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Purpose: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis.Experimental Design: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro.Results: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients.Conclusions: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. Clin Cancer Res; 19(19); 5423–33. ©2013 AACR.

PDF file, 34K, Supplementary Table 1. Clinical demographic information of 43 lung ADC cases. NAT is normal adjacent tissue. Supplementary Table 2. Clinical demographic information of lung adenocarcinoma TCGA patients. Supplementary Table 3. IPA analysis for the downstream targets for miR-31. Supplementary Table 4. Genetic alteration overview of the cell lines used in this study. Supplementary Table 5. Correlation coefficient between EMT-related genes and miR-31 expression.

Supporting Figure S1 to S14 Legends

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients.Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome.Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients.Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis. Clin Cancer Res; 24(21); 5282–91. ©2018 AACR.

Supporting Figures Figure S1. Extracellular and intracellular metabolites of commercially available and patient derived GBM cells and NHAs Figure S2. Total and extracted ion chromatograms of intracellular metabolites Figure S3. Total and extracted ion chromatograms of extracellular metabolites Figure S4. Targeted analysis MS/MS product ion spectrum of methionine Figure S5. Targeted analysis MS/MS product ion spectrum of tryptophan Figure S6. Targeted analysis MS/MS product ion spectrum of kynurenine Figure S7. Targeted analysis MS/MS product ion spectrum of MTA Figure S8. Total ion chromatogram and multiple reaction monitoring of different concentrations of methionine Figure S9. Total ion chromatogram and multiple reaction monitoring of different concentrations of kynurenine Figure S10. Key metabolites in methionine pathway Figure S11. Calibration Curve and Multiple Reaction Monitoring of SAM and SAH Figure S12. Key metabolites in tryptophan pathway Figure S13. Insilico analysis - Connecting metabolome and proteome in GBM cells Figure S14. Densitometric quantification of the chemiluminescence signals

Characteristics and tumor features in four cases with IDH-mutant/TERTp-mutant gliomas (oligodendrogliomas).

PDF file, 450K, Supplementary Figure 1. The length distribution of reads for ten miR-seq samples Supplementary Figure 2. Flow diagram illustrating microRNA quantification techniques used and sample sizes of each step of the analysis. NAT: normal adjacent tissue. Supplemental Figure 3. Identification of differentially expressed miRNAs between N0 and N1+ groups of patients. Supplementary Figure 4. The receiver operator characteristic (ROC) curve as well as area under curve (AUC) was determined using CART. The results show that AUC is 0.79 in 43 lung ADC samples (cohort 1 +2). Supplementary Figure 5. Higher miR-31 expression is associated with adverse outcome in T2N0 patients (n=75, log-rank p=0.0194) Supplementary Figure 6. IPA showing the top five canonical pathways for miR-31 target genes is the CDK5 (A), PTEN (B), p70S6K (C) , ERK/MAPK (D) and PI3K/AKT (E)signaling. Supplementary Figure 7. Ectopic expression of miR-31 increases migration/invasion capabilities of H2228 cells. (A) Expression of miR-31 following infection with Lenti-miR vector containing miR-31 precursor was confirmed by TaqMan real-time PCR. (B) Cell invasion assay for miR-31 overexpressing H2228 cells. (C) Cell migration assay for miR-31 overexpressing H2228 cells using transwell membranes (upper panel, representative pictures of migration chambers; bottom panel, average counts from 10 random microscopic fields). The average counts were derived from ten random microscopic fields. (D) Cell proliferation assay for miR-31 overexpressing H2228 cells. Data are presented as mean plus-minus S.D. *P

Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies.Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes.Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A.Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513–23. ©2016 AACR.

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Using a non-targeted isotope-assisted metabolomics approach, we identified erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We provide data supporting a possible alternative route to erythronate production involving the dephosphorylation of the pentose phosphate pathway intermediate erythrose-4-phosphate to form erythrose, followed by the oxidation of erythrose by an aldehyde dehydrogenase. Finally, we detected increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated level of erythronate may serve as a biomarker of certain types of cancer.

Background Thoracic vascular structures often preclude transbronchial access to central lung parenchymal lesions and lymph nodes, thereby necessitating either a surgical or transvascular needle aspiration (TVNA) approach for diagnostic sampling. The aim of this study was to evaluate the safety and efficacy of endobronchial ultrasound (EBUS) TVNA in the diagnosis and staging of mediastinal tumors. Patients and Methods We performed a retrospective analysis of 35 cases of EBUS-TVNA. Cases were reviewed in the Cerner electronic medical records between March 2013 and October 2018. Records were reviewed for patient comorbidities, smoking status, anticoagulation intake, procedural details, sample results, and postprocedural complications. Results Thirty-five EBUS-TVNA procedures were reviewed. Twenty-nine of them were performed by traversing the main pulmonary artery or its branches. Three involved transvascular access through the azygous vein, 2 via the brachiocephalic artery and 1 through the superior vena cava. Only 4 patients (11.4%) experienced postprocedural complications, which included mild hemoptysis, moderate hemoptysis requiring epinephrine and saline infusion, acute exacerbation of chronic obstructive pulmonary disease, and a rapid ventricular rate on top of preexisting atrial fibrillation. The yield of TVNA for malignancy was 22 (95.6%) of 23 patients. Overall yield was 31 (88.6%) of 35, with a need for additional intervention in 4 (11.4%) of 35 patients. Mutational analysis was adequate when ordered. Conclusion In our single-center experience, the EBUS-TVNA procedure had a high diagnostic yield and was associated with low rates of postprocedural complications. Further trials are needed to assess its efficacy compared to more invasive procedures.

Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients.Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs.A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively.Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity.

The treatment of brain metastases with stereotactic radiosurgery (SRS) in combination with immune checkpoint inhibitors (ICI) has become more common in recent years, but there is a lack of prospective data on cancer control outcomes when these therapies are administered concurrently.Data were retrospectively reviewed for patients with non-small cell lung cancer (NSCLC) and melanoma brain metastases treated with SRS at a single institution from May 2008 to January 2017. A parametric proportional hazard model is used to detect the effect of concurrent ICI within 30, 60, or 90 days of ICI administration on local control and distant in-brain control. Other patient and lesion characteristics are treated as covariates and adjusted in the regression. A frailty term is added in the baseline hazard to capture the within-patient correlation.We identified 144 patients with 477 total lesions, including 95 NSCLC patients (66.0%), and 49 (34.0%) melanoma patients. On multivariate analysis, concurrent SRS and ICI (SRS within 30 days of ICI administration) was not associated with local control but was associated with distant brain control. When controlling for prior treatment to lesion, number of lesions, and presence of extracranial metastases, patients receiving this combination had a statistically significant decrease in distant brain failure compared to patients that received non-concurrent ICI or no ICI (HR 0.15; 95% CI 0.05-0.47, p = 0.0011).Concurrent ICI can enhance the efficacy of SRS. Prospective studies would allow for stronger evidence to support the impact of concurrent SRS and ICI on disease outcomes.

Aim: To identify demographic predictors of patients who miss oncology follow-up, considering that missed follow-up has not been well studies in cancer patients. Methods: Patients with solid tumors diagnosed from 2007 to 2016 were analyzed (n = 16,080). Univariate and multivariable logistic regression models were constructed to examine predictors of missed follow-up. Results: Our study revealed that 21.2% of patients missed ≥1 follow-up appointment. African–American race (odds ratio [OR] 1.33; 95% CI: 1.17–1.51), Medicaid insurance (OR 1.59; 1.36–1.87), no insurance (OR 1.66; 1.32–2.10) and rural residence (OR 1.78; 1.49–2.13) were associated with missed follow-up. Conclusion: Many cancer patients miss follow-up, and inadequate follow-up may influence cancer outcomes. Further research is needed on how to address disparities in follow-up care in high-risk patients.

Introduction Up to 20% of patients with brain metastases treated with immune checkpoint inhibitor (ICI) therapy and concomitant stereotactic radiosurgery (SRS) suffer from symptomatic radiation necrosis. The goal of this study is to evaluate Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) on six-month symptomatic radiation necrosis rates. Methods This study is a prospective single arm Phase I pilot study which will recruit patients with brain metastases receiving ICI delivered within 30 days before SRS. All patients will be treated with RADREMI dosing, which involves SRS doses of 18 Gy for 0−2 cm lesions, 14 Gy for 2.1−3 cm lesions, and 12 Gy for 3.1−4 cm lesions. All patients will be monitored for six-month symptomatic radiation necrosis (defined as a six-month rate of clinical symptomatology requiring steroid administration and/or operative intervention concomitant with imaging findings consistent with radiation necrosis) and six-month local control. We expect that RADREMI dosing will significantly reduce the symptomatic radiation necrosis rate of concomitant SRS + ICI without significantly sacrificing the local control obtained by the present RTOG 90−05 SRS dosing schema. Local control will be defined according to the Response Assessment in Neuro-Oncology (RANO) criteria. Discussion This study is the first prospective trial to investigate the safety of dose-reduced SRS in treatment of brain metastases with concomitant ICI. The findings should provide fertile soil for future multi-institutional collaborative efficacy trials of RADREMI dosing for this patient population. Trial Registration Clinicaltrials.gov identifier: NCT04047602 (registration date: July 25, 2019).

Motivation: Receiving radiation to the heart has been recognized as a risk factor for the development of major adverse cardiovascular events (MACEs) for many years. However, recent data suggests that radiation dosing to substructures of the heart serve as a better surrogate for evaluating the risk of developing a MACE than whole heart radiation dose. Recent papers suggest that dosing to the left anterior descending artery (LAD) can be used as a robust marker for cardiotoxicity risk; however, this association lacks corroborative data and is currently not incorporated into clinically routine care. Problem: In this paper we seek to investigate the relationship between radiation dose to the LAD and risk of developing a MACE in lung cancer patients treated with curative intent radiation. Approach: Chart review to confirm the presence of MACE events was performed in patients who were identified based on elevated troponin values to potentially have had a MACE after receiving their last dose of radiation therapy. Patients who had multiple courses of radiation therapy separated in time (>60 days) that received greater than 0.2 Gy whole heart dose during their subsequent courses before having a MACE were excluded. Selected patients were then stratified based on presence cardiovascular co-morbidities. Contours of patient’s LADs were made after patient selection, and will be verified by an expert (e.g., cardiologist or thoracic radiologist). Results: Dose to the LAD will be calculated and an assessment of the correlation between radiation dose and risk of having a MACE will be made. Analysis will assess the cardiac event rate at various times as well as time to MACE. Implications: This paper can help set a quantifiable standard with which radiation oncologists can use to minimize their patient’s risk of developing a MACE by minimizing radiation dosing to specific cardiac substructures while maintaining tumor coverage.

Purpose:Transforming growth factor-β1 (TGF-β1), a known immune suppressor, plays an important role in tumor progression and overall survival (OS) in many types of cancers. We hypothesized that genetic variations of single nucleotide polymorphisms (SNPs) in the TGF-β1 pathway can predict survival in patients with non-small cell lung cancer (NSCLC) after radiation therapy.Materials and Methods:Fourteen functional SNPs in the TGF-β1 pathway were measured in 166 patients with NSCLC enrolled in a multi-center clinical trial. Clinical factors, including age, gender, ethnicity, smoking status, stage group, histology, Karnofsky Performance Status, equivalent dose at 2 Gy fractions (EQD2), and the use of chemotherapy, were first tested under the univariate Cox's proportional hazards model. All significant clinical predictors were combined as a group of predictors named “Clinical.” The significant SNPs under the Cox proportional hazards model were combined as a group of predictors named “SNP.” The predictive powers of models using Clinical and Clinical + SNP were compared with the cross-validation concordance index (C-index) of random forest models.Results:Age, gender, stage group, smoking, histology, and EQD2 were identified as significant clinical predictors: Clinical. Among 14 SNPs, BMP2:rs235756 (HR = 0.63; 95% CI:0.42–0.93;p= 0.022), SMAD9:rs7333607 (HR = 2.79; 95% CI 1.22–6.41;p= 0.015), SMAD3:rs12102171 (HR = 0.68; 95% CI: 0.46–1.00;p= 0.050), and SMAD4: rs12456284 (HR = 0.63; 95% CI: 0.43–0.92;p= 0.016) were identified as powerful predictors of SNP. After adding SNP, the C-index of the model increased from 84.1 to 87.6% at 24 months and from 79.4 to 84.4% at 36 months.Conclusion:Genetic variations in the TGF-β1 pathway have the potential to improve the prediction accuracy for OS in patients with NSCLC.

Introduction Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a very rare disease, comprising approximately 3% of lung cancers. Even for Stage I disease, recurrence after resection is common, with a poor five-year overall survival. We present the first report of stereotactic body radiotherapy (SBRT) for pulmonary LCNEC. Methods A 54-year-old woman with a left upper lobe pulmonary nodule underwent a wedge resection with thoracoscopic mediastinal lymph node dissection, revealing a 2.3 cm pT1b N0 LCNEC. Approximately one year later, surveillance imaging demonstrated a new left upper lobe PET-avid nodule, resulting in completion left upper lobectomy revealing LCNEC, with 0/6 involved lymph nodes and negative staging studies. The patient subsequently chose surveillance over adjuvant chemotherapy; unfortunately 23 months later imaging revealed an enlarging 0.7 cm nodule adjacent to the previous resection site, despite the patient remaining in good health (KPS = 90). Subsequent restaging demonstrated no evidence of metastatic disease. Due to the morbidity of a third operation in this region, and based on the safety of SBRT for Stage I non small-cell lung cancer, the consensus decision from our thoracic oncology team was to proceed with SBRT as preferred management for presumptive second recurrence of LCNEC. The patient shortly thereafter underwent SBRT (50 Gy in 10 Gy/fraction) to this new nodule, 41 months following initial LCNEC diagnosis. Results Four months following SBRT, the patient remains in excellent clinical condition (KPS 90), with no evidence of disease spread on surveillance studies. The nodule itself demonstrated no evidence of growth following SBRT. Conclusions This first report of SBRT for pulmonary LCNEC demonstrates that SBRT is a feasible modality for this rare disease. A multidisciplinary thoracic oncology approach involving medical oncology, thoracic surgery, radiation oncology and pulmonology is strongly recommended to ensure proper patient selection for receipt of SBRT.

2013 Background: Symptomatic radiation necrosis rates in patients treated with immune checkpoint inhibitor (ICI) therapy and concomitant single-fraction stereotactic radiosurgery (SRS) are as high as 20% (PMID: 29327059). We present updated results from the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) trial following completion of an a priori interim analysis, aimed to identify reduced-dose SRS that is safe and efficacious for this patient population. Methods: RADREMI (clinicaltrials.gov, NCT04047602) is a prospective multicenter single arm Phase I trial involving patients age > 18 receiving ICI with SRS for 1-10 brain metastases on MRI. Patients had biopsy-confirmed primary malignancy with disease-specific graded prognostic assessment estimated median survival of at least 6 months and no previous whole brain radiation therapy. Six-month symptomatic radiation necrosis (radiographic radiation necrosis + clinical symptoms requiring steroid administration and/or operative intervention) was the primary endpoint, based on an expected rate of 5% and a historical rate of 16%. Secondary endpoints included 6-month local control and radiographic radiation necrosis. Response Assessment in Neuro-Oncology criteria defined local control; findings were compared to historical 6-month local control of 87-91% with RTOG 90-05 SRS dosing. A pre-determined interim futility analysis (based on the null hypothesis of no fewer than 15 of the first 20 patients reaching the primary endpoint achieving 6-month local control for RADREMI dosing) was performed using the Fisher’s exact test. Results: Between December 18, 2019 and September 10, 2021, 43 lesions were treated in 16 patients receiving ICI delivered within 30 days before SRS who were enrolled on trial and met the primary endpoint (median follow-up = 9.1 months). All patients received RADREMI SRS dosing (18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm). The most common ICI used was single-agent pembrolizumab (51% of lesions, 56% of patients), followed by single-agent nivolumab (28% of lesions, 13% of patients). The six-month rates of symptomatic and radiographic radiation necrosis were zero; the six-month local control rate was 98% per treated lesion (42/43), and 94% per treated patient (15/16), comparable to historical controls (p > 0.05) and sufficient to not reject the interim futility analysis null hypothesis. Conclusions: Interim analysis reveals that the safety and efficacy of RADREMI dosing for reducing SRS dose in brain metastasis patients receiving concomitant ICI persists with excellent local control and no morbidity in a multi-institutional collaborative trial. Further results following completion of trial enrollment will provide additional evidence regarding the safety and efficacy of RADREMI SRS dosing. Clinical trial information: NCT04047602.

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome. Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis. Clin Cancer Res; 24(21); 5282–91. ©2018 AACR.

Background: Current guidelines recommend chemotherapy (CT) with or without radiotherapy (RT) for unresected intrahepatic cholangiocarcinoma (IC). Although there is currently lack of consensus, previous smaller studies have illustrated the efficacy of local therapy for this population. This investigation evaluated outcomes of chemoradiotherapy (CRT) versus CT alone in unresected IC using a large, contemporary national database. Methods: The National Cancer Data Base (NCDB) was queried for primary IC cases (2004–2013) receiving CT alone or CRT. Patients undergoing resection or not receiving CT were excluded, as were those with M1 disease or unknown M classification. Logistic regression analysis ascertained factors associated with CRT administration. Kaplan-Meier analysis evaluated overall survival (OS) between both groups. Cox proportional hazards modeling assessed variables associated with OS. Results: In total, 2,842 patients were analyzed [n=666 (23%) CRT, n=2,176 (77%) CT]. CRT was less likely delivered at community centers, in more recent time periods (2009–2013), to older patients, and in certain geographic locations. Median OS in the CRT and CT groups were 13.6 vs . 10.5 months, respectively (P Conclusions: As compared to CT alone, CRT was independently associated with improved survival in unresected IC. These findings support a randomized trial evaluating this question that is currently accruing.

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01–2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14–22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8–45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14–22 Gy) to brainstem metastases.

PURPOSE/OBJECTIVE(S) Although the effects of effective radiation dose to the immune cells (EDRIC) in advanced stage non-small cell lung cancer (NSCLC) on overall survival (OS) and progression free survival (PFS) have been studied, no other study has shown its impact in early-stage NSCLC. In this retrospective cohort, we evaluated the role of EDRIC in this population. MATERIALS/METHODS The study cohort was generated using the cancer registry data including patients with early-stage NSCLC (T1-2, N0) who received stereotactic body radiation therapy (SBRT) in our institute since 2007. Patient were excluded if the dosimetric data were not available. EDRIC was calculated as a function of the number of radiation fractions and mean doses to the lung, heart, and the remaining body. Failure was defined as any type of failure including in-field, out-field, nodal and distant metastases. Variables that were included in the univariate and multivariate analysis were age, sex, positron emission tomography (PET) scan at diagnosis, Karnofsky Performance Status (KPS), Charlson Comorbidity Index (CCI), smoking history, histology, tumor location (central versus peripheral), TNM stage, Gross Tumor Volume (GTV) size, BED and EDRIC. RESULTS 148 patients were included. 55% are female with a median age of 73 years. 23% had central lesions. 97% had diagnostic PET scan and all were treated with a mean dose of 50 Gy and Biological Effective Dose (BED) above 100 Gy. With a median follow up of 29 months, 34% of patients developed failure. The 2-year OS was 54%. In multivariate analysis, higher EDRIC (HR: 2.04) and lower KPS (HR: 0.35) continued to be associated with worse OS (P = 0.02 and P = 0.008). Considering each EDRIC quartile, there was a statistically significant difference in OS between 1st and 4th and 1st and 3rd quartile (P = 0.01, P = 0.02). The median OS in each quartile is as followed: not reached, 47, 21, 21 months. There was no association between EDRIC and PFS. However, in multivariate analysis, KPS was associated with any type of failure (HR: 0.12, P = 0.013) CONCLUSION: This study showed that EDRIC can affect OS in patients with early staged NSCLC treated with SBRT. However, it does not affect PFS and any type of failure after receiving SBRT.

PURPOSE/OBJECTIVE(S) We aimed to evaluate the safety of and maximum tolerated dose (MTD) for 5-fraction stereotactic ablative radiotherapy (SABR) for early-stage lung squamous cell carcinoma (SCC), for which local failure rates appears higher than that of early-stage adenocarcinomas. MATERIALS/METHODS A single institution phase I study was conducted in pathologically confirmed early-stage lung SCC. The 3+3 design involved 4 dose levels of 11, 12, 13, and 14 Gy x 5 fractions delivered every other day (dose levels DL1, DL2, DL3, and DL4, respectively). The primary objective was to determine the MTD of 5-fraction SABR, which was defined as the dose associated with a 33% rate of dose-limiting toxicities, defined as grade ≥3 respiratory/mediastinal or cardiac events (or grade ≥4 gastrointestinal or chest wall events), with toxicities reported until data lock in October 2020. Target volume delineation and organ-at-risk (OAR) constraints were based on RTOG 0813, using OAR constraints expressed in percent of prescription as fixed constraints from the 11 Gy per fraction prescription for all DL. Institutional constraints for the chest wall were used (V30 < 30cm3, up to 70 cm3 acceptable; maximum point dose 52.5 Gy). Target coverage objectives included ≥95% of the planning target volume (PTV) to be covered by 100% of the prescription dose, and 100% of the internal target volume (ITV) to receive ≥110% of the prescription dose. For technically challenging cases, it was permitted to prescribe as low as 50 Gy (BED of 100 Gy10) to a small portion of the GTV, ITV (if used) and corresponding PTV adjacent to a critical OAR (split target volume prescription). SABR was delivered using free breathing, deep inspiration breathhold, or expiratory gating. Thus, ITVs were not used for all patients. RESULTS From October 2017 to June 2020, 13 patients were enrolled: 3 in DL1, 3 in DL2, 4 in DL3, and 3 in DL4. Seven (IASLC definition) or 6 (RTOG) patients had central lesions, and the rest abutted the chest wall. All patients completed SABR per protocol without major deviations. At 18.4 months median follow-up (range, 2.4-25.6 months), no patient developed dose limiting toxicities. There were no grade 4-5 events and 1 grade 3 event (painful brachial plexopathy, which occurred in DL1 at 16 months post-SABR at the time of local progression). There were 7 instances of grade 2 toxicities. These included fatigue (n = 1, DL2), chest wall pain (n = 2, DL2 & DL4), cough (n = 1, DL3), dyspnea (n = 2, DL3 & DL4), nausea (n = 1, DL4), and wheezing (n = 1, DL4). Eight (62%) patients required utilization of "split target volume" prescriptions. The mean total dose to the GTV ranged from 60.9-62.2 Gy for DL1, 63.2-68.6 Gy for DL2, 67.3-78.8 Gy for DL3, and 75.5-82.2 Gy for DL4. The median GTV was 19.9 cc (range 5-57cc). CONCLUSION 5-fraction SABR for early-stage lung SCC up to 14 Gy x 5 fractions using a split target prescription for OAR adjacent tumor appears safe. Long term follow up will be needed to assess late toxicities and tumor control. (NCT03321747).

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has intracranial activity in EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). The optimal timing of brain radiotherapy (RT) and appropriate patients who need early brain RT remains undetermined. This is a retrospective study of EGFR-mutant NSCLC patients with newly diagnosed brain metastases (BMs) before EGFR-TKI initiation. Intra-cranial progression free survival (IC-PFS) and overall survival (OS) were measured from the date of EGFR-TKI treatment. A total of 113 patients were eligible, 49 received concurrent early brain RT with EGFR-TKI and 64 were treated with EGFR-TKI alone as initial therapy, including 27 with salvage RT upon BM progression. The patients with early brain RT had superior IC-PFS than those without early brain RT (21.4 vs 15.0 months, P=0.001), which remained significant in multivariate analysis (HR 0.30, P

Purpose This review explores the use of intensity modulated radiation therapy (IMRT) after lung-sparing surgery in malignant pleural mesothelioma (MPM). Because severe toxicities have been documented after radiation therapy for MPM, its use remains controversial, especially as modern surgical management has shifted toward lung-sparing pleurectomy/decortication. IMRT is an advanced technique that may allow for safer radiation therapy delivery, but there remains limited data (including no summative data) to support this notion. Methods and Materials We performed a systematic review evaluating the safety and efficacy of post-pleurectomy IMRT (P-IMRT). A systematic review of PubMed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted for publications of all dates that specifically reported clinical outcomes and/or toxicities of P-IMRT in patients with MPM. Ten original studies were included in this review. Results The incidence of grade 3 pneumonitis ranged from 0% to 16%, with all but 2 studies reporting rates below 9%. Grade 4 and 5 pneumonitis were observed in less than 1.5% of cases, except in one publication that used hypofractionated radiation therapy to doses >60 Gy. Crude local failure rates ranged from 19% to 60%, median progression free survival ranged from 12 to 16 months, and median overall survival ranged from 19 to 28 months. Conclusions P-IMRT produces relatively few higher-grade toxicities and has reasonable disease-related outcomes, especially when delivered using conventionally fractionated regimens to doses of 45 to 54 Gy and exercising careful attention to dose constraints during treatment planning. IMRT can thus be considered in well-selected patients in whom adequate survival after pleurectomy is expected. These data also support the initiation of the phase III NRG-LU006 trial of extended pleurectomy/decortication and chemotherapy with or without IMRT.

Background Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 (IDH1) mutational (mut) status is understudied, and its incidence may alter clinical decision making. Methods We retrospectively evaluated 120 patients with IDH1-mut (n = 60) and IDH1–wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion. Results Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] IDH1-mut and 8 [13.3%] IDH1-WTs) demonstrated true progression, whereas 17 patients (3 [5%] IDH1-muts and 14 [23.3%] IDH1-WTs) demonstrated psPD (P = .004). IDH1-mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, P = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the IDH1-mut GBMs and 14 of 22 (63.6%) of the IDH1-WT GBMs (P = .496). Median overall survival for IDH1-mut and IDH1-WT GBM patients was 40.3 and 23.0 months, respectively (P < .001). Conclusions IDH1-mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for IDH1-mut GBMs is suggested if radiologic progression is suspected during this time interval.

INTRODUCTION: For patients with brain metastases, palliative radiation therapy (RT) has long been a standard of care for improving quality of life and optimizing intracranial disease control. The duration of time between completion of palliative RT and patient death has rarely been evaluated. METHODS: A compilation of two prospective institutional databases encompassing April 2015 through December 2018 was used to identify patients who received palliative intracranial radiation therapy. A multivariate logistic regression model characterized patients adjusting for age, sex, admission status (inpatient versus outpatient), Karnofsky Performance Status (KPS), and radiation therapy indication. RESULTS: 136 consecutive patients received intracranial palliative radiation therapy. Patients with baseline KPS

Purpose: We demonstrate proof of principle that normal tissue doses can be greatly reduced in lung stereotactic body radiation therapy (SBRT) for mobile tumors, if the delivered dose is split between opposite respiratory states. Methods: Patients that underwent 5 fraction lung SBRT at our institution and had deep inspiration breath hold (DIBH) and free breathing 4D computed tomography scans were included. Volumetric modulated arc therapy plans were generated on both respiratory phases and a third composite plan was generated delivering half the dose using the DIBH plan and the other half using the expiratory phase plan for each fraction. Computed tomography scans for the composite plan were fused based on ribs adjacent to the tumor to evaluate the dose volume histogram of critical structures. Results: Four patients with 4 total tumors had requisite planning scans available. Tumor size was between 0.7 to 2.9 cm and tumor movement 1.4 to 2.9 cm. Median reduction in the chest wall (CW) V30Gy for the composite plan was 74.6% (range 33.7 to 100%), 76.9% (range 32.9 to 100%), and 89.3% (range 69.5 to 100%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Median reduction in CW maximum dose for the composite plan was 23.3% (range 0.27% to 46.4%), 23.5% (range 3.2 to 48.2%), and 23.4% (range 0.27% to 48.4%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Greater reduction in CW maximum dose was observed when patients had no overlap in planning target volumes between DIBH and expiration phases (median reduction 43.9% for no overlap vs 2.7% with overlap). Between all plans, lung V20Gy absolute differences were within 1.3%. For 2 of 4 patients, the composite plan met constraints for 3 fraction SBRT, while standard plans did not. Conclusions: We conclude that composite DIBH-expiration SBRT planning has the potential to improve organ at risk sparing.

2025 Background: The rate of symptomatic radiation necrosis in patients treated with immune checkpoint inhibitor (ICI) therapy and concomitant single-fraction stereotactic radiosurgery (SRS) is as high as 20% (Martin et al., JAMA Oncology 2018). Here, we present the first results from the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) trial, aimed to identify reduced-dose SRS that is safe and efficacious for this patient population. Methods: RADREMI is a prospective multicenter, single arm phase I pilot study. Patients age > 18 receiving ICI with SRS for 1-10 brain metastases on MRI from biopsy-confirmed primary malignancy with estimated median survival of at least 6 months (by disease-specific graded prognostic assessment) and no history of whole brain radiation therapy were eligible. The primary endpoint was six-month symptomatic radiation necrosis (defined as a six-month rate of clinical symptomatology requiring steroid administration and/or operative intervention concomitant with imaging findings consistent with radiation necrosis), based on a historical six-month symptomatic radiation necrosis rate of 16% and an expected rate of 5%. Secondary endpoints included six-month local control and six-month radiographic radiation necrosis. Local control was defined according to Response Assessment in Neuro-Oncology (RANO) criteria, and was compared to historical controls of 87-91% six-month local control with RTOG 90-05 SRS dosing. The Fisher’s exact test was used for statistical analysis. This trial is registered at clinicaltrials.gov, NCT04047602. Results: Between December 18, 2019 and January 21, 2021, 39 lesions were treated in 17 patients receiving ICI delivered within 30 days before SRS from whom we recruited and obtained consent. All patients were treated with RADREMI dosing, which involved SRS doses of 18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm. The most common ICI used was single-agent pembrolizumab (49% of lesions, 59% of patients), followed by single-agent nivolumab (31% of lesions, 12% of patients). For the 11 lesions (six patients) meeting the primary endpoint (median follow-up = 259 days), the six-month symptomatic radiation necrosis rate was 0% per treated lesion, and 0% per treated patient, which was not significantly different from historical controls (p = 0.478). The six-month local control rate was 100% per treated lesion, and 100% per treated patient, comparable to historical controls (p = 0.476). Conclusions: In the first prospective trial to investigate dose-reduced SRS with concomitant ICI in treating metastatic brain disease, early results support the safety and efficacy of RADREMI dosing in this patient population. These findings warrant further multi-institutional collaborative trials of RADREMI dosing for this population. Clinical trial information: NCT04047602.

Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes. Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513–23. ©2016 AACR.

This is the first National Resident Matching Program analysis evaluating historical patterns of international medical graduates (IMGs) in radiation oncology (RO) and providing comparison with American (MD) medical graduates (AMGs), osteopathic students (DOs), unfilled positions, and other specialties.National Resident Matching Program data for IMGs were available from 2003 to 2015, with limited data for other specialty matches. The following RO-specific figures were obtained per year: total positions available; total matched positions; number of unfilled positions; and number of IMG, AMG, and DO matches. In addition, the number of IMG matches and total matched positions were obtained for 19 other specialties. Fisher exact tests and χ(2) tests were considered significant at α.05.From 2010 to 2015, 0.8% of RO matches were IMGs, a decline from 2.4% in 2003 to 2009 (P=.006). Proportions of DO matches during these intervals increased by 40% (from 1.0% to 1.4%), significantly lower than IMGs for 2003 to 2009 (P=.03) but not 2010 to 2015 (P=.26). From 2003 to 2015, the percentage of IMG matches, at 1.5%, was significantly lower than the percentage of unfilled seats, at 3.5% (P.001). In comparison with other specialties (2003-2015), RO had the fewest IMG matches (1.5%), followed by otolaryngology (1.9%) and orthopedics (2.2%); specialties with the highest IMG proportions were internal medicine (37.1%), family medicine (35.7%), and neurology (31.1%).Presently, IMGs represent1% of RO matches, the lowest among major specialties. There are several speculative factors associated with this low proportion. There are significantly more unfilled positions than those filled by IMGs; programs at risk of not matching could weigh the advantages and disadvantages of interviewing IMGs.

Introduction: MicroRNAs (miRs), small sequences of RNA regulating various cellular processes, are implicated to play major roles in cancer. Herein, we discuss the association of several miRs with non-small cell lung cancer (NSCLC), specifically relating to tumor invasion and metastasis to lymphatics and/or distant organs, which can often be correlated with overall prognosis.Areas covered: There exists strong evidence that presence of several miR combinations correlates with prognosis in both early- and advanced-stage NSCLCs. Principally, miR alterations could be useful in enhancing current imaging-based methods to more accurately estimate the extent of invasion/metastases.Expert Commentary: Despite the immature nature of this subject, its large ramifications on clinical oncology are clearly evident. Based on miR signature-related stratification, radiotherapy could be potentially personalized beyond current treatment standards.

Background The incidence of superior vena cava syndrome within the United States is roughly 15,000 cases per year. Superior vena cava syndrome is a potentially life-threatening medical condition; however, superior vena cava syndrome is not fatal in the majority of cases. Superior vena cava syndrome encompasses a collection of signs and symptoms resulting from obstruction of the superior vena cava, including swelling of the upper body of the head, neck, arms, and/or breast. It is also associated with cyanosis, plethora, and distended subcutaneous vessels. Lung cancer, including both non-small cell lung cancer and small cell lung cancer, is the most common extrinsic cause of superior vena cava syndrome. Intrinsic disruption of superior vena cava flow can also precipitate superior vena cava syndrome. This case report describes an unusual presentation and potential etiology of superior vena cava syndrome. Case presentation Our patient was a 51-year-old black woman with locally advanced, stage IIIB non-small cell lung cancer who had no clinical symptoms of superior vena cava syndrome at the time of diagnosis. However, she did have radiographic evidence of superior vena cava stenosis caused by extrinsic compression from her large right hilar primary tumor. She was treated with definitive chemoradiation, receiving 60 Gy of external beam radiation therapy given concurrently with chemotherapy. Three months after completion of radiotherapy, she developed signs of superior vena cava syndrome, including breast and supraclavicular swelling. She had a chest computed tomography scan showing over 50% reduction in the size of a right hilar mass; however, she had continued radiographic stenosis of the superior vena cava. The distribution of stenosis appeared to be inferior to the caudal extent of pretreatment tumor volume. She had no other radiographic indications for superior vena cava syndrome. Conclusions Generally, superior vena cava syndrome is the result of extrinsic compression of the superior vena cava by tumor. Our patient’s case represents the development of superior vena cava syndrome after an excellent response of tumor with near-complete tumor response. We suspect chemoradiation therapy as a potential etiology for the precipitation of the superior vena cava syndrome, which is currently not well reported in the medical literature.

Background Although stereotactic radiosurgery (SRS) is an effective modality in the treatment of brainstem metastases (BSM), radiation-induced toxicity remains a critical concern. To better understand how severe or life-threatening toxicity is affected by the location of lesions treated in the brainstem, a review of all available studies reporting SRS treatment for BSM was performed. Methods Twenty-nine retrospective studies investigating SRS for BSM were reviewed. Results The rates of grade 3 or greater toxicity, based on the Common Terminology Criteria for Adverse Events, varied from 0 to 9.5% (mean 3.4 ± 2.9%). Overall, the median time to toxicity after SRS was 3 months, with 90% of toxicities occurring before 9 months. A total of 1243 cases had toxicity and location data available. Toxicity rates for lesions located in the medulla were 0.8% (1/131), compared with midbrain and pons, respectively, 2.8% (8/288) and 3.0% (24/811). Conclusions Current data suggest that brainstem substructure location does not predict for toxicity and lesion volume within this cohort with median tumor volumes 0.04–2.8 cc does not predict for toxicity.

Introduction It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. Results At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.