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OBJECTIVE Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of patients with many tumor histologies. Simultaneously, stereotactic body radiotherapy (SBRT) provides excellent local control (LC) and plays an important role in the management of spine metastasis. Promising preclinical work suggests the potential therapeutic benefit of combining SBRT with ICI therapy, but the safety profile of combined therapy is unclear. This study aimed to evaluate the toxicity profile associated with ICI in patients receiving SBRT and, secondarily, whether ICI administration sequence with respect to SBRT affects LC or overall survival (OS) outcomes. METHODS The authors retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI by using Cox proportional hazards analyses. Primary outcomes were long-term sequelae, including radiation-induced spinal cord myelopathy, esophageal stricture, and bowel obstruction. Secondarily, models were created to evaluate OS and LC in the cohort. RESULTS Two hundred forty patients who received SBRT to 299 spine metastases were included in this study. The most common primary tumor types were non–small cell lung cancer (n = 59 [24.6%]) and renal cell carcinoma (n = 55 [22.9%]). One hundred eight patients received at least 1 dose of ICI, with the most common regimen being single-agent anti–PD-1 (n = 80 [74.1%]), followed by combination CTLA-4/PD-1 inhibitors (n = 19 [17.6%]). Three patients experienced long-term radiation-induced sequelae: 2 had esophageal stricture and 1 had bowel obstruction. No patients developed radiation-induced myelopathy. There was no association between receipt of ICI and development of any of these adverse events (p > 0.9). Similarly, ICI was not significantly associated with either LC (p = 0.3) or OS (p = 0.6). In the entire cohort, patients who received ICI prior to beginning SBRT had worse median survival, but ICI sequence with respect to SBRT was not significantly prognostic of either LC (p > 0.3) or OS (p > 0.07); instead, baseline performance status was most predictive of OS (HR 1.38, 95% CI 1.07–1.78, p = 0.012). CONCLUSIONS Treatment regimens that combine ICIs before, concurrent with, and after SBRT for spine metastases are safe, with minimal risk for increased rates of long-term toxicity.

PDF file - 1004K, S1. The Twist box domain is required for full Twist1 transcriptional activity. S2. Quantification of immunofluorescence from isogenic prostate cancer cell lines stably expressing Twist1 and Twist1-F191G. S3. The Twist box domain is required for full Twist1-induced EMT marker phenotypes of prostate cancer cells. S4. Twist1 overexpression induces temporal changes in the material properties of prostate cancer cells during their migration in a wound healing assay. S5. The overexpression of Twist1 or Twist1-F191G does not increase cellular proliferation of prostate cancer cells in vitro. S6. The Twist box domain is required for full Twist1-induced cellular migration in PC3 cells. S7. Twist1 overexpression increases cell traction forces of individual androgenindependent PC3 prostate cancer cells. S8. Twist1 overexpression confers radioresistance to prostate cancer cells which is attenuated by mutation of the Twist box domain. S9. The Twist box domain is required for Twist1-induced soft agar anchorageindependent growth of 22Rv1 prostate cancer cells. S10. Twist1 overexpression does not confer prostate cancer cells increased primary tumorigenicity and slows primary tumor cell growth in vivo. S11. The Twist box domain is required for full Twist1-induced expression of Hoxa9/HOXA9.

PDF file - 116K, Supplemental Table S2 - Myc-CaP + Twist1-F191G versus Myc-CaP + Vector Differentially.

PDF file - 384K, Supplemental Table S1 - Myc-CaP + Twist1 versus Myc-CaP + Vector Differentially.

PURPOSE Early identification of patients who may be at high risk of significant weight loss (SWL) is important for timely clinical intervention in lung cancer radiotherapy (RT). A clinical decision support system (CDSS) for SWL prediction was implemented within the routine clinical workflow and assessed on a prospective cohort of patients. MATERIALS AND METHODS CDSS incorporated a machine learning prediction model on the basis of radiomics and dosiomics image features and was connected to a web-based dashboard for streamlined patient enrollment, feature extraction, SWL prediction, and physicians' evaluation processes. Patients with lung cancer (N = 37) treated with definitive RT without prior RT were prospectively enrolled in the study. Radiomics and dosiomics features were extracted from CT and 3D dose volume, and SWL probability (≥ 0.5 considered as SWL) was predicted. Two physicians predicted whether the patient would have SWL before and after reviewing the CDSS prediction. The physician's prediction performance without and with CDSS and prediction changes before and after using CDSS were compared. RESULTS CDSS showed significantly better prediction accuracy than physicians (0.73 v 0.54) with higher specificity (0.81 v 0.50) but with lower sensitivity (0.55 v 0.64). Physicians changed their original prediction after reviewing CDSS prediction for four cases (three correctly and one incorrectly), for all of which CDSS prediction was correct. Physicians' prediction was improved with CDSS in accuracy (0.54-0.59), sensitivity (0.64-0.73), specificity (0.50-0.54), positive predictive value (0.35-0.40), and negative predictive value (0.76-0.82). CONCLUSION Machine learning–based CDSS showed the potential to improve SWL prediction in lung cancer RT. More investigation on a larger patient cohort is needed to properly interpret CDSS prediction performance and its benefit in clinical decision making.

Background Patients with non‐small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies. Materials and Methods We systematically compared computed tomography (CT) features of RT‐ versus ICI‐pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics‐based machine learning (ML) model to discern pneumonitis etiology. Results Between 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI‐pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT‐pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI‐ from RT‐pneumonitis with an area under the receiver‐operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus. Conclusion RT‐ and ICI‐pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision‐making. Implications for Practice Patients with non‐small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI‐pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment., Patients with non‐small cell lung cancer often receive thoracic radiotherapy and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. The results of this study can help guide clinicians in triaging patients who develop pneumonitis after receipt of radiation and/or immune checkpoint inhibitor treatment.

BACKGROUND: Cancer therapy is associated with severe financial burden. However, the magnitude and longitudinal patient relationship with financial toxicity (FT) in the initial course of therapy is unclear. METHODS: Patients with stage II-IV lung cancer were recruited in a prospective longitudinal study between July 2018 and March 2020. FT was measured via the validated COmprehensive Score for financial Toxicity (COST) at the time of cancer diagnosis and at 6-month follow-up (6MFU). 6MFU data were compared with corresponding baseline data. A lower COST score indicates increased financial hardship. RESULTS: At the time of analysis, 215 agreed to participate. Subsequently, 112 patients completed 6MFU. On average, slightly more FT was observed at diagnosis compared with 6MFU (median COSTbase 25 v COST6M 27; P < .001); however, individual patients experienced large changes in FT. At 6MFU, 27.7% of patients had made financial sacrifices to pay for treatment but only 4.5% refused medical care based on cost. Median reported out-of-pocket (OOP) costs for the initial 6 months of cancer treatment was $2,496 (range, $0-25,900). Risk factors for FT at diagnosis were unique from risk factors at 6MFU. Actual OOP expenses were not correlated with FT; however, inability to predict upcoming treatment expenses resulted in higher FT at 6MFU. DISCUSSION: FT is a pervasive challenge during the initiation of lung cancer treatment. Few patients are willing to sacrifice medical care regardless of the cost. Risk factors for FT evolve, resulting in unique interventional targets throughout therapy.

Background We investigate the time to and clinical factors associated with patient-reported difficulty swallowing in lung cancer patients treated with radiation therapy (RT). Methods Between October 2016 and October 2019, lung cancer patients treated with conventionally fractionated RT at a tertiary cancer center were identified. Weekly, patients reported difficulty swallowing (patient-reported outcome version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE] v.1: 0-none, 1-mild, 2-moderate, 3-severe, 4-very severe). Physicians graded dysphagia (CTCAE v.4: 0-none, 1-symptoms without altered intake, 2-symptomatic; altered eating/swallowing, 3-severely altered eating/swallowing, 4-life-threatening consequences, 5-death). Tumor-related difficulty swallowing was not recorded at baseline; thus, patients reporting ≥moderate symptoms ≤7 days of RT start were excluded. We evaluated the time to new patient reports of ≥moderate difficulty swallowing and CTCAE grade 2+ dysphagia and development over time using the cumulative incidence method. Multivariable logistic regression evaluated associations between clinical factors, esophageal V60, and development of esophageal symptoms. Results Of the 200 patients identified: median age was 69 years, 52% were male, and 89% had stage III+ disease. Patients received a median of 63 Gy with chemotherapy (91.5%). At least moderate difficulty swallowing during RT was reported by 76 of 200 patients (38%); clinicians rated dysphagia as altering oral intake or worse for 26 of 200 (13%). Median time to first report of symptoms was 21 days (interquartile ratio [IQR], 18-34.5) for the 76 patients who reported ≥moderate symptoms and 33 days (IQR, 24-42) in the 26 patients whose provider reported grade 2+ dysphagia. The 30-day incidence of patient-reported ≥moderate swallowing difficulty and provider grade 2+ dysphagia was 26% (95% CI: 20%-32%) and 6% (95% CI: 3%-9%), respectively. Esophageal V60 >7 % was the clinical factor most associated with patient-reported ≥moderate esophageal symptoms (odds ratio 6.1, 95% CI: 3.0-12.3). Conclusions Patients report at least moderate difficulty swallowing more often and earlier than providers report grade 2+ dysphagia. Esophageal V60 ≥7% was most associated with development of moderate severity or worse patient-reported swallowing difficulty.

Introduction: There is a critical need to incorporate molecular assessments of minimal residual disease (MRD) during neoadjuvant immunotherapy, in order to identify individuals at high risk for disease recurrence based on analyses of circulating cell-free tumor DNA (ctDNA) landscapes. Here we employed longitudinal liquid biopsies to dynamically assess clinical outcomes with neoadjuvant immuno-chemoradiotherapy in patients with esophageal/gastroesophageal junction (E/GEJ) cancer. Methods: We utilized targeted error-correction sequencing to perform high-depth ctDNA next-generation sequencing for 141 serial plasma and 32 matched white blood cell (WBC) DNA samples from 32 patients with operable stage II/III E/GEJ cancer that received neoadjuvant immune checkpoint blockade (ICB) with chemoradiotherapy prior to surgery (NCT03044613). ctDNA analyses were performed at baseline, post-ICB induction, after completion of chemoradiotherapy (pre-op), and post-operatively (post-op). Using a tumor-agnostic WBC DNA-informed panel NGS approach we determined the cellular origin of plasma variants, filtering out germline and clonal hematopoiesis (CH) variants and evaluated ctDNA clonal dynamics over time. Molecular MRD was evaluated post-ICB, pre-op and post-op and correlated with recurrence-free (RFS) and overall survival (OS). Results: Twenty out of 32 patients had detectable ctDNA at any timepoint. Of the 12 patients with undetectable ctDNA, 9 had only CH- and/or germline-derived variants, while 3 patients had no detectable variants of any origin. ctDNA clearance post-ICB was correlated with tumor regression >80% at the time of resection (Fischer’s exact p=0.04). The subset of patients that did not attain complete pathologic response was heterogeneous with respect to ctDNA dynamics; such that ctDNA clearance pre-op identified patients with longer OS despite residual tumor of >0% at the time of resection (log rank p=0.06). Patients with undetectable ctDNA or ctDNA clearance pre-op had a longer RFS (log rank p=0.007) and OS (log rank p=0.03). Molecular MRD was associated with RFS and OS such that patients with ctDNA clearance post-op had longer RFS (log-rank p=0.007) and OS (log-rank p=0.017). Conclusion: ctDNA clearance post-ICB, pre-op and post-op reflects differential clinical outcomes for patients with E/GEJ cancer receiving neoadjuvant immuno-chemoradiotherapy. Understanding ctDNA dynamics and their relationship with pathological response and long-term outcomes can help identify patients at higher risk for recurrence and open a therapeutic window for future intervention. Citation Format: Blair V. Landon, Ronan J. Kelly, Ali H. Zaidi, Archana Balan, Jenna V. Canzoniero, Gavin Pereira, Zineb Belcaid, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Fyza Y. Shaikh, James R. White, Cynthia L. Sears, Eun J. Shin, Ali I. Amjad, Benny Weksler, Josephine L. Feliciano, Chen Hu, Vincent K. Lam, Valsamo Anagnostou. Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3374.

Introduction: With the increasing use of immune checkpoint inhibitors (ICI) for cancer, there is a growing burden on the healthcare system to provide care for the toxicities associated with these agents. Herein, we aim to identify and describe the distribution of encounters seen in an urgent care setting for immune-related adverse events (irAEs) and the clinical outcomes from irAE management. Methods: Patient demographics, disease characteristics, and treatment data were collected retrospectively from encounters at an oncology Urgent Care Clinic (UCC) from a single tertiary center for upper aerodigestive malignancies from 1 July 2018 to 30 June 2019. Data were summarized using descriptive statistics with odds ratios for associations between patient features and hospitalization after UCC evaluation. Results: We identified 494 encounters from 289 individual patients over the study period. A history of ICI therapy was noted in 34% (n = 170/494) of encounters and 29 encounters (29/170, 17%) were confirmed and treated as irAEs. For those treated for irAEs, the majority (n = 19/29; 66%) were discharged home. Having an irAE was associated with an increased risk of hospitalization compared to non-irAEs (OR 5.66; 95% CI 2.15–14.89; p < 0.001). Conclusion: In this single institution experience, the majority of UCC encounters for confirmed irAEs were safely managed within the UCC. In ICI-treated patients, having an irAE was associated with an increased risk of hospitalization versus non-irAEs.

Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes.We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression.Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015).Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.

This review covers the state-of-the-art imaging in therapy assessment and surveillance of lung cancer with focus on the utility of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). We review different qualitative and quantitative response assessment criteria in lung cancer, common pitfalls and atypical patterns of response to immunotherapy, and imaging features of common immune-related adverse events. In addition, the currently recommended imaging workup in surveillance of asymptomatic patients with non-small-cell and small-cell lung cancer and future developments will be discussed.

BACKGROUND Patients with stage IV oligometastatic (≤ 3 sites) non-small-cell lung cancer have a progression-free survival (PFS) and overall survival benefit when all sites of metastatic disease and the primary tumor are treated radically with consolidative radiotherapy (cRT). However, the optimal selection of patients most likely from cRT is yet to be defined. PATIENTS AND METHODS Patients with metastatic non-small-cell lung cancer treated with definitive radiotherapy to all metastatic sites and primary tumor (2008-2019) were retrospectively identified. Univariable Cox proportional-hazards model was used to compare outcomes with demographic and clinical characteristics. A predictive nomogram model for selection of patients most likely to benefit from cRT was constructed. RESULTS There were 91 patients identified with a total of 114 metastases treated. Median PFS from the start of cRT was 10.9 months (95% confidence interval [CI], 8.1-16.6), while the median survival time was 37.0 months (95% CI, 31.3-NR). On univariable modeling, patients with squamous histology (hazard ratio, 4.16; 95% CI, 1.99-8.71; P < .001) and those treated with non-stereotactic body radiotherapy hypofractionated therapy (hazard ratio, 5.43; 95% CI, 2.10-14.01; P < .001) had worse overall survival, while patients with targetable mutations (hazard ratio, 0.49; 95% CI, 0.25-0.98; P = .04) had a longer survival. Using a predictive nomogram model, patients with a solitary site of metastasis, targetable mutations, intracranial disease, and metachronous timing of oligometastases had a larger PFS benefit from cRT. CONCLUSION cRT is associated with favorable outcomes in PFS and overall survival. These results may aid in patient counseling, selection for aggressive local therapy, and stratification in future prospective clinical trials.

Background Here, we investigated radiological responses following chemotherapy alone as compared to both radiation/chemotherapy (chemoRT) in patients with thymic epithelial tumors (TETs) who did not receive upfront surgery. Methods TETs treated at a tertiary academic cancer center between January 2007 and July 2018 were identified. Patients received chemotherapy or chemoRT as initial therapy and pre‐ and post‐treatment scans were available. Student's t‐test, Wilcoxon rank‐sum tests, and Cox proportional hazards method were used to compare clinical details and survival between groups. The primary outcome was change in tumor size, which was compared between groups using linear mixed‐effects regression models, adjusting for baseline tumor size, age, and histology. Results A total of 24 of 114 patients with TETs identified met the inclusion criteria. The majority of patients had 67% thymoma (67%, n = 16) and AJCC8 III–IVA disease (58%, n = 14). Median age was 58.5 years (range: 33–76), median initial tumor volume was 187.1 cc (range: 28.7–653.6) and diameter was 8.5 cm (range: 4.5–14.3). Half of the patients received upfront chemotherapy (n = 12: 83% cisplatin/adriamycin/cyclophosphamide) or chemoRT (n = 12: 58% carboplatin/paclitaxel; median RT dose: 63 Gy [range: 60–70 Gy]). At a median imaging follow‐up of 15 months (range: 0–86): ChemoRT was associated with increased average radiological response compared to chemotherapy alone (volume: −47.0 cc more, P, ChemoRT was associated with a greater radiologic response than chemotherapy alone in patients with upfront unresectable TET

BACKGROUND: Progressive, metastatic non-small cell lung cancer (NSCLC) often requires the initiation of new systemic therapy. However, in patients with NSCLC that is oligoprogressive (≤3 lesions), local radiotherapy (RT) may allow for the eradication of resistant microclones and, therefore, the continuation of otherwise effective systemic therapy. METHODS: Patients treated from 2008 to 2019 with definitive doses of RT to all sites of intracranial or extracranial oligoprogression without a change in systemic therapy were identified. Radiographic progression-free survival (rPFS) and time to new therapy (TNT) were measured. Associations between baseline clinical and treatment-related variables were correlated with progression-free survival via Cox proportional hazards modeling. RESULTS: Among 198 unique patients, 253 oligoprogressive events were identified. Intracranial progression occurred in 51% of the patients, and extracranial progression occurred in 49%. In the entire cohort, the median rPFS was 7.9 months (95% CI, 6.5-10.0 months), and the median TNT was 8.8 months (95% CI, 7.2-10.9 months). On adjusted modeling, patients with the following disease characteristics were associated with better rPFS: better performance status (P = .003), fewer metastases (P = .03), longer time to oligoprogression (P = .009), and fewer previous systemic therapies (P = .02). Having multiple sites of oligoprogression was associated with worse rPFS (P

PURPOSE: We investigate whether esophageal dose–length parameters (L(dose)) can robustly predict significant weight loss—≥5% weight loss during radiation therapy (RT) compared with the weight before RT—in patients with lung cancer treated with definitive intent. METHODS AND MATERIALS: Patients with lung cancer treated with conventionally fractionated RT between 2010 and 2018 were retro-spectively identified. L(Fdose) and L(Pdose), the length of full- and partial-circumferential esophagus receiving greater than a threshold dose in Gy, respectively, were created. Multivariate logistic regression examined the associations between individual L(dose) and weight loss after adjusting for clinical parameters and correcting for multiple comparisons. Ridge logistic regression examined the relative importance of L(dose) compared with dose–volume (V(dose)), mean dose (D(mean)), and clinical parameters in determining weight loss. Univariate logistic regression examined the unadjusted probability of weight loss for important L(dose) parameters. RESULTS: Among the 214 patients identified, median age was 66.9 years (range, 31.5–88.9 years), 50.5% (n = 108) were male, 68.2% (n = 146) had stage III lung cancer, median RT dose was 63 Gy (range, 60–66 Gy), and 88.3% (n = 189) received concurrent chemotherapy. Esophagus lengths receiving high full-circumferential (L(F50)-L(F60)) and high partial-circumferential doses (L(P60)) were associated with significant weight loss (P ≤.05). L(F65) and L(P65) reached near significance (P = .06 and .053, respectively). L(F65) > L(F60) > L(P65) were the most important dose parameters in determining weight loss compared with other L(dose), V(dose), and D(mean) parameters. CONCLUSIONS: Esophageal L(dose) parameters are an efficient way of interpreting complex dose parameters in relation to weight loss toxicity among patients with lung cancer receiving definitive RT.

Objectives Definitive intent treatment of isolated locoregional recurrence (iLR) for non-small cell lung cancer (NSCLC) is becoming more common. This study explores outcomes associated with the definitive local treatment of iLR and compares these outcomes to newly diagnosed locally advanced NSCLC (LA-NSCLC) patients. Materials and methods Patients with NSCLC treated with curative therapy between 2008 and 2019 at a tertiary academic institution were screened for iLR treated with subsequent definitive salvage therapy. Progression free survival (PFS), time to distant metastasis (TTDM), and overall survival (OS) were calculated via Kaplan–Meier methodology. Clinical outcomes were compared to a separate group of patients with de novo LA-NSCLC after adjusting for propensity score (PS). Results Sixty five cases of definitively salvaged iLR were compared to 302 patients with de novo LA-NSCLC. Most patients were treated with chemoradiotherapy (83.1% in iLR, 74.5% in LA-NSCLC). The median PFS, TTDM, and OS for the iLR cohort was 16.7 months (95% CI: 9.6–24.7), 35.8 months (95% CI: 17.1-NR), and 49.5 months (95% CI: 30.1-NR), respectively. After adjusting for PS, the iLR group was no different from the LA-NSCLC group in risk for progression (HR 0.78, 95% CI: 0.53–1.16, p = 0.22), distant metastasis (HR 0.81, 95% CI: 0.52–1.27, p = 0.36), or death (HR 0.90, 95% CI: 0.47–1.73, p = 0.75). Patterns of failure did not different significantly between groups. In the iLR cohort, patients with older age (HR 1.06, 95 CI: 1.01–1.10, p = 0.01) had a higher risk of death on multivariate analysis. Conclusion To our knowledge, this is the first report that compares the definitive treatment of iLR to de novo LA-NSCLC. When treated with definitive local therapy, patients with iLR had no difference in clinical outcomes from de novo LA-NSCLC. The use of curative local therapy according to a LA-NSCLC paradigm is advisable in patients with iLR of NSCLC for whom definitive therapy is feasible.

Advances in lung cancer therapy have resulted in improved clinical outcomes. Unfortunately, advances can come at a financial cost to patients and their families that poses a significant risk to overall quality of life (QoL). Financial distress has been shown to be associated with increased symptom burden and decreased treatment compliance but the magnitude of financial distress is not well characterized in lung cancer populations.Patients with stage II-IV newly diagnosed lung cancer and starting first-line therapy were recruited at a tertiary academic institution between July 2018 and April 2019. The comprehensive score for financial toxicity (COST) was used to assess financial toxicity and the Functional Assessment of Cancer Therapy-Lung (FACT-L) was used to assess QoL. Associations between financial toxicity and baseline variables were assessed using multivariable linear regression and correlations were assessed using the Pearson correlation.In this study, 143 consecutive patients were approached and 91.6% agreed to participate (N = 131). The median age was 65 years (35-90); 52.7% were male (n = 69), and 75.6% were white (n = 99). The inability to afford basic necessities and having1 month of savings was associated with increased financial toxicity (P0.001) after adjusting for other factors such as age, race, insurance, and income. There was also a trend toward increased financial toxicity among those who were employed but on sick leave (P = 0.06). Increased financial toxicity was correlated with a decrease in QoL (correlation coefficient 0.41, P0.001). Patients' anticipated out-of-pocket (OOP) expenses for the upcoming 6 months ranged from $0 to $50 000 (median $2150). However, there was no correlation between anticipated OOP expenses and either financial toxicity or QoL.These data identify key factors for identifying at-risk patients and builds a framework for exploring the benefit of financial counseling interventions, which may improve QoL and oncologic outcomes.

Nonhomogeneous dose optimization (NHDO) is exploited in stereotactic body radiation therapy (SBRT) to increase dose delivery to the tumor and allow rapid dose falloff to surrounding normal tissues. We investigate changes in plan quality when NHDO is applied to inverse-planned conventionally fractionated radiation therapy (CF-RT) plans in patients with non-small cell lung cancer.Patients with near-central non-small cell lung cancer treated with CF-RT in 2018 at a single institution were identified. CF-RT plans were replanned using NHDO techniques, including normalizing to a lower isodose line, while maintaining clinically acceptable normal tissue constraints and target coverage. Tumor control probabilities were calculated. We compared delivered CF-RT plans using homogenous dose optimization (HDO) versus NHDO using Wilcoxon signed-rank tests. Median values are reported.Thirteen patients were replanned with NHDO techniques. Planning target volume coverage by the prescription dose was similar (NHDO = 96% vs HDO = 97%, P = .3). All normal-tissue dose constraints were met. NHDO plans were prescribed to a lower-prescription isodose line compared with HDO plans (85% vs 97%, P = .001). NHDO increased mean dose to the planning target volume (73 Gy vs 67 Gy), dose heterogeneity, and dose falloff gradient (P .03). NHDO decreased mean dose to surrounding lungs, esophagus, and heart (relative reduction of 6%, 14%, and 15%, respectively; P .05). Other normal tissue objectives improved with NHDO, including total lung V40 and V60, heart V30, and maximum esophageal dose (P .05). Tumor control probabilities doubled from 31.6% to 65.4% with NHDO (P = .001).In select patients, NHDO principles used in SBRT optimization can be applied to CF-RT. NHDO results in increased tumor dose, reduction in select organ-at-risk dose objectives, and better maintenance of target coverage and normal-tissue constraints compared with HDO. Our data demonstrate that principles of NHDO used in SBRT can also improve plan quality in CF-RT.

Background Pulmonary Cryptococcosis (PC) is diagnosed with increasing incidence in recent years, but it does not commonly involve the pleural space. Here, we report a HIV-negative case with advanced stage IIIB non-small cell lung cancer (NSCLC) treated with radiation therapy presented with dyspnea, a new PET-positive lung mass and bilateral pleural effusion suspecting progressive cancer. However, the patient has been diagnosed as pulmonary cryptococcal infection and successfully treated with oral fluconazole therapy. Case presentation A 77-year-old male with advanced stage non-small cell lung cancer treated with combined chemo-radiation therapy who presented with progressive dyspnea, a new PET-positive left lower lobe lung mass and bilateral pleural effusions. Initial diagnostic thoracentesis and bronchoscopy yielded no cancer, but instead found yeast forms consistent with cryptococcal organisms in the transbronchial biopsies of the left lower lobe lung mass. Subsequent to this, the previously collected pleural fluid culture showed growth of Cryptococcus neoformans. The same sample of pleural effusion was tested and was found to be positive for crytococcal antigen (CrAg) by a lateral flow assay (LFA). The patient has been treated with oral fluconazole therapy resulting in gradual resolution of the nodular infiltrates. Conclusion PC should be considered in immunosuppressed cancer patients. Additionally, concomitant pleural involvement in pulmonary cryptococcal infections may occur. The incidence of false positive 18FDG-PET scans in granulomatous infections and the use of CrAg testing in pleural fluid to aid in diagnosis are reviewed.

In patients with non–small-cell lung cancer treated with anti–PD-1/PD-L1 agents, no specific radiation parameter was significantly associated with immune-related (IR) pneumonitis. We identify on subset analysis of patients who developed IR pneumonitis and received chest radiation, patients were numerically more likely to have received chest radiation with curative intent than with palliative intent (89% vs. 11 that approached statistical significance. PURPOSE: To investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non–small-cell lung cancer (NSCLC) patients treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-LI). PATIENTS AND METHODS: Between June 2011 and July 2017, NSCLC patients treated with anti–PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests. RESULTS: Of the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30–79.3) months and median age 66 (range, 39–91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti–PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-I/PD-LI -based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8–25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions. CONCLUSION: No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti –PD-I/PD-LI agents.

Background National costs of lung cancer care exceed $12 billion. We investigate the resource-savings benefit of a single-day thoracic oncology multidisciplinary clinic (MDC) in the diagnostic period prior to non–small-cell lung cancer (NSCLC) treatment. Materials and Methods From July 2007 to January 2015, patients with NSCLC treated with multimodality therapy at a tertiary hospital-based cancer center in Maryland were identified. Patient and treatment details were collected. Health care resources utilized in the 90 days prior to receipt of first oncologic treatment were identified using billed activity codes. Associated total charges, including professional fees and hospital-based technical fees, were identified and inflated to 2014 dollars using the Consumer Price Index. Codes were categorized into provider visits, procedures, pathology/laboratory, radiology, and other tests. χ2, Student t, and Wilcoxon rank-sum tests compared charges of patients seen in and out of the MDC. Results Two-hundred ninety-seven (non-MDC = 161, 54%; MDC = 136, 46%) of 308 patients identified had total charges available. Patients seen through MDC had on average a 23% decrease in total charges per patient incurred ($5839 savings; range, $5213-$6464) compared with patients seen through non-MDC settings. Evaluation through MDC reduced the average number of provider visits per patient (non-MDC, 6.8 vs. MDC, 4.8; P Conclusions Evaluation of patients with NSCLC through a coordinated single-day MDC reduced hospital charges per patient by 23% during the diagnostic period prior to treatment when compared with evaluation through traditional referral-based thoracic oncology clinics.

Genetic and environmental interactions predispose certain groups to lung cancer, including families. Families or caregiving units experience the disease interdependently. We have previously evaluated the concerns and preferences of patients in addressing the lung cancer experience and cancer risks in their families. This qualitative study evaluates the concerns and preferences of family members and caregivers of patients with lung cancer in the lung cancer experience and familial cancer risks. We held focus groups to discuss the format and timing of addressing these preferences and concerns. Qualitative data generated was analyzed using a grounded theory approach. Five focus groups totaling 19 participants were conducted. Seven themes were identified: (1) journey to lung cancer diagnosis has core dimensions for patient and family, (2) importance of communication between patients, families, and providers, (3) challenges for caregivers and family, (4) mixed perceptions of lung cancer causation among relatives, (5) discussion of cancer risk with relatives has complex dynamics, (6) impact of diagnosis on family health behaviors and screening, (7) role of genetic counseling. Family members of patients with lung cancer are interested in discussing risk factors, prevention, and diagnoses and also would like access to other supportive services do learn about and cope with some of the stresses and barriers they experience in the family lung cancer journey. The diagnosis represents a potential teachable moment with the opportunity to reduce the risk of LC development or improve early detection in LC patient’s family members.

With increasing use of immune checkpoint inhibitors (ICIs) for advanced NSCLC, there is increasing recognition of immune-related adverse events associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of immune-related adverse events in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we used a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. We found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multivariate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.

Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells and PD-L1 expression. LAG-3 is also highly expressed in esophagogastric cancers. The microbiome, a novel and potentially modifiable, biomarker of IO response, has not yet been examined in the neoadjuvant setting in esophageal cancer and is the goal of our study. Methods: Fecal samples were collected from patients with stage II/III esophageal or gastroesophageal junction carcinoma eligible for curative resection treated with the standard of care regimen of carboplatin paclitaxel (50mg/m2), radiation 50.4 Gy in 28 fractions and an Ivor-Lewis esophagectomy 6-10 weeks after last CRT and immunotherapy (IO) dose. Patients on arm A (n=11) received 2 cycles of induction with nivolumab plus 3 additional cycles on week 1, 3 and 5 of CRT. Patients on arm B (n=8) received nivolumab plus relatlimab on the same schedule (Clinical trial: NCT03044613). We examined longitudinal fecal samples from n=19 patients across both arms (n=90 samples) using 16S rRNA amplicon sequencing. Patients were classified based on pathological response: complete response (CR) and grades 1, 2, and 3 (G1, G2, G3) with increasing residual tumor visible in the resected specimen. Sequencing data was trimmed and filtered for contaminants, followed by high-resolution taxonomic assignment and normalization of reads across all samples. Analysis was performed using multiple metrics for alpha diversity and beta-diversity, with principal coordinates analysis/PERMANOVA, and pathway analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Results: Patients with improved response in the neoadjuvant setting (CR/G1 vs G2/G3) grouped in distinct clusters using Bray-Curtis (p < 0.001). Patients with CR had higher alpha diversity, using both measures of richness and evenness, compared to patients with a G3 responses (p < 0.03). Specifically, family Bacteroidaceae and genus Bacteroides were enriched in patients with CR vs G3 (p < 0.02). At the species level, B. finegoldii, B. ovatus, and B. uniformis were enriched in patients with CR vs G3 (p < 0.02). In contrast, genus Klebsiella and Clostridium termitidis were enriched in patients with a poor response, G3 (p Conclusions: Patients with operable esophageal cancer and improved responses to combined CRT and IO had distinct microbiome profiles enriched in multiple Bacteroides species. Further analyses and validation efforts are underway to confirm metabolomic pathways. Citation Format: Fyza Y. Shaikh, James R. White, Ronan J. Kelly, Ali H. Zaidi, Jenna V. Canzoniero, Josephine L. Feliciano, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Eun J. Shin, Ali I. Amjad, Patrizia Guerrieri, Benny Weksler, Chen Hu, Valsamo Anagnostou, Vincent K. Lam, Cynthia L. Sears. Patients with operable esophageal cancer and improved responses to combined chemoradiotherapy and immunotherapy display distinct microbiome profiles enriched in multiple Bacteroides species [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1973.

e16092 Background: Brain metastasis (BRM) in gastroesophageal (GE) cancer is uncommon, but contributes to poor prognosis and significant symptom burden. While HER2 overexpression has been suggested as a potential driver of BRM, clinicopathologic and molecular determinants of BRM in GE cancer and their impact on clinical outcome remain incompletely understood. Methods: We retrospectively analyzed clinicopathologic data from 323 advanced esophageal/GEJ patients (pts) at Johns Hopkins from 2003 to 2021. Univariate and multivariate logistic regression were performed to investigate the association between several clinical and molecular features and the occurrence of BRM, with particular focus on HER2 overexpression (by IHC and FISH) and PD-L1 expression (by IHC) as measured by the combined positive score (CPS). Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 64 and most pts were white (90.4%). Tumors were 73.7% esophageal primary, 82.7% adenocarcinoma, 43.8% HER2+, and 11.1% CPS ≥ 1. Cumulative incidence of BRM in overall cohort and within HER2+ subgroup was 14.6% (47 pts) and 25.4% (16 pts), respectively. Pts with BRM (not already present at time of stage IV diagnosis) had median onset of 10.8 months. Seventeen (36.2%) pts had a solitary brain lesion and 10 (21.7%) were asymptomatic. On univariate analysis, adenocarcinoma and HER2 overexpression were associated with increased risk of BRM (OR 3.45; 95% CI 0.09-0.96; p = 0.043 and OR 2.72; 95% CI 1.11-6.67; p = 0.028, respectively). Notably, the HER2 association was strengthened when HER2 equivocal tumors were re-classified as positive in an exploratory analysis (OR 3.55; 95% CI 1.38-9.14; p = 0.009). Adenocarcinoma and HER2 overexpression were collinear in the multivariate model. In pts with BRM, OS was improved in HER2+ pts (16.72 months; 95% CI 12.3-21.1 months; log-rank p = 0.039 and OR 0.33; 95% CI 0.11-0.99; Cox regression p = 0.049). CPS and primary tumor location were not associated with increased BRM. Conclusions: HER2 overexpression identifies an esophageal/GEJ molecular subtype that is significantly associated with increased risk of BRM; though with improved OS (compared to non-HER2+ BRM) and later onset CNS progression, likely reflecting durable extra-CNS control on targeted systemic therapy and a potential HER2+ subgroup with relatively indolent biology. Prevalence of asymptomatic and solitary brain lesions supports increased brain surveillance for this population.

Purpose/objective(s) Patient reported outcomes (PRO) show promise in predicting which patients are at risk for worst outcomes after chemoradiation (CRT) and may be used to improve symptom management. We investigate if patient-reported symptoms collected during thoracic radiation (TRT) may help identify patients at risk of developing radiation pneumonitis (RP) post-TRT. Materials/methods Between 2016 to 2020, patients with stage III NSCLC treated with definitive-intent TRT at our institution were identified. Patients completed a 10-item symptom-report questionnaire using the PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE v.1.0) weekly during RT and at follow-up. Physicians graded lung-specific symptoms and side-effects using CTCAE v4.0 at the same time-points. RP was defined as radiographic inflammation of the lung within the radiation field attributable to TRT, and excluding other causes. Patient and treatment characteristics were recorded. Descriptive statistics and univariate competing risks analysis were performed to describe and identify variables associated with development of RP. Results Of 131 patients identified: median age was 66 years, 53% were male, and 45.8% patients had co-morbid lung disease. Patients received a median of 63 Gy (Interquartile range (IQR): 60-63 Gy) with chemotherapy (88%). The median mean-lung-dose (MLD) was 14.5 Gy (IQR: 12-17 Gy) and the median lung V20 was 20% (IQR: 20%-30%). After TRT, 61 patients received immunotherapy. In the entire cohort, twenty-four patients (18%) developed any grade RP, of which n = 21 were grade ≥2. The median time to diagnosis of RP after TRT was 3.0 months. Factors associated with the development of RP included: age (HR 1.06, P = 0.0004) and MLD (P = 0.0005). In terms of PROs associated with development of RP: patient reported severe pain was significantly associated (HR 3.4, P = 0.01), while moderate anxiety (HR 2.3, P = 0.06), and cough (HR 4.53, P = 0.06) were non-significantly associated with RP. Physician assessed grade 2 dyspnea where medical intervention was needed was associated with RP (HR 3.43, P = 0.02). Conclusion Patient symptom reports during treatment may be associated with the risk development of RP. Larger studies of prospectively collected PROs during TRT are needed to further explore these potential associations with RP.

Purpose/Objective(s) Palliative radiation may be beneficial for patients with metastatic or locally advanced disease causing malignant airway obstruction (MAO). However, the subset of patients most likely to benefit from palliative airway radiation is unknown. In this study, we seek to report local control and survival outcomes for patients treated with palliative radiation for MAO and provide prognostic factors for improved overall survival. Materials/Methods An IRB approved single institution retrospective review of patients treated with palliative thoracic radiation for MAO from 2008-2016 was undertaken. The primary study endpoint was overall survival (OS) and secondary endpoints included local response and airway specific progression free survival. Kaplan-Meier survival, and Cox proportional hazards regression analyses were performed to identify factors associated with OS. Variables with clinical and univariate significance were modelled using multivariate logistic regression analysis. Results Palliative radiation for MAO was identified for 237 patients (median age of 63.8 yrs). 88.6% of patients were treated for primary lung cancer and 41.6% of those patients had adenocarcinoma histology. At time of analysis, 78.5% patients had died. Median follow-up was 2 months. Out of 116 patients with imaging follow-up: 31.0% had airway specific progression, 68.9% had complete or partial response at last follow up. For those patients with palliative tumor response, median time to progression was 5.0 (Range 1.1-17.8) months. Kaplan-Meier estimate of median overall survival following start of radiation therapy was 5.0 (95% CI 3.8-5.8) months. In multivariable analyses, there was a marginally increased hazard ratio for patients who had dyspnea at rest HR 2.09 (95% CI 0.78-5.62), oxygen requirement at presentation HR 1.28 (95% CI 0.81-2.01), and higher ECOG level 2-4 HR 1.21 (95% CI 0.81-1.80). Conversely, squamous cell histology and treatment with BED10 greater than or equal to 39 (equivalent to the commonly used 30Gy in 10 fraction regimen) were significantly predictive of improved OS, HR 0.56 (95% CI 0.32-0.97) and HR 0.42 (95% CI 0.28-0.64) respectively. Conclusion To our knowledge, this analysis is the largest collection of patients receiving palliative thoracic radiotherapy for MAO. These data show that MAO is a poor prognostic feature for survival, but treatment responses are seen. Increased BED delivered and squamous cell carcinoma, a radiosensitive tumor histology, were associated with improved survival. These results may help to inform optimized patient selection for and outcomes of patients with MAO receiving palliative RT.

Purpose/Objective(s) Radiotherapy, especially high-dose radiation in the form of stereotactic body radiotherapy (SBRT), may stimulate the therapeutic effect of immune checkpoint inhibitors (ICIs). Both SBRT and ICIs play an increasingly important role in the management of spine metastasis. We hypothesize that SBRT and ICI may act synergistically to improve the outcomes of patients with spine metastasis. Materials/Methods We retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center between 2009 and 2019. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI. Cox proportional hazard analyses were performed for overall survival (OS) and local control (LC), adjusting for primary tumor type, age, performance status, and prior spine surgery and/or radiation. Results 153 patients with 194 unique spine lesions were treated with SBRT. The most common primary tumor types were renal cell carcinoma (RCC), non-small cell lung cancer (N = 48, 31% each), colorectal cancer (N = 21, 14%), melanoma and liver cancer (N = 10, 6% each). 82 patients received at least one course of ICI. The most common type of ICI was single-agent anti-PD-1 (N = 71, 88%), followed by dual anti-CTLA-4/PD-1 inhibitors (N = 14, 17%). Of patients receiving ICI, 44 (53.6%) initiated ICI before SBRT, and 38 (46.4%) received ICI after SBRT. The median survival (MS) after SBRT was 14.8 months (95% confidence interval [CI] 11.4-19.6). On univariable analysis, MS was significantly longer for patients starting ICI after SBRT (27.3 months, 95% CI 16.0-33.9) than for those who did not receive any ICI (MS 11.3 months, 95% CI 8.9-15.8, P = 0.04). Patients with RCC (HR 0.67, 95% CI 0.45-1.00, P = 0.05) and higher body mass index (BMI, HR 0.97 as continuous variable, 95% CI 0.93-1.00, P = 0.05) trended toward longer OS. On multivariable analysis after adjusting for primary tumor type, performance status and BMI, only ICI treatment after SBRT was significantly associated with increased survival (HR 0.62, 95% CI 0.39-0.98, P = 0.04). LC after SBRT was numerically higher in patients receiving ICI (1-year LC 91.3%, 95% CI 82.4-95.8%; 2-year 79.7%, 95% CI 65.7-88.5%), than those who did not (1-year 81.5%, 95% CI 65.9-90.5%; 2-year LC 55.5%, 95% CI 35.6-71.4%), although this was not statistically significant (P = 0.18). ICI Initiation before SBRT trended toward superior LC compared to no ICI (multivariable HR 0.49, 95% CI 0.22-1.08, P = 0.08). Both epidural disease and paraspinal extension were associated with worse LC on univariable and multivariable analyses. Conclusion ICIs may enhance survival and tumor control after SBRT for patients with spine metastasis. Post-SBRT ICI may improve systemic disease control and survival, while pre-SBRT ICI may augment LC. Further research is needed to maximize the synergy between these two treatment modalities. Author Disclosure X. Chen: None. M.C. LeCompte: None. L.R. Kleinberg: Research Grant; Novartis, Novocure, Accuray, Arbor. Honoraria; Accuray. Advisory Board; Novocure. Travel Expenses; Accuray. R.K. Hales: Research Grant; Genentech. K. Voong: Research Grant; Radiation Oncology Institute, Lung Cancer Research Foundation, Canon, Inc. P. Forde: Research Grant; Bristol Myers-Squibb, AstraZeneca, Kyowa-Kirin, Novartis. Honoraria; Bristol Myers-Squibb, AstraZeneca, Novartis, Merck, AbbVie, EMD, Inivata. J.R. Brahmer: Research Grant; AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines. Consultant; Amgen, Bristol Myers Squibb, Genentech, Eli Lilly, GlaxoSmithKline, Merck, Sanofi. M. Markowski: Honoraria; Clovis Oncology, Exelixis. D.M. Ryan II: None. L. Lo: None. D.M. Sciubba: Consultant; Medtronic, DePuy-Synthes, Baxter. K.J. Redmond: Research Grant; Elekta AB, Accuray. Honoraria; AstraZeneca, Accuray. Travel Expenses; Elekta AB, Accuray.

This review covers the state-of-the-art imaging in therapy assessment and surveillance of lung cancer with focus on the utility of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (

Background Unplanned hospitalization during cancer treatment is costly, can disrupt treatment, and affect patient quality of life. However, incidence and risks factors for hospitalization during lung cancer radiotherapy are not well characterized. Methods Patients treated with definitive intent radiation (≥45 Gy) for lung cancer between 2008 and 2018 at a tertiary academic institution were identified. In addition to patient, tumor, and treatment related characteristics, specific baseline frailty markers (Charlson comorbidity index, ECOG, patient reported weight loss, BMI, hemoglobin, creatinine, albumin) were recorded. All cancer-related hospitalizations during or within 30 days of completing radiation were identified. Associations between baseline variables and any hospitalization, number of hospitalizations, and overall survival were identified using multivariable linear regression and multivariable Cox proportional-hazards models, respectively. Results Of 270 patients included: median age was 66.6 years (31–88), 50.4% of patients were male (n = 136), 62% were Caucasian (n = 168). Cancer-related hospitalization incidence was 17% (n = 47), of which 21% of patients hospitalized (n = 10/47) had > 1 hospitalization. On multivariable analysis, each 1 g/dL baseline drop in albumin was associated with a 2.4 times higher risk of any hospitalization (95% confidence interval (CI) 1.2–5.0, P = 0.01), and baseline hemoglobin ≤10 was associated with, on average, 2.7 more hospitalizations than having pre-treatment hemoglobin > 10 (95% CI 1.3–5.4, P = 0.01). After controlling for baseline variables, cancer-related hospitalization was associated with 1.8 times increased risk of all-cause death (95% CI: 1.02–3.1, P = 0.04). Conclusions Our data show baseline factors can predict those who may be at increased risk for hospitalization, which was independently associated with increased mortality. Taken together, these data support the need for developing further studies aimed at early and aggressive interventions to decrease hospitalizations during treatment.

321 Background: The phase III CheckMate 577 study resulted in adjuvant nivolumab becoming a new standard of care for patients with completely resected E/GEJ cancer with residual pathologic disease post neoadjuvant chemoradiotherapy. We evaluated if neoadjuvant nivolumab (N) or nivolumab/relatlimab (N/R) combined with chemoradiotherapy (CRT) can further improve patient outcomes. Methods: Patients with stage II/III E/GEJ carcinoma eligible for curative resection were treated with standard of care regimen of carboplatin (AUC2), paclitaxel (50mg/m2), RT 41.1Gy in 23 fractions and an Ivor-Lewis esophagectomy (E/MIE) 6-10 weeks after last CRT/IO dose. Patients on arm A (n=16) received 2 cycles of induction N (240mg q2 wks) plus three additional cycles of N on week 1, 3 and 5 of CRT. After safety and feasibility evaluation of arm A, patients on arm B (n=16) received N (240mg q 2 wks) plus R (80mg q 2 wks) following the same schedule. The primary endpoints of the study were safety and feasibility. Secondary endpoints include pCR, MPR (

Purpose In patients with non-small cell lung cancer (NSCLC) who undergo trimodality therapy (chemoradiation followed by surgical resection), it is unknown whether limiting preoperative radiation dose to the uninvolved lung reduces postsurgical morbidity. This study evaluated whether radiation fall-off dose parameters to the contralateral lung that is unaffected by NSCLC are associated with postoperative complications in NSCLC patients treated with trimodality therapy. Methods and materials We retrospectively reviewed NSCLC patients who underwent trimodality therapy between March 2008 and October 2016, with available restored digital radiation plans. Fischer's exact test was used to assess associations between patient and treatment characteristics and the development of treatment-related toxicity. Spearman rank correlation was used to measure the strength of association between dosimetric parameters. Results Forty-six patients were identified who received trimodality therapy with intensity modulated radiation (median, 59.4 Gy; range, 45-70) and concurrent platinum doublet chemotherapy, followed by surgical resection. The median age was 64.9 years (range, 45.6-81.6). The median follow-up time was 1.9 years (range, 0.3-8.4). Twenty-four (52.2%) patients developed any-grade pulmonary toxicity and 14 (30.4%) patients developed grade 2+ pulmonary toxicity. There was an increased incidence of any-grade pulmonary toxicity in patients with contralateral lung volume receiving at least 20 Gy (V20) ≥7% compared with P = .01). Similarly, contralateral lung V10 ≥20% was associated with an increased rate of any-grade pulmonary toxicity compared with V10 P = .01). Pneumonectomy/bilobectomy was associated with grade 2+ pulmonary toxicity ( P = .04). Conclusions Patients who received a higher radiation fall-off dose volume parameter (V20 ≥7% and V10 ≥20%) to the contralateral uninvolved lung had a higher incidence of any-grade postoperative pulmonary toxicity. Limiting radiation fall-off dose to the uninvolved lung may be an important modifiable radiation parameter in limiting postoperative toxicity in trimodality patients.

Background Smoking among patients with cancer is associated with poor outcomes, however, smoking cessation interventions have had limited success. Methods This randomized controlled trial compared a novel smoking cessation intervention ("intervention") with enhanced usual care ("control"). Participants were smokers with head and neck or thoracic malignancies undergoing radiation. Controls received brief counseling. Intervention participants received intensive counseling, pharmacotherapy, text-messaging, and financial incentives. Biochemically confirmed 7-day abstinence at 8 weeks was compared using Fisher's exact t test. Smoking abstinence and intensity were also analyzed using time-series panel regression. Results The study population comprised 19 intervention and 10 control participants. More intervention (74%) than control (30%) participants abstained from smoking at 8 weeks (P = .05). Intervention participants were significantly more likely to abstain (adjusted odds ratio [OR] 14.70; 95% confidence interval [CI] 3.56-60.76) and smoked fewer cigarettes (adjusted incidence rate ratio [IRR], 0.16; 95% CI 0.06-0.40) during weeks 1 to 8. Conclusion This intervention decreased smoking among patients with upper aerodigestive cancers during radiotherapy.

Background and objective Malignant airway obstruction (MAO), a common complication of patients with advanced lung cancer, causes debilitating dyspnoea and poor quality of life. Two common interventions used in the treatment of MAO include bronchoscopy with airway stenting and external beam radiotherapy (EBRT). Data are limited regarding their clinical effectiveness and overall effect on survival. Methods A retrospective chart review of patients treated with airway stenting and/or EBRT at the Johns Hopkins Hospital for MAO between July 2010 and January 2017 was reviewed. Demographics, performance status, cancer histology, therapeutic intervention and date of death were recorded. Survival was calculated using cox regression analysis. Results Of the 606 patients who were treated for MAO, 237 were identified as having MAO and included in the study. Sixty-eight patients underwent rigid bronchoscopy and stenting, 102 EBRT and 67 a combined approach. Patients who underwent stenting hand an increased hazard ratio (HR) of death in comparison to those who received combination therapy (HR: 2.12, 95% CI: 1.02, 4.39), while there was a trend towards significance in the EBRT alone group in comparison to the combination therapy group (HR: 1.62, 95% CI: 0.93, 2.83). Conclusion In this retrospective analysis, combination therapy with stenting and EBRT led to better survival in comparison to stenting or EBRT alone. Prospective cohort trials are needed to confirm these results.

Computer-aided diagnosis significantly reduces the low-dose CT screening false-positive rate and increases the positive predictive value of lung nodule evaluation.

BackgroundDurvalumab consolidation after chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. However, up to 25% of patients progress within 18 months following durvalumab consolidation. Little is known regarding the genomic determinants of response to therapy.1 2MethodsWe retrospectively reviewed medical records of 76 patients with stage III NSCLC who received definitive chemoradiation and durvalumab consolidation between 2015–2020 at a large tertiary academic center. Tumor characteristics, molecular profiling, and clinical outcomes including response, progression-free survival (PFS), and overall survival (OS) were documented in an IRB-approved database. Outcomes were assessed by molecular alterations identified from diagnostic biopsy samples using Kaplan-Meier analysis.ResultsOf 76 patients with stage III NSCLC treated with definitive chemoradiation and durvalumab consolidation, 74 were evaluable for PFS and OS. Median age at diagnosis was 66.5 years and 43% were women (n=32). Histology included adenocarcinoma (55%, n=41) and squamous cell carcinoma (32%, n=24). Median follow-up time was 23.0 months from start of durvalumab. The cohort’s median PFS was 15.9 months with 36 patients having documented radiographic progression. Overall survival for the cohort was 32.0 months with 28 deaths. Molecular profiling was performed at time of diagnosis in 35 patients (47%), of which 30 had adenocarcinoma histology. 18 patients had KRAS mutations including KRAS p.G12C (n=8), which were mutually exclusive with 8 patients who had other clinically targetable alterations (EGFR mutations n=1, ALK fusion n=1, RET fusion n=1, MET exon 14 skipping mutation n=1, or ERBB2 mutation n=4). Three patients had non-targetable mutations (BRAF non-p.V600E, STK11, KEAP1) and the remaining six patients lacked an identifiable alteration. There was no significant difference in PFS (p=0.92 by log-rank) or OS (p=0.36 by log-rank) between patients with KRAS mutations, other targetable alterations, non-targetable mutations, or those without molecular profiling. Within patients with KRAS mutations, there was no significant difference in PFS (p=0.33 by log-rank) or OS (p=0.69 by log-rank) when comparing KRAS p.G12C to non-p.G12C mutations.ConclusionsOur study of real-world cohort of patients with stage III NSCLC examined genomic determinants of response to treatment with definitive chemoradiation and durvalumab. Results from this retrospective study suggest that patients with KRAS-mutated tumors derive similar benefit from therapy than patients with other targetable, non-targetable or no identifiable genomic alterations. Future directions for this cohort include analysis of post-progression therapy, subgroup analysis comparing genomic alterations to patterns of progression, and examination of molecular signatures of patients with progression.ReferencesAntonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 2017;377(20):1919–1929. doi:10.1056/NEJMoa1709937Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. Journal of Thoracic Oncology 2021;16(5):860–867. doi:10.1016/j.jtho.2020.12.015Ethics ApprovalThis retrospective chart review study has obtained ethics approval from the Institutional Review Board at the Johns Hopkins School of Medicine (number: IRB00232313).

Introduction Checkpoint inhibitor pneumonitis (CIP) is a serious toxicity of anti–programmed death-(ligand) 1 immunotherapy. Whether pretreatment differences in pulmonary function exist in patients who develop CIP is unknown. We analyzed the pulmonary function tests (PFTs) of patients with NSCLC treated with immune checkpoint inhibitors (ICIs) to evaluate whether pretreatment lung function was associated with CIP development. Methods Patients were included if they completed greater than or equal to 1 PFT within 2 years preceding ICI initiation. CIP status (CIP+: developed CIP, CIP−: did not develop CIP) was determined clinically. Generalized estimating equation–based linear regression was used to evaluate the effects of time and CIP on lung function. Primary outcomes included the following: percent-predicted forced expiratory volume in 1 second (FEV1pp), percent-predicted forced vital capacity (FVCpp), and FEV1/FVC. Results A total of 43 patients (34 CIP−, 9 CIP+) with 79 PFTs (59 CIP−, 20 CIP+) were included. CIP+ patients had a 21.7% lower pretreatment FEV1pp compared with the CIP− group (95% confidence interval: −38.6 to −4.7). No statistically significant differences in FVCpp or FEV1/FVC were observed. The prevalence of obstructive lung disease was similar in both groups at 67% and 62% for the CIP+ and CIP− cohorts, as was the prevalence of current/former smoking at 100% and 93%, respectively. Conclusions Pretherapy differences in lung function were evident between patients who did and did not develop CIP, though the prevalence of obstructive lung disease was similar. Prospective studies are needed to validate these findings, inform potential risk factors for CIP, and investigate the effects of ICI treatment and CIP on pulmonary function in patients with NSCLC.

Background and purpose To prospectively evaluate hippocampal radiation dose volume effects and memory decline following cranial irradiation. Material and methods Effects of hippocampal radiation over a wide range of doses were investigated by combining data from three prospective studies. In one, adults with small cell lung cancer received hippocampal-avoidance prophylactic cranial irradiation. In the other two, adults with glioblastoma multiforme received neural progenitor cell sparing radiation or no sparing with extra dose delivered to subventricular zone. Memory was measured by the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 6 months after radiation. Dose–volume histograms were generated and dose–response data were fitted to a nonlinear model. Results Of 60 patients enrolled, 30 were analyzable based on HVLT-R DR testing completion status, baseline HVLT-R DR and intracranial metastasis/recurrence or prior hippocampal resection status. We observed a dose–response of radiation to the hippocampus with regard to decline in HVLT-R DR. D50% of the bilateral hippocampi of 22.1 Gy is associated with 20% risk of decline. Conclusions This prospective study demonstrates an association between hippocampal dose volume effects and memory decline measured by HVLT-R DR over a wide dose range. These data support a potential benefit of hippocampal sparing and encourage continued trial enrollment.

To prospectively evaluate cognitive function and intracranial failure patterns after hippocampal-sparing prophylactic cranial irradiation (PCI) for limited-stage small cell lung cancer (SCLC).Adults with limited-stage SCLC, achieving a complete response to chemoradiotherapy and no brain metastases, were eligible. Patients received PCI 25 Gy/10 fractions, with a mean hippocampal dose limited to8 Gy and ≥90% of the brain receiving 90% of the prescription. A diverse battery of neuropsychological testing was performed at baseline and 6 and 12 months after PCI. Brain MRI scans were performed at baseline and 6, 12, 18, and 24 months. The primary endpoint was memory measured by the Hopkins Verbal Learning Test-Revised Delayed Recall at 6 months after PCI. The 25-Gy arm of Radiation Therapy Oncology Group protocol 0212 was used as a reference of potential efficacy. Development of intracranial metastases was recorded. Overall survival and progression-free survival were estimated using the Kaplan-Meier method.Eight men and 12 women with a median age of 61 years enrolled. Two-year overall survival was 88% (95% confidence interval 68%-100%). There was no significant decline in performance between baseline and 6 or 12 months for any of the tests. The association between baseline intelligence quotient and change in performance on testing was not significant. Magnetic resonance imaging revealed asymptomatic brain metastases at a cumulative rate of 20%, with no concurrent extracranial progression. Two patients developed a metastasis in the under-dosed region. Neither involved the dentate gyrus, but 1 involved the avoidance region. Both patients concurrently developed additional metastasis in fully treated brain regions. There were 2 neurologic deaths.This prospective study suggests a potential benefit of hippocampal sparing in limiting the neuropsychological sequelae of brain radiation, but with a risk of failures in the spared region. These data strongly support continued enrollment on ongoing cooperative group randomized trials. Clinical Trials registration number: NCT01797159.