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Purpose: To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors., Methods: We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR 20BED3 ) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV)., Results: Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR 20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV 1 /FEV 1pre , p=0.04); n=7 had VR 20BED3 >1 (high regional ventilation) and worse ΔFEV 1 /FEV 1pre (median=-0.16, range=-0.230 to -0.20). Five had VR 20BED3 <1 (low regional ventilation) and improved ΔFEV 1 /FEV 1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR 20BED3 and time to post-SABR PFT predicted decreasing ΔFEV 1 /FEV 1pre (R 2 =0.25, p=0.03)., Conclusions: After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR 20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR., (Copyright © 2017. Published by Elsevier B.V.)

Purpose: To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR)., Methods: We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake., Results: Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001)., Conclusions: Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction., Methods: We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV)., Results: Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2) = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2) = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted., Conclusions: We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

Purpose: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema., Methods and Materials: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3)., Results: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001)., Conclusions: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in the In This Issue feature, p. 1775.

BackgroundWe evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose≥60 Gy) for locally advanced non-small cell lung cancer (NSCLC).MethodsWe retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured the MTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.ResultsWe identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68 years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7 months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC = 0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P = 0.004 and P = 7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P = 0.001).ConclusionPer-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.