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Purpose/Objective(s) Local therapy (LTX) prolongs progression-free and overall survival (OS) in patients with oligometastatic non-small cell lung cancer. We previously reported substantial LTX benefit in time to progression or next therapy (TTP/TTNT) in patients with EGFR-mutant lung adenocarcinoma treated with tyrosine kinase inhibitors (TKI). Here, we investigate the role of LTX in patients who progressed on TKI for ALK/ROS1/RET-rearranged stage IV lung adenocarcinoma. Materials/Methods This single-institution IRB-approved retrospective review included all patients with pathologically confirmed stage IV ALK/ROS1-rearranged or RET fusion-positive lung adenocarcinoma who underwent radiation therapy (RT), surgery, or percutaneous thermal ablation (PTA) from 2012 to 2020 for progressive disease (PD) while on an ALK, ROS1, or RET TKI and for whom TKI therapy was continued post LTX. Patients receiving consolidative LTX after initial response to TKI without PD were not included. PD was classified as solitary- (one site), oligo- (2-5 sites), or poly- (> 5 sites) PD. TTP and TTNT were measured from start of any LTX. OS was evaluated from start of first LTX and from diagnosis. Significance was assessed with the Kruskal-Wallis test and Cox Univariate Analysis. Results 61 eligible patients (37 ALK, 12 ROS1, 12 RET; 37 female, median age 62 at LTX) were identified. Most common TKIs were alectinib (34), selpercatinib (17), and crizotinib (11). 92% of patients underwent RT (82 RT courses: median dose 27 Gy, 72% ≤5 fractions), 13% and 8% underwent surgery and PTA, respectively, with 13% undergoing > 1 LTX modality. In 87% of interventions, LTX addressed all sites of PD. PD prior to LTX was predominantly oligoPD (94%). Most frequent LTX sites were brain (41%), bone (28%), and lung (27%). Subsequent PD after LTX was also mostly oligoPD (81%; 38% solitary). In-field local failure occurred in 19%. Median follow-up post LTX was 18 mo. Median TTP and TTNT from LTX were 5.1 and 7.8 mo, respectively. TTP and TTNT were not significantly different in the sub-cohort in which all sites of PD were treated with LTX. Median OS was 51 mo from diagnosis and 19.4 mo from first LTX. TTP was significantly shorter for ≥3rd LTX course v. Conclusion Local therapy for PD on ALK, ROS1 or RET TKIs was associated with clinically meaningful time on continued TKI therapy beyond progression.

PURPOSE/OBJECTIVE(S) Older patients with inoperable early-stage non-small cell lung cancer (NSCLC) are mainly treated with definitive stereotactic body radiation therapy (SBRT) and represent an especially frail patient subset with unique challenges that may impact treatment tolerability and survival outcomes. The Electronic Rapid Fitness Assessment (eRFA) is a validated web-based comprehensive geriatrics assessment used for measuring frailty. We report our initial experience prospectively applying the eRFA to inoperable NSCLC patients treated with SBRT. MATERIALS/METHODS We collected baseline pretreatment eRFAs from early-stage (cT1a-T3N0) NSCLC patients aged 60 years and older receiving definitive SBRT (48-60 Gy in 3-8 fractions) from June 2019 to December 2020. Patient demographics and Charlson comorbidity index (CCI) were assessed. Geriatric assessment domains measured by the eRFA include functional status, social and emotional wellbeing, cognitive function, fall risk, nutritional status and polypharmacy. Our primary endpoint was the association between pretreatment eRFA scores and physician-assessed SBRT toxicity per CTCAE v5.0. Secondary outcomes included overall survival (OS), local control (LC) and distant metastasis-free survival (DMFS). Survivals were assessed using the Kaplan-Meier method. Univariate and multivariate logistic regression and Cox proportional hazards modeling were performed. RESULTS We enrolled 80 patients (median age: 78) with 88 primary tumors. We observed high baseline rates of geriatric vulnerabilities with a median of four eRFA impairments (IQR: 2-6). More than 50% of patients reported limited social activity, poor social support, depression, and dependency for activities of daily living, and more than 40% reported significant distress. Karnofsky Performance Status was ≤80 in 38% of patients. Cumulative toxicity rates after SBRT were 13% and 1% for Grade II and III toxicities, respectively. After a median follow-up of 12.9 months, 1-year OS, LC and DMFS rates were 96%, 92% and 97%, respectively. Comprehensive eRFA scores were significantly associated with increased likelihood of developing posttreatment toxicities on univariate analysis (LR: 2.20, P < 0.001), as were CCI scores (LR: 1.47, P = 0.025). Due to co-correlation of CCI and eRFA multivariate analysis was not performed. eRFA scores did not predict overall survival. CONCLUSION In this cohort, definitive SBRT was well-tolerated with excellent oncologic outcomes despite high observed rates of baseline geriatric vulnerabilities. Frailty assessed by the eRFA score was associated with higher cumulative toxicity rate. Future studies should further explore such relationships and assess interventions aimed at minimizing toxicity for patients with higher degree of geriatric frailty.

Purpose/objective(s) Although clinical trial enrollment is critical to development of new cancer therapies, Materials/methods All patients enrolled on radiation oncology therapeutic clinical trials at community-based partner sites from Q2 2018 - Q1 2021 were included in this analysis. Guided by Expert Recommendation for Implementing Change (ERIC), strategies to increase trial enrollment were implemented prior to Q2 2020, and included: 1) altered incentive structure (per-patient cost paid to partner site, leaderboards), 2) building a coalition of physicians in metastatic disease, and 3) practice facilitation. An interrupted time series analysis included a two-tailed student's t-test to compare mean trial enrollments per quarter pre- and post-implementation. Protocol deviations were assessed in quality assurance (QA) review. Results Among 52 total patients enrolled in community-based, partner sites, 28 (54%) identify as Black or Hispanic. The number of clinical trials open to enrollment pre- and post-implementation was 5 vs. 8, respectively, while the number of patients enrolled was 6 vs. 46, respectively, representing an overall increase in mean number of quarterly patient enrollments from 1 to 11 (P Conclusion These implementation strategies were associated with increased therapeutic trial enrollment in community-based partner sites. With high variation in enrollment between physicians and prior research suggesting limited impact of site-level financial incentives, qualitative research will further investigate non-financial incentives and other facilitators to clinical trial enrollment within community-academic partnerships. Over-representation of minority patients further supports the benefit of enrolling patients on clinical trials in the community-based setting.

Purpose/Objective(s) Pulmonary toxicity attributed to the proximal bronchial tree (PBT) is dose-limiting in stereotactic body radiation therapy (SBRT) for central lung tumors. The toxicity is of particular concern in ultracentral lesions, which are defined as the gross tumor volume abutting the PBT, esophagus, or other mediastinal structures. In this work we tested published pulmonary toxicity models associated with dose to the airway structures after SBRT for ultracentral tumors in an independent institutional cohort of patients. Materials/Methods The PubMed database was scrutinized for toxicity models evaluating pulmonary and airway toxicity for SBRT or hypofractionated radiation treatment for central tumors in the lung. The following search term criteria were used: (central) AND (lung tumor) AND (normal tissue complication probability) AND (radiation). Identified models were explored in all patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60% primary lung and 40% metastatic patients that had been treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx. 16% of the patients received anti-VEGF therapy, which as previously shown, was associated with higher incidence of grade 5 hemorrhage. Results A total of six NTCP models were identified from work by Tekatli et al 2018. Of these, three models were for ≥grade 3 and three for grade 5 toxicity and included bronchial max dose, V60, V100, and V130. Clinical pulmonary toxicity consisted of radiation pneumonitis, atelectasis due to main stem bronchus occlusion, and/or hemoptysis. The pulmonary toxicity rate was 15% and 8% for ≥grade 3 toxicity and grade 5 toxicity, respectively, in the original study. Within the independent cohort, the corresponding values were 18% and 10%. Two maximum dose models were shown to be valid in our institutional dataset; other models failed this validation test. The model was made more robust by expanding the max dose region of the bronchial volume by focusing on the max dose to 0.1 cm3, 1 cm3 and 3 cm3. The max dose (0.1 cm3) model had improved performance with increased steepness. Generally, models from literature underestimated our institutional complication rates. Conclusion Pulmonary toxicity models for central tumors were identified from one study and explored within an independent cohort. The models derived from primarily central lung tumors systematically underestimated the pulmonary toxicity rate in the solely ultracentral tumor cohort, possibly also due to anti-VEGF therapy used in the independent cohort. A modified model from the best-performing max dose model was designed, and this model could be utilized for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation. Author Disclosure I. Chen: None. M. Thor: None. A.J. Wu: Research Grant; CivaTech Oncology, Inc. Honoraria; 1199SEIU. Consultant; AstraZeneca, MORE Health. Advisory Board; Simphotek, Inc. Travel Expenses; AlphaTau Medical. Stock; Simphotek, Inc. A. Iyer: None. A. Apte: None. A. Rimner: Research Grant; Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Pfizer, Merck. Consultant; MoreHealth. Advisory Board; Boehringer Ingelheim, Astra Zeneca, Merck; International Thymic Malignancies Interest Group, International Mesothelioma Interest Group. D.R. Gomez: Research Grant; Merck, AstraZeneca. Honoraria; BMS, Varian, Research to Practice. Speaker's Bureau; Merck. Advisory Board; AstraZeneca, Olympus. J.O. Deasy: Research Grant; Varian Corp., NIH, Breast Cancer Research Foundation. Stock; Paige.AI; AAPM.A. Jackson: None.

Purpose/Objective(s) The CREST trial demonstrated improvement in progression free survival (PFS) with consolidative thoracic radiation (TRT) in extensive stage small cell lung cancer (ES-SCLC) using a dose of 30Gy in 10 fractions. However, observed rates of intrathoracic recurrence remained high, occurring in > 40% of patients. These results, and the higher doses used in earlier studies of consolidative TRT, suggest that doses > 30Gy may provide superior progression free survival and local control. Materials/Methods A single institution review of all consecutive patients with ES-SCLC who received consolidative TRT between 2010 and 2019 was performed. Consolidative TRT was defined as treatment occurring concurrently or sequentially with first-line chemotherapy. TRT for progression of disease was excluded. Baseline characteristics, toxicity, and outcome data were collected. Patients were sorted into two cohorts based on radiation dose: “standard” if treated with 30 Gy in 10 fractions, or “escalated” if treated with > 30 Gy. Overall survival (OS), PFS, and incidence of local failure were analyzed with log-rank and Gray tests. Results A total of 71 patients who met inclusion criteria were identified. Of these, 54 received the standard dose and 17 received escalated dose. The median dose in the escalated cohort was 45 Gy (range 36 – 70 Gy) and the median dose per fraction was 3 Gy (range 1.5 – 10 Gy). Two patients in the escalated cohort received concurrent chemoradiation in twice-daily fractions, whereas the remainder of the patients in both cohorts received sequential chemoradiation with once-daily fractions. Patients in the escalated cohort were younger (median age 62.5 vs. 66 years, P = 0.05). Otherwise, cohort characteristics were well balanced in terms of sex, pre-TRT Karnofsky performance status, number of pre-TRT chemotherapy cycles (median 6 in both cohorts), receipt of immunotherapy with first line chemotherapy (6.7% escalated vs 13.0% standard, P = 0.42), percentage with brain metastases at presentation (41.2% escalated vs 36.7% standard, P = 0.55), and receipt of prophylactic cranial irradiation (29.4% escalated vs 44.4% standard, P = 0.50). The were no significant differences between cohorts in OS (12 month 71% escalated vs 70% standard, P = 0.97) or PFS (12 month 35.3% escalated vs 29.6% standard, P = 0.64). There was no significant difference in the incidence of local failure between cohorts (12 month 14.1% escalated vs 25.6% standard, P = 0.86). The escalated cohort had higher rates of grade 2+ esophagitis (47.1% vs 16.7%, P = 0.01) and grade 2+ fatigue (29.1% vs 9.3%, P = 0.04). Conclusion In this retrospective study, consolidative thoracic RT doses higher than 30 Gy in 10 fractions did not significantly improve local recurrence or survival outcomes, and higher doses were associated with more acute toxicity. These data suggest that escalated doses do not provide an incremental benefit in disease outcomes and provide evidence for maintaining 30 Gy as the standard of care.

Purpose/Objective(s) Pleurectomy/Decortication (P/D) has become a common lung-sparing surgical approach for MPM. Chemotherapy may be delivered in the neoadjuvant or adjuvant setting. Adjuvant hemithoracic IMPRINT was developed at Memorial Sloan Kettering Cancer Center and found safe in a multi-institutional phase II study, with promising survival outcomes. CTEP approved a phase III randomized cooperative group trial (NRG LU-006) to evaluate the efficacy of this lung-sparing trimodality treatment approach for resectable MPM. Materials/Methods Patients with newly diagnosed MPM amenable to P/D are enrolled and undergo upfront P/D followed by adjuvant platinum/pemetrexed chemotherapy (preferred approach) or neoadjuvant chemotherapy followed by P/D. Patients are stratified by epithelioid vs. biphasic histologic subtype, achievement of a macroscopic complete resection (R0/1 vs. R2), and center patient volume (≤10 vs. > 10 P/Ds per year). Within 8 weeks after completion of the second modality, patients are randomized 1:1 to undergo hemithoracic IMPRINT vs. no further therapy. All IMPRINT contours and treatment plans are centrally reviewed. A contouring atlas and treatment planning constraints for target structures and organs at risk, including acceptable and unacceptable variations and deviations, were developed. Photon and proton therapy are permitted. The primary endpoint of the study is overall survival. Secondary endpoints include local failure-free, distant-metastases free and progression-free survival, treatment-related toxicities (CTCAE v5.0) and change in quality-of-life (EORTC QLQ-C30 mean score changes at 9 months post randomization). Exploratory objectives include correlation of clinical/radiographic staging with pathologic stage, immunologic and pathologic biomarkers as predictors of response, the rate of R0/R1 vs. R2 resections, and EORTC QLQ-C30 and LC13 symptom scores changes over time. This study was activated on January 29, 2020. As of 02/2021,16 sites are approved and 46 sites are pending approval to open the study. Treatment planning guidelines and helpful hints for photon and proton therapy will be presented. Two patients have been accrued, and the target accrual is 150 patients. Results TBD Conclusion NRG LU-006 is now open to accrual. This is the first NRG Oncology randomized phase III trial on malignant pleural mesothelioma and evaluates the use of IMPRINT following lung-sparing P/D and chemotherapy. Treatment planning aspects and current status will be presented.

8540 Background: The standard of care for patients with inoperable early stage or locally advanced NSCLC is definitive stereotactic body radiotherapy (SBRT) or conventional radiation therapy (RT) with systemic therapy. Circulating tumor DNA (ctDNA) testing can be used for the assessment of MRD and predict risk of recurrence. Few studies have prospectively evaluated MRD detection and ctDNA dynamics specifically among patients with early or locally advanced NSCLC receiving definitive RT. Methods: In a prospective clinical cohort of patients with stage I-III NSCLC (n = 17), serial plasma samples (n = 70) were collected before and after SBRT as well as before, during, and after conventional RT with or without concurrent systemic therapy and adjuvant durvalumab. Patients were followed-up for a median of 29 months (range: 4 to 54 months) with the last serial plasma collected at a median of 5 months from completion of RT (range: 1 – 26 months). A personalized, tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA and tracked 16 tumor variants among 16 patients and 15 tumor variants in one patient. This study evaluated the prognostic value of ctDNA, correlating MRD status with clinical outcomes, in addition to ctDNA clearance kinetics during RT. Results: Among 17 patients with early-stage and locally advanced NSCLC, baseline ctDNA was detected in 82% of patients (14/17). Clinical progression was confirmed radiographically for 53% (9/17). All events of clinical progression were detectable by ctDNA (sensitivity 100%, 0.63 – 1.0), with a median lead-time of 5.5 months for MRD detection compared to radiographic disease progression. Durable ctDNA clearance was observed in 29% (5/17) of patients, all of whom then remained recurrence-free until the end of follow-up (median 12 months; specificity 100%, 95% CI 0.6 – 1.0). Transient ctDNA clearance was observed in 3 patients, and recurrent ctDNA was detected before or at the time of disease progression in all 3. ctDNA status after treatment at a single time point and longitudinally were highly predictive of disease recurrence (p < 0.0001). Conclusions: ctDNA detection is feasible for patients with stage I-III NSCLC undergoing definitive chemoradiation. and can serve as a powerful predictive biomarker for disease recurrence. High baseline detection rate is essential for feasibility of a ctDNA-based MRD assay. Residual detectable ctDNA represents a powerful predictive tool to identify patients who might benefit from intensification of adjuvant therapy following definitive RT.

8504 Background: The CALGB 30610 trial demonstrated that 70Gy QD TRT was not associated with a superior overall survival compared to standard BID 45Gy TRT in limited stage small cell lung cancer. Since both arms appeared to provide similar clinical benefit, other factors such as quality of life may help oncologists decide on the best treatment approach for their patients. The present analysis was conducted to compare patients’ quality of life between these regimens in terms of their physical symptoms, physical functioning and psychological state. Methods: In the CALGB 30610 planned sub-study CALGB 70702, patients were administered the FACT-L, FACT Trial Outcome Index-Lung Cancer (FACT-L TOI), FACT-Esophageal Cancer Eating and Swallowing Indices, ECOG Acute Esophagitis Scale, Hospital Anxiety and Depression Scale (HADS), the EQ-5D at baseline and a single item assessing difficulty swallowing at baseline, 3, 5, 7, 12, 26, and 52 weeks after starting radiation therapy. Patients were also asked to assess treatment inconvenience at these time points. The primary endpoints of CALGB 70702 were FACT-L TOI and FACT eating and swallowing subscales at 12 weeks. Mean changes from baseline were compared between arms using general linear mixed models. Results: 417 patients consented to participate in the patient-reported outcomes substudy. The completion rate of the questionnaires was 87% at baseline and 71% at week 52. The FACT-L total score mean worsening was significantly less in the QD arm compared to the BID arm at week 3 (-1.0 vs -7.0; P=.003), and marginally less at week 5 (-5.3 vs -11.0; P=.06). The FACT-L TOI mean worsening was significantly less in the QD arm than in the BID arm at week 3 (-2.9 vs -7.6; P=.003) and greater at week 12 (-7.6 vs -2.8; P=.03). The QD arm also had a lesser EQ-5D index mean worsening at 3 weeks (-0.04 vs 0.03; P=.002). Mean increase in the acute esophagitis score (1.06 vs 2.89; P

BACKGROUND: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use. METHODS: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided. RESULTS: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P

Purpose Localizing lung tumors during treatment delivery is critical for managing respiratory motion, ensuring tumor coverage, and reducing toxicities. The purpose of this project is to develop a real-time system that performs markerless tracking of lung tumors using simultaneously acquired MV and kV images during radiotherapy of lung cancer with volumetric modulated arc therapy. Method Continuous MV/kV images were simultaneously acquired during dose delivery. In the subsequent analysis, a gantry angle-specific region of interest was defined according to the treatment aperture. After removing imaging artifacts, processed MV/kV images were directly registered to the corresponding daily setup cone-beam CT (CBCT) projections that served as reference images. The registration objective function consisted of a sum of normalized cross-correlation, weighted by the contrast-to-noise ratio of each MV and kV image. The calculated 3D shifts of the tumor were corrected by the displacements between the CBCT projections and the planning respiratory correlated CT (RCCT) to generate motion traces referred to a specific respiratory phase. The accuracy of the algorithm was evaluated on both anthropomorphic phantom and patient studies. The phantom consisted of localizing a 3D printed tumor, embedded in a thorax phantom, in an arc delivery. In an IRB-approved study, data were obtained from VMAT treatments of two lung cancer patients with three electromagnetic (Calypso) beacon transponders implanted in airways near the lung tumor. Result In the phantom study, the root mean square error (RMSE) between the registered and actual (programmed couch movement) target position was 1.2 mm measured by the MV/kV imaging system, which was smaller compared to the MV or kV alone, of 4.1 and 1.3 mm, respectively. In the patient study, the mean and standard deviation discrepancy between electromagnetic-based tumor position and the MV/KV-markerless approach was -0.2 ± 0.6 mm, 0.2 ± 1.0 mm, and -1.2 ± 1.5 mm along the superior-inferior, anterior-posterior, and left-right directions, respectively; resulting in a 3D displacement discrepancy of 2.0 ± 1.1 mm. Poor contrast around the tumor was the main contribution to registration uncertainties. Conclusion The combined MV/kV imaging system can provide real-time 3D localization of lung tumor, with comparable accuracy to the electromagnetic-based system when features of tumors are detectable. Careful design of a registration algorithm and a VMAT plan that maximizes the tumor visibility are key elements for a successful MV/KV localization strategy.

Purpose To compare single-shot echo-planar (SS-EPI)-based and turbo spin-echo (SS-TSE)-based diffusion-weighted imaging (DWI) in Non-Small Cell Lung Cancer (NSCLC) patients and to characterize the distributions of apparent diffusion coefficient (ADC) values generated by the two techniques. Methods Ten NSCLC patients were enrolled in a prospective IRB-approved study to compare and optimize DWI using EPI and TSE-based techniques for radiotherapy planning. The imaging protocol included axial T2w, EPI-based DWI and TSE-based DWI on a 3 T Philips scanner. Both EPI-based and TSE-based DWI sequences used three b values (0, 400, and 800 s/mm2 ). The acquisition times for EPI-based and TSE-based DWI were 5 and 8 min, respectively. DW-MR images were manually coregistered with axial T2w images, and tumor volume contoured on T2w images were mapped onto the DWI scans. A pixel-by-pixel fit of tumor ADC was calculated based on monoexponential signal behavior. Tumor ADC mean, standard deviation, kurtosis, and skewness were calculated and compared between EPI and TSE-based DWI. Image distortion and ADC values between the two techniques were also quantified using fieldmap analysis and a NIST traceable ice-water diffusion phantom, respectively. Results The mean ADC for EPI and TSE-based DWI were 1.282 ± 0.42 × 10-3 and 1.211 ± 0.31 × 10-3 mm2 /s. The average skewness and kurtosis were 0.14 ± 0.4 and 2.43 ± 0.40 for DWI-EPI and -0.06 ± 0.69 and 2.89 ± 0.62 for DWI-TSE. Fieldmap analysis showed a mean distortion of 13.72 ± 8.12 mm for GTV for DWI-EPI and 0.61 ± 0.4 mm for DWI-TSE. ADC values obtained using the diffusion phantom for the two techniques were within 0.03 × 10-3 mm2 /s with respect to each other as well as the established values. Conclusions Diffusion-weighted turbo spin-echo shows better geometrical accuracy compared to DWI-EPI. Mean ADC values were similar with both acquisitions but the shape of the histograms was different based on the skewness and kurtosis values. The impact of differences in respiratory technique on ADC values requires further investigation.

Purpose To correlate semiquantitative parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) for non-small cell lung cancer (NSCLC). Methods and Materials Twenty-four NSCLC patients who underwent pretreatment 18F-FDG-PET and DCE-MRI were analyzed. The maximum standardized uptake value (SUVmax) was measured from 18F-FDG-PET. Dynamic contrast-enhanced MRI was obtained on a 3T MRI scanner using 4-dimensional T1-weighted high-resolution imaging with a volume excitation sequence. The DCE-MRI parameters, consisting of mean, median, standard deviation (SD), and median absolute deviation (MAD) of peak enhancement, time to peak (TTP), time to half peak (TTHP), wash-in slope (WIS), wash-out slope (WOS), initial gradient, wash-out gradient, signal enhancement ratio, and initial area under the relative signal enhancement curve taken up to 30, 60, 90, 120, 150, and 180 seconds, TTP, and TTHP (IAUCtthp), were calculated for each lesion. Univariate analysis (UVA) was performed using Spearman correlation. A linear regression model to predict SUVmax from DCE-MRI parameters was developed by multivariate analysis (MVA) using least absolute shrinkage selection operator in combination with leave-one-out cross-validation (LOOCV). Results In UVA, mean(WOS) (ρ = −0.456, P = .025), mean(IAUCtthp) (ρ = −0.439, P = .032), median(IAUCtthp) (ρ = −0.543, P = .006), and MAD(IAUCtthp) (ρ = −0.557, P = .005) were statistically significant; all these parameters were negatively correlated with SUVmax. In MVA, a linear combination of SD(WIS), SD(TTP), MAD(TTHP), and MAD(IAUCtthp) was statistically significant for predicting SUVmax (LOOCV-based adjusted R2 = 0.298, P = .0006). A decrease in SD(WIS), MAD(TTHP), and MAD(IAUCtthp) and an increase in SD(TTP) were associated with a significant increase in SUVmax. Conclusion An association was found between SUVmax, the SD, and MAD of DCE-MRI metrics derived during contrast uptake in NSCLC, reflecting that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Although MAD(IAUCtthp) was a significant feature in both UVA and MVA, the LASSO-based multivariate regression model yielded better predictability of SUVmax than a univariate regression model using MAD(IAUCtthp). This study will facilitate understanding of the complex relationship between tumor vascularization and metabolism and eventually help in guiding targeted therapy.

Despite the widespread availability of in-treatment room cone beam computed tomography (CBCT) imaging, due to the lack of reliable segmentation methods, CBCT is only used for gross set up corrections in lung radiotherapies. Accurate and reliable auto-segmentation tools could potentiate volumetric response assessment and geometry-guided adaptive radiation therapies. Therefore, we developed a new deep learning CBCT lung tumor segmentation method. Methods: The key idea of our approach called cross modality educed distillation (CMEDL) is to use magnetic resonance imaging (MRI) to guide a CBCT segmentation network training to extract more informative features during training. We accomplish this by training an end-to-end network comprised of unpaired domain adaptation (UDA) and cross-domain segmentation distillation networks (SDN) using unpaired CBCT and MRI datasets. Feature distillation regularizes the student network to extract CBCT features that match the statistical distribution of MRI features extracted by the teacher network and obtain better differentiation of tumor from background.} We also compared against an alternative framework that used UDA with MR segmentation network, whereby segmentation was done on the synthesized pseudo MRI representation. All networks were trained with 216 weekly CBCTs and 82 T2-weighted turbo spin echo MRI acquired from different patient cohorts. Validation was done on 20 weekly CBCTs from patients not used in training. Independent testing was done on 38 weekly CBCTs from patients not used in training or validation. Segmentation accuracy was measured using surface Dice similarity coefficient (SDSC) and Hausdroff distance at 95th percentile (HD95) metrics., The paper has been accepted to Medical Physics

Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Radiation therapy plays a vital role in the definitive management of early stage and locally advanced lung cancer. Local treatment failure is a primary cause of disease progression in lung cancer and improved local control has been associated with improved overall survival in both non-small cell (NSCLC) and small cell lung cancers (SCLC) (Arriagada et al. 1991; Machtay et al. 2012; Pignon et al. 1992). Delivery of radiation to the intrathoracic sites of disease is limited by the sensitivity of the surrounding non-neoplastic tissues, in particular the normal lung, esophagus, and heart. As such, substantial effort has been made to optimize radiation treatments to maximize tumor control while minimizing toxicity. Technological advancements have led to better imaging of tumors and organs at risk at the time of treatment planning and more precise delivery of therapeutic radiation. Other ways to improve the therapeutic ratio for lung radiotherapy include altering variables such as radiation dose, fractionation schedule, and time interval between treatments. This chapter will focus on the seminal trials that have established the standards for these factors in modern lung radiotherapy, specifically in the nonoperative management of early stage NSCLC (defined as stage I-IIB according to the American Joint Committee on Cancer staging system), locally advanced NSCLC (defined as stages IIIA-B according to the American Joint Committee on Cancer staging system), and limited stage SCLC (LS-SCLC, defined as disease limited to the ipsilateral hemithorax and regional lymph nodes).

Purpose. Current magnetic resonance imaging (MRI) guided radiotherapy (MRgRT) applies sagittal/coronal 2D-cine to monitor major tumor motions, however, the beam eye’s view (BEV) with volumetric tumor projection would be the best measure for radiation beam conformality, independent of tumor through-plane motion. The goal is to assess the feasibility, accuracy, and performance of the BEV approach. Methods. Beam-specific BEV 2D-cine with volume-projected tumor contours were simulated to establish a 2D/3D tumor match against a tumor-motion library based on multi-breath time-resolved (TR) 4DMRI images. Two BEV-library-matching methods were developed: (1) fast screening with tumor center-of-mass (∆COM), in-plane area ratio, and DICE similarity, and finalizing with the highest DICE score and (2) DICE screening for top-3 candidates and finalizing with rigid registration. A 4D-XCAT digital phantom and 8 lung-cancer patients were used for assessment. For each patient, 3 sets of 40 s TR-4DMRI were acquired at 2 Hz and 6 representative BEV were created with the isocenter set at tumor COM in mid-respiration. One TR-4DMRI set (40 × 2 = 80-images) was used to simulate BEV 2D-cine and the other two (160-images) were used to create a library. The matching result was validated against the ground truth within the test set. Using a leave-one-out strategy, the success rate, accuracy, and speed of tumor matching were assessed for volume-projected tumors over 11520 time-points (=8patients•3sets•80images•6BEVs). Results. Volume-projected tumor contour area on the 6 BEVs varies by 60% ± 8% and % A V I (in-plane/volume-projected) varies by 82% ± 9%. The % A V I changes with tumor shape, orientation, and through-plane motion. Method-1 produces 96% matching success (ΔCOM = 0.7 ± 0.2 mm, % A V V =1.01 ± 0.02, Dice=0.92 ± 0.02) with the computational time of 15 ± 1 ms/match, while method-2 produces 94% ± 1% success (ΔCOM = 0.2 ± 0.1 mm, % A V V =1.00 ± 0.01, Dice = 0.94 ± 0.02) with 223 ± 13 ms/match. Conclusion. This study has demonstrated the feasibility, accuracy, and benefits of BEV 2D-cine imaging with tumor-volume projection, allowing real-time tumor motion monitoring and beam conformality checking. Further clinical evaluation is necessary before MRgRT applications.

PURPOSE: Radiation pneumonitis (RP) is a common and potentially life-threatening toxicity from lung cancer radiotherapy. Data sets reporting RP rates after post-operative radiation therapy (PORT) have historically been small and with predominantly outdated field designs and radiation techniques. We examined a large cohort of patients in this context to assess the incidence and causes of RP in the modern era. MATERIALS AND METHODS: We reviewed 285 patients with non-small cell lung cancer (NSCLC) treated with PORT at our institution from 5/2004 to 1/2017. Complete dosimetric data and clinical records were reviewed and analyzed with grade 2 or higher RP as the endpoint (RP2+) (CTCAE v4.0). Patients were a median of 67 yo (range 28-87), and most had pathologic stage III NSCLC (91%) and received trimodality therapy (90%). Systematic dosimetric analyses using Dx increments of 5% and Vx increments of 2Gy were performed to robustly evaluate dosimetric variables. Lung V(5) was also evaluated. RESULTS: The incidence of RP2+ after PORT was 12.6%. Dosimetric factors most associated with RP2+ were total lungV(4) (HR 1.04, p

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (