean RCA dose were not associated with MACE. Using the log-rank statistic, we identified threshold mean doses of 1.82, 12.71, 15.45, and 31.29 Gy for the heart, LCX, LAD, and LMCA, respectively. Patients exceeding all three threshold doses to the LCX, LAD, and LMCA had a two-year rate of MACE of 57.1% versus 15.9% (P =0.005). On multivariable analysis after adjusting for ASCVD, patients exceeding all identified doses to the LCX, LAD, and LMCA were at nearly 5 times the risk of MACE (HR=4.76, P =0.0005). Our results suggest that patients receiving doses above our identified thresholds to all of the left coronary arteries (LCX, LAD, and LMCA) are at highest risk of MACE. If validated, our findings may inform RT treatment planning, where sparing of at least one vessel may lead to lower risk of MACE. [ABSTRACT FROM AUTHOR]

Recent randomized trials have supported the existence of a limited metastatic disease state that may benefit from definitive local therapy in patients with non-small cell lung cancer (NSCLC). Due to limits of current staging systems, it is not possible to evaluate the spectrum of metastatic disease with commonly used cancer registries. The purpose of this study is to evaluate the extent and burden of metastatic disease in NSCLC patients presenting to an academic medical center and determine the incidence of patients meet existing criteria for 'oligometastatic' disease. An observational cohort of patients with de novo or recurrent metastatic NSCLC diagnosed from 2016 to 2019 were randomly sampled from a tumor registry. Patients were excluded if they did not receive any tumor directed therapy. Baseline demographic, staging, and treatment data were obtained from the registry and structured electronic health record (EHR) data. Manual chart review was performed to obtain details on metastatic presentation, local therapy, and progression. Definitions for oligometastatic disease were obtained from NRG LU002, MDACC Gomez et al., SINDAS and SABR COMET clinical trials. One hundred eight patients were evaluated with a median age of 68 years (range, 22 – 92) at initial diagnosis and median follow up of 23.5 months. 75% of patients (n=81) presented with de novo metastatic disease, while 25% (n=27) presented with recurrence. Histologies included adenocarcinoma (66%, n=71), squamous cell carcinoma (9%, n=10), and 'other' (20%, n=22). Targetable mutations were present in 31% (n=34) of patients including EGFR (n=27) and ALK (n=2) and MET (n=6). 41% (n=48) of patients had a suspected malignant effusion present at the time of diagnosis. Common sites of metastases included lymph nodes (n=85, 79%), lungs (n=60, 56%), brain (n=49, 45%), and bone (n=48, 44%). 19% (n=21) presented with only one total metastatic tumor, 29% (n=31) with 2-3, 17% (n=18) with 4-5, 19% (n=21) with 6-10, and 16% (n=17) with 10+ tumors. 28% (n=30) of all patients were eligible for at least one oligometastatic NSCLC clinical trial, with 16% meeting eligibility for LU-002 (n=17), 19% for MDACC (n=22), 16% for SABR COMET (n=17), and 5% for SINDAS (n=5). Among those that met trial criteria for oligometastatic disease 40% (n=12) were treated with local therapy including surgery or radiation. Most patients presenting with metastatic NSCLC to our institution had initial de novo metastatic presentation, multi-organ involvement, and adenocarcinoma histology. Roughly one third of patients were classified as oligometastatic using existing trial criteria. A minority of oligometastatic patients were treated with local therapy after metastatic diagnosis during the study period. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): 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).Materials/methods: 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.Results: 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.Conclusion: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.Materials/methods: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.Results: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).Conclusion: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.Materials/methods: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.Results: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.Conclusion: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Hemoptysis is a rare but potentially fatal toxicity associated with thoracic stereotactic ablative radiotherapy (SABR). Prior studies have suggested that vascular endothelial growth factor inhibitors (VEGFI) may potentiate the risk for pulmonary hemorrhage in patients treated with SABR for centrally located lung tumors. To what degree the risk of toxicity varies by timing of therapies or tumor location is uncertain. The purpose of this study is to evaluate the combined toxicity of VEGFIs and SABR for peripheral, central, or ultra-central tumors.Materials/methods: We evaluated patients with primary or metastatic lung tumors treated with SABR between 2008 and 2018 at a single institution. Baseline patient, tumor and treatment characteristics were evaluated. Pulmonary bleeding events were graded using CTCAE version 5.0. Rates of a grade three or higher (G3+) or any ipsilateral pulmonary hemorrhage at three years were estimated using the Kaplan-Meier method. We compared rates of bleeding by tumor location, treatment with a VEGFI, sequence of therapy and VEGFI within 90 days of SABR using the log-rank test.Results: This retrospective cohort study included a total of 925 pulmonary tumors treated with SABR in 691 patients. There were 44 patients treated with a VEGFI (bevacizumab, sorafenib, pazopanib, sunitinib or ramucirumab), with the majority receiving bevacizumab (n = 38, 86.3%). Among those treated with a VEGFI, the median interval between VEGFI therapy and SABR was 16 weeks, ranging from zero days to 3.7 years, with 15 (34.0%) patients treated within 90 days of SABR. Patients were treated with SABR to peripheral (738, 79.8%), central (137, 14.8%) and ultra-central (50, 5.4%) locations with a median BED10 of 87.5 Gy. Median follow-up was 32.2 months for the overall cohort and 46.4 months for VEGFI patients. The rate of G3+ hemorrhage was significantly higher in patients treated with a VEGFI (7.3 vs 0.8%, P < 0.01). The rate of any grade hemorrhage did not significantly vary between groups (9.4 vs 2.7%, P = 0.1). When stratified by location, both central/ultra-central tumors (21.1 vs 3.2%, P = 0.03) and peripheral tumors (3.4 vs 0.1%, P = 0.03) had increased rates of G3+ hemorrhage when treated with a VEGFI. Among patients treated with SABR and VEGFI, there was no significant difference in rates of hemorrhage when the interval was > or ≤ 90 days (12.0 vs 0.0%, P = 0.17). Similarly, there was no significant difference between rates of G3+ hemorrhage when VEGFI was given before (12.9%), after (8.3%), or before and after SABR (0.0%).Conclusion: VEGFI therapy was associated with an increased rate of high-grade hemorrhage in patients undergoing SABR to pulmonary tumors. Rates of high-grade hemorrhage were increased with VEGFI for both central/ultra-central and peripheral tumors although the absolute rate was low for peripheral tumors. While limited by low sample size and event rate, there was no correlation observed between interval or sequence of VEGFI and SABR and rate of high-grade hemorrhage. [ABSTRACT FROM AUTHOR]