Locally Advanced Non-small Cell Lung Cancer Research Articles

Sequential Hypofractionated Radiotherapy can Offer Similar Disease Control and Survival of Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer?

Concurrent conventional fractionated chemoradiation (ccCRT) is the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC) when compared with convectional fractionated radiation therapy (cfRT) after chemotherapy. The main benefit of ccCRT is associated to disease locoregional control. Sequential Hypofractionated Radiation therapy (s-HypoRT) is a treatment option for these patients. We compared the outcomes of the ccCRT with sequential treatment cfRT and s-HypoRT. It was a retrospective analysis of all inoperable stage III LA-NSCLC submitted to radical radiotherapy (RT) in a single institution from January 2013 to October 2018. Patients submitted to ccCRT and cfRT received 60Gy in 30 fractions. The patients submitted to s-HypoRt received 55Gy in 20 fractions. All patients were treated with conformal RT or IMRT. All chemotherapy schedule was platinum doublet based. Patients submitted All Patients were (re)staged according to the AJCC 8a ed. The criteria for disease progression was based on RECIST v1.1 and the toxicity criteria used was the CTCAE.v4. Survival analysis was evaluated by Kaplan–Meier method and log-rank test. Multivariate models were tested including all covariates with p values < .20 in the univariate analysis. It was recorded the medical charts and treatment planning of 140 patients. The median age was 63 years (range, 25–83). Most were male (61%) and had ECOG Performance Status 1 (72%). The stage distribution was IIIA 32%, IIIB 51% and IIIC 17%. The patient populations were divided in 3 groups: 52 patients (37%) were submitted to cc-CRT, 38 patients (27%) was submitted to sequential cfRT (cfRTSeq) and 50 patients (36%) received s-HypoRT. With the median follow up of 16 months, the median Overall Survival (OS) for the entire population was 23 months and there was no difference in OS between the 3 groups (p = 0,686). Large tumor volume (p = 0,039) and use of IMRT (p = 0,031), was associated with OS on univariate analysis. The 2-years Locoregional Progression Free Survival (LPFS) 62.9% for ccCRT, x 60.0% for s-HypoRT and 41.0% for cfRTSeq (p = 0.031). On multivariate analysis the cfRTSeq (HR 2,11, IC 1,06—4,19) was associated with worse LRPFS. The treatment was well tolerated for all groups, and the rates of grade ≥ 3 acute esophagitis of 1.9% for ccCRT and 4.0% for s-HypoRT (p = ns). Only one case of grade 3 fatigue was evidenced in the cfRTSeq and one case of grade 3 pneumonitis was evidenced in the ccCRT and cfRT group. Our data demonstrated that s-HypoRT results in similar LRPFS when compared with the standard ccCRT. There was no difference in OS. S-HypoRT is a safe and fast treatment strategy for patients not suitable for ccCRT and can be considered a better option than cfRTSeq.

Validating the SumMean 18F-FDG PET Textural Feature as a Prognostic Marker in an Independent Cohort of Locally Advanced Non-Small Cell Lung Cancer Patients Undergoing Concurrent Chemoradiation Therapy

PurposeAnalyses from the ACRIN6668/RTOG0235 trial data identified the SumMean textural feature, calculated from 18-fluorodeoxyglucose positron emission tomography for tumors with a metabolic tumor volume >93 cm3, as a predictor of overall survival (OS) for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy. Here, we validated that finding in a completely independent patient cohort from a single institution. Methods and MaterialsWe identified patients with LA-NSCLC who underwent staging 18-fluorodeoxyglucose positron emission tomography and received definitive chemoradiation therapy at our institution between 2007 and 2018. Primary tumors were segmented semiautomatically, and SumMean score was calculated for each tumor and categorized according to the previously proposed cutoff of 0.018. In patients with metabolic tumor volume >93 cm3, SumMean was evaluated as a predictor of progression-free survival (PFS) and OS using log rank and Cox proportional hazards testing. ResultsOne hundred forty-eight patients met inclusion criteria, and 34 had large tumors (>93 cm3). Twelve (35%) had high SumMean, and 22 (65%) had low SumMean. SumMean was not significantly associated with other clinical variables. Median PFS for patients with large tumors and low SumMean was 5.8 months, compared with 41.1 months for patients with large tumors and high SumMean (log rank P = .022). Median OS for patients with large tumors and low SumMean was 15.0 months; median OS was not reached for patients with large tumors and high SumMean (log rank P = .014). In multivariable analysis, high SumMean was an independent predictor of improved OS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.94; P = .041) and PFS (hazard ratio, 0.30; 95% confidence interval, 0.10-0.86; P = .026). ConclusionsWe externally validated SumMean as a prognostic marker for patients with LA-NSCLC treated with chemoradiation therapy in an independent patient cohort. Future studies will explore potential mechanisms for this association and how textural features may help guide treatment decisions.

Chronic Lung Injury After Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury [CLI]) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for greater than 1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. CLI at 1 year after surgery and its progression were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis as the first manifestation of CLI progression was most frequent after right middle and lower lobectomy. Cavity formation was the subsequent manifestation after progressive lung fibrosis , and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included 7 cases of pulmonary aspergillosis and 2 cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

Multiple Immune Features-Based Signature for Predicting Recurrence and Survival of Inoperable LA-NSCLC Patients.

IntroductionThe immune status of the tumor microenvironment is extremely complex. One single immune feature cannot reflect the integral immune status, and its prognostic value was limited. We postulated that the immune signature based on multiple immuno-features could markedly improve the prediction of post-chemoradiotherapeutic survival in inoperable locally advanced non-small-cell lung cancer (LA-NSCLC) patients.MethodsIn this study, 100 patients who were diagnosed as having inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A five immune features-based signature was then constructed using the nested repeat 10-fold cross validation with least absolute shrinkage and selection operator (LASSO) Cox regression model. Nomograms were then established for predicting prognosis.ResultsThe immune signature combining five immuno-features was significantly associated with overall survival (OS) and progression-free survival (PFS) (P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of −0.05 stratified patients into two groups with 5-year OS rates of 39.8 and 8.8%, and 2-year PFS rates of 22.2 and 5.5% for the high- and low-immune signature groups, respectively. Integrating immune signature, we proposed predictive nomograms that were better than the traditional TNM staging system in terms of discriminating ability (OS: 0.692 vs. 0.588; PFS: 0.672 vs. 0.586, respectively) or net weight classification (OS: 32.96%; PFS: 9.22%), suggesting that the immune signature plays a significant role in improving the prognostic value.ConclusionMultiple immune features-based immune signature could effectively predict recurrence and survival of inoperable LA-NSCLC patients and complemented the prognostic value of the TNM staging system.

Impact of chemoradiotherapy on the immune-related tumour microenvironment and efficacy of anti-PD-(L)1 therapy for recurrences after chemoradiotherapy in patients with unresectable locally advanced non-small cell lung cancer.

A history of radiotherapy and chemoradiotherapy (CRT) reportedly increases the efficacy of the PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC). We investigated the efficacy of anti-PD-(L)1 therapy after CRT failure and how CRT changes the status of PD-L1 expression on tumours and on tumour-infiltrated lymphocytes (TILs). We retrospectively reviewed patients with unresectable locally advanced NSCLC (LA-NSCLC) who were treated with CRT between 2007 and 2018 and evaluated the efficacy of the PD-(L)1 blockade after CRT failure. We also compared the PD-L1 (clone: 22C3) expression levels and the tumoral and stromal distributions of CD8-positive TILs using paired formalin-fixed, paraffin-embedded specimens obtained before and after CRT. We identified 422 patients and 65 patients who had relapsed after CRT received anti-PD-(L)1 therapy. The objective response rate (ORR) and the progression-free survival (PFS) after anti-PD-(L)1 therapy were 48% and 8.7 months (95% CI, 4.5-13), respectively. The RR and PFS did not differ according to the pre-CRT PD-L1 expression levels. PD-L1 expression changed in 16 of the 18 patients between before and after CRT, but a specific trend was not seen (increased, 9 patients; decreased, 7 patients; no change, 2 patients). In contrast, the density of tumoral CD8-positive TILs increased after CRT treatment (pre-CRT median, 110/mm2 versus post-CRT median, 470/mm2; p=0.025). Anti-PD-(L)1 therapy was effective in patients with LA-NSCLC who had progressed after CRT regardless of their pre-CRT PD-L1 expression. The efficacy of anti-PD-(L)1 therapy for patients with NSCLC with CRT failure was superior to that of standard second-line treatment for patients with advanced NSCLC.

Sensitivity analysis of FDG PET tumor voxel cluster radiomics and dosimetry for predicting mid-chemoradiation regional response of locally advanced lung cancer

We investigated the sensitivity of regional tumor response prediction to variability in voxel clustering techniques, imaging features, and machine learning algorithms in 25 patients with locally advanced non-small cell lung cancer (LA-NSCLC) enrolled on the FLARE-RT clinical trial. Metabolic tumor volumes (MTV) from pre-chemoradiation (PETpre) and mid-chemoradiation fluorodeoxyglucose-positron emission tomography (FDG PET) images (PETmid) were subdivided into K-means or hierarchical voxel clusters by standardized uptake values (SUV) and 3D-positions. MTV cluster separability was evaluated by CH index, and morphologic changes were captured by Dice similarity and centroid Euclidean distance. PETpre conventional features included SUVmean, MTV/MTV cluster size, and mean radiation dose. PETpre radiomics consisted of 41 intensity histogram and 3D texture features (PET Oncology Radiomics Test Suite) extracted from MTV or MTV clusters. Machine learning models (multiple linear regression, support vector regression, logistic regression, support vector machines) of conventional features or radiomic features were constructed to predict PETmid response. Leave-one-out-cross-validated root-mean-squared-error (RMSE) for continuous response regression (ΔSUVmean) and area-under-receiver-operating-characteristic-curve (AUC) for binary response classification were calculated. K-means MTV 2-clusters (MTVhi, MTVlo) achieved maximum CH index separability (Friedman p < 0.001). Between PETpre and PETmid, MTV cluster pairs overlapped (Dice 0.70–0.87) and migrated 0.6–1.1 cm. PETmid ΔSUVmean response prediction was superior in MTV and MTVlo (RMSE = 0.17–0.21) compared to MTVhi (RMSE = 0.42–0.52, Friedman p < 0.001). PETmid ΔSUVmean response class prediction performance trended higher in MTVlo (AUC = 0.83–0.88) compared to MTVhi (AUC = 0.44–0.58, Friedman p = 0.052). Models were more sensitive to MTV/MTV cluster regions (Friedman p = 0.026) than feature sets/algorithms (Wilcoxon signed-rank p = 0.36). Top-ranked radiomic features included GLZSM-LZHGE (large-zone-high-SUV), GTSDM-CP (cluster-prominence), GTSDM-CS (cluster-shade) and NGTDM-CNT (contrast). Top-ranked features were consistent between MTVhi and MTVlo cluster pairs but varied between MTVhi-MTVlo clusters, reflecting distinct regional radiomic phenotypes. Variability in tumor voxel cluster response prediction can inform robust radiomic target definition for risk-adaptive chemoradiation in patients with LA-NSCLC.FLARE-RT trial: NCT02773238.

A phase II study of daily carboplatin plus irradiation followed by durvalumab for stage III non-small cell lung cancer patients with PS 2 up to 74\u2009years old and patients with PS 0 or 1 from 75\u2009years: NEJ039A (trial in progress)

BackgroundDurvalumab is a standard drug used during maintenance therapy after chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the clinical benefits of durvalumab after chemoradiotherapy in patients with LA-NSCLC with a performance status (PS) of 2 and/or aged > 75 years. As daily carboplatin plus concurrent thoracic radiotherapy is recommended for elderly patients according to guideline, the current phase II study aims to investigate the effect of daily carboplatin plus radiotherapy followed by durvalumab for patients with stage III NSCLC who have a PS of 2 and/or are older.MethodsDaily carboplatin plus radiotherapy followed by durvalumab is performed for the patients with stage III NSCLC who have a PS of 2 and/or are older. This is a trial in progress manuscript.Study treatmentDaily, intravenous, low-dose carboplatin (30 mg/m2 in a 30-min infusion) is administered to patients 1 h before radiotherapy for the first 20 fractions. Radiotherapy for all patients consisted of 60 Gy administered as 30 fractions over 6 weeks. Durvalumab at a dose of 10 mg/kg/body is intravenously administered every 2 weeks for up to 12 months after chemoradiotherapy.Exploratory assessmentIn the future, an exploratory investigation will be performed to determine whether the combined assessment of T-cell markers, PD-L1 expression, and tumor mutation burden could predict the outcomes of the regimen.DiscussionThe results of our study will exhibit the efficacy and tolerability of durvalumab as maintenance therapy after daily carboplatin plus radiotherapy.Trial registrationDuring the first registration (before induction chemoradiotherapy), 70 patients will be included; then, we include 58 patients during the second registration (before durvalumab treatment after chemoradiotherapy). https://jcrb.niph.go.jp/.Primary endpointThe primary endpoint of the current study is the 12-month progression-free survival (PFS) rate after the initiation of durvalumab.Secondary endpointsThe secondary endpoints are the feasibility, objective response, PFS, overall survival, and adverse events.

A narrative review of synergistic drug administration in unresectable locally advanced non-small cell lung cancer: current landscape and future prospects in the era of immunotherapy.

Based on the PACIFIC study, the standard care of unresectable locally advanced non-small cell lung cancer (LA-NSCLC) shifted from concurrent chemo-radiotherapy (CCRT) alone to CCRT followed by durvalumab consolidation in 2017. In the era of immunotherapy, two kinds of therapeutic drugs are involved in the management of LA-NSCLC: chemotherapeutics and anti-PD-1/PD-L1 agents. However, the best choices of systematic chemotherapy, immunotherapy, and treatment schedule remain controversial. The immune modulation effects of chemotherapy, as well as the potential immunosuppressive impact of pretreatment medications, should be taken into consideration. Indeed, chemotherapeutics are double-edged swords to immunotherapy, with both stimulatory and suppressive effects on the immune system. Moreover, low-dose chemotherapy is reported to enhance anti-tumor immune responses with reduced toxicities. As for glucocorticoids, there is no consensus about its exact impact on the efficacy of immunotherapy. In addition, the timing of anti-PD-1/PD-L1 agent related to CCRT has three modes: induction, concurrent, and consolidation therapy. Although CCRT followed by durvalumab consolidation is the standard of care, the best sequence of immunotherapy and chemo-radiotherapy is still under debate. Furthermore, the efficacy and toxicity of various PD-1/PD-L1 inhibitors should be compared, especially in the background of CCRT. In this review, we will summarize the detailed knowledge about chemotherapeutics and anti-PD-1/PD-L1 axis agents, and discuss the potential implications in designing novel, effective treatment strategies for LA-NSCLC.

Radiotherapy for unresectable locally advanced non-small cell lung cancer: a narrative review of the current landscape and future prospects in the era of immunotherapy.

Significant recent advances have occurred in the use of radiation therapy for locally advanced non-small cell lung cancer (LA-NSCLC). In fact, the past few decades have seen both therapeutic gains and setbacks in the evolution of radiotherapy for LA-NSCLC. The PACIFIC trial has heralded a new era of immunotherapy and has raised important questions for future study, such as the future directions of radiation therapy for LA-NSCLC in the era of immunotherapy. Modern radiotherapy techniques such as three-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) provide opportunities for improved target conformity and reduced normal-tissue exposure. However, the low-dose radiation volume brought by IMRT and its effects on the immune system deserve particular attention when combing radiotherapy and immunotherapy. Particle radiotherapy offers dosimetric advantages and exhibits great immunoregulatory potential. With the ongoing improvement in particle radiotherapy techniques and knowledge, the combination of immunotherapy and particle radiotherapy has tremendous potential to improve treatment outcomes. Of particular importance are questions on the optimal radiation schedule in the settings of radio-immunotherapy. Strategies for the reduction of the irradiated field such as involved-field irradiation (IFI) and omission of clinical target volume (CTV) hold promise for better preservation of immune function while not compromising locoregional and distant control. In addition, different dose-fractionation regimens can have diverse effects on the immune system. Thus, prospective trials are urgently needed to establish the optimal dose fractionation regimen. Moreover, personalized radiotherapy which allows the tailoring of radiation dose to each individual’s genetic background and immune state is of critical importance in maximizing the benefit of radiation to patients with LA-NSCLC.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BackgroundInflammation plays a vital role in tumor growth and progression and can be affected by radiotherapy (RT) and chemotherapy. We sought to investigate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and their associations with dosimetric factors in locally advanced non-small cell lung cancer (LA-NSCLC).MethodsIn this retrospective study, subjects consisted of 244 patients who had received definitive RT ± chemotherapy for LA-NSCLC between 2012 and 2016. Absolute lymphocyte count (ALC), NLR and PLR recorded at pretreatment, during RT and post-RT were analyzed. Multivariable analysis (MVA) was performed to correlate clinical factors and inflammatory biomarkers with progression-free survival (PFS) and overall survival (OS) using a Cox regression model. Relationships between NLR or PLR with OS and PFS were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multiple stepwise linear regression was used to assess the associations between dosimetric factors and NLR or PLR.ResultsThe median PFS and OS for all patients were 8.6 and 15.8 months, respectively. On MVA for PFS and OS, higher 1-month post-RT start NLR [hazard ratio (HR) 1.049; 95% CI: 1.018–1.080; P=0.001] or higher 1-month post-RT start PLR (HR 1.001; 95% CI: 1.000–1.002; P<0.001) was associated with inferior PFS. Higher 1-month post-RT start NLR (HR 1.040; 95% CI: 1.013–1.069; P=0.004) or PLR (HR 1.001; 95% CI: 1.001–1.002; P<0.001) was also an independent predictor of OS. ALCmin, baseline NLR and PLR were not associated with treatment outcomes. Multiple stepwise linear regression analysis confirmed that baseline NLR (P<0.001), heart V20 (P<0.001), heart V40 (P<0.001), and mean body dose (MBD) were significantly associated with 1-month post-RT start NLR. Also, baseline PLR (P<0.001) and MBD (P<0.001) were significantly associated with 1-month post-RT start PLR.ConclusionsHigher NLR and PLR during treatment were associated with worse patient outcomes, and heart dose or body dose was correlated with NLR or PLR in advanced NSCLC patients treated with definitive RT.

Is clinical target volume necessary?-a failure pattern analysis in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy using intensity-modulated radiotherapy technique.

BackgroundOur previous dosimetric study showed that for locally advanced non-small cell lung cancer (LA-NSCLC), radiotherapy with intensity-modulated radiotherapy (IMRT) technique could deliver sufficient dose coverage to subclinical regions and reduce the dose to normal tissues with the omission of clinical target volume (CTV). To further clinically validate this strategy, we conducted the current study to analyze the failure pattern for patients with LA-NSCLC treated with concurrent chemotherapy and CTV-omitted IMRT. We also investigated the effects of target volumes on lymphopenia during radiotherapy to further test the potential benefits of CTV omission in anti-tumor immunotherapy.MethodsA total of 63 patients with LA-NSCLC treated with CTV-omitted IMRT with concurrent chemotherapy were enrolled in this study. Their planning target volume (PTV) (also PTV-g) was expanded directly from gross tumor volume (GTV). A virtual CTV was expanded from GTV, and the PTV generated from virtual CTV was named planning target volume with CTV expansion (PTV-c). Treatment failures were divided into local, regional, and distant failures, and local–regional recurrences were classified into inside PTV-g (IN-PTV-g), between PTV-g and PTV-c (PTV-g-c), and outside PTV-c (OUT-PTV-c). The relationship between lymphopenia during radiotherapy and the target volumes was also evaluated using Spearman’s correlation analysis.ResultsAmong the 60 patients with detailed follow-up data for recurrences, 46 (76.7%) experienced recurrences, with 18 (30.0%) being local recurrence, 5 (8.4%) being regional failure, and 33 (55.0%) being distant failure. For the 21 patients with local–regional recurrences, 16, 6, and 1 were IN-PTV-g, OUT-PTV-c, and PTV-g-c recurrences, respectively. Lymphopenia during radiotherapy was associated with both GTV and PTV, with larger volumes linked to severe lymphopenia.ConclusionsCTV omission is feasible for LA-NSCLC treated with concurrent chemoradiotherapy and does not compromise failure inside the subclinical region. The radiation volumes were associated with lymphopenia during radiotherapy, with larger volumes related to severe lymphopenia. This finding supports the further exploration of CTV omission for immunotherapy.

Systemic thromboembolism from a misdiagnosed non‑bacterial thrombotic endocarditis in a patient with lung cancer: A case report

Thromboembolic events are frequent in patients with cancer, commonly involving the venous and pulmonary circulation. The arterial system is rarely implicated in embolism and, when involved, a cardiogenic origin should always be excluded. In the present study, a case of a patient who developed multiple embolic events concomitantly with the diagnosis of locally-advanced non-small cell lung cancer with high expression levels of programmed death-ligand 1 (PD-L1) in >50% of tumor cells is reported. A cardiac defect interpreted as a patent foramen ovale required low molecular weight heparin administration. Despite the anti-coagulant therapy, before first-line anticancer treatment with pembrolizumab immunotherapy could be administered due to high PD-L1 expression levels, a new hospitalization was required due to the onset of novel ischemic manifestation. New transthoracic and transesophageal echocardiography revealed a previously misdiagnosed vegetation of the mitral valve that caused systemic embolization. The lack of any sign of infection led to the diagnosis of a non-bacterial thrombotic endocarditis (NBTE), whose embolic sprouting gave rise to the widespread ischemic events. No active anticancer treatment was feasible due to the rapid progression of the disease. NBTE can evolve quickly, eventually preventing any chance of treatment targeting the primary cause, which in the present study was lung cancer. If NBTE can be correctly diagnosed sooner then there may be the potential for anticancer therapy that does not worsen the hypercoagulability state, thus improving cancer-associated survival.

Cost-effectiveness of endoscopic mediastinal staging.

Lung cancer is the first cause of cancer-related mortality. Mediastinal staging has a main role in the definition of the therapeutic strategy in early-stage and locally-advanced non-small cell lung cancer (NSCLC). Non-invasive mediastinal staging with CT or PET imaging has relatively limited accuracy, and nodal biopsy may be required to reach adequate staging results. In the last two decades endoscopic techniques have been increasingly used in the field of mediastinal staging thanks to a reduced invasiveness and to the possibility of obtaining a more thorough assessment in comparison with surgical techniques. However, the ideal staging strategy is still a matter for debate, particularly considering the cost-effectiveness of the different approaches. Complication-rate, costs, impact on quality of life, time delay to treatment and survival of the different staging techniques still have to be analyzed in detail. Other issues to be discussed are the optimal combination of staging approaches and the influence of factors as the prevalence of nodal disease on the cost-effectiveness of the different methods. Future issues of invasive staging concern the possibility of extending the definition of nodal status to N1 intrapulmonary nodes, in the light of the development of new oncological and surgical therapeutic approaches.

1236MO A single-arm phase II study of gefitinib with concurrent thoracic radiotherapy in unresectable locally-advanced non-small cell lung cancer patients with EGFR mutation (West Japan Oncology Group 6911L)

1236MO A single-arm phase II study of gefitinib with concurrent thoracic radiotherapy in unresectable locally-advanced non-small cell lung cancer patients with EGFR mutation (West Japan Oncology Group 6911L)

Efficacy and safety of recombinant human endostatin combined with radiotherapy or chemoradiotherapy in patients with locally advanced non-small cell lung cancer: a pooled analysis

PurposeTo assess the efficacy and safety of recombinant human endostatin in combination with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC).MethodsWe searched eligible literature in available databases using combinations of the following search terms: lung cancer, endostatin or endostar, radiotherapy or radiation therapy or chemoradiotherapy. The inclusion criteria were: prospective or retrospective (including single-arm) studies that evaluated the efficacy and safety of endostatin plus radiotherapy (ERT) or concurrent chemoradiotherapy (ECRT) in patients with LA-NSCLC. Primary outcomes included the following: objective response rate (ORR), local control rates (LCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Tests of heterogeneity, sensitivity, and publication bias were performed.ResultsA total of 271 patients with LA-NSCLC from 7 studies were enrolled, including six prospective trials and one retrospective study. The pooled median PFS was 11.3 months overall, 11.2 months in the ECRT group, and 11.8 months in the ERT group. Pooled median OS and ORR were 18.9 months and 77.2% overall, 18.4 months and 77.5% in the ECRT group, and 19.6 months and 76.1% in the ERT group, respectively. The incidences of major grade ≥ 3 AEs for all patients, subgroups of ECRT and ERT were 10.9% vs 11.9% vs 9.4% for radiation pneumonitis, 11.6% vs 12.2% vs 9.4% for radiation esophagitis, 35.5% vs 43.4% vs 0 for leukopenia, 27.8% vs 40.7% vs 2.1% for neutropenia, and 10.5% vs 12.3% vs 2.1% for anemia.ConclusionsCombined endostatin with RT or CCRT is effective and well tolerated in treating LA-NSCLC, and less toxicities occur. Further validation through prospective randomized control trials is required.

Abstract 6497: Early assessment of liquid biomarkers to predict pneumonitis after chemoradiation in patients with locally advanced non-small cell lung cancer (LA-NSCLC)

Abstract PURPOSE: Patients undergoing chemoradiation (CRT) for LA-NSCLC are at significant risk of developing radiation pneumonitis. As consolidation checkpoint inhibitor immunotherapy (IO) becomes standard of care after chemoradiation, pneumonitis (either radiation or immune-mediated) is also the most common rationale for cessation of IO and management with steroids. Our goal is to develop an early predictive biomarker for pneumonitis post-CRT, to risk stratify patients for treatment toxicity. We analyzed relationships between plasma cytokine levels, single cell functional assays, and pneumonitis prevalence within a prospective phase II clinical trial of chemoradiation for LA-NSCLC. METHODS: 35 Patients with AJCC v7 stage IIB-IIIB NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238) from 2016-2019. All patients underwent chemoradiation; 18 patients also received consolidation IO (durvalumab) after it became standard of care in late 2017. 24 patients consented to peripheral blood collection at baseline and 21 patients during week 3 of CRT. Plasma concentrations of 43 common inflammatory cytokines were measured at both time points. Pneumonitis was defined as CTCAE v4 grade 2 or higher, irrespective of radiation-induced or immune-mediated causality. Bootstrapping over 100 iterations of LASSO feature selection was performed to reduce dimensionality and guard against false discoveries. Univariate Cox regression of selected cytokine concentrations were evaluated for associations to time-dependent pneumonitis incidence. RESULTS: Grade 2+ pneumonitis occurred in 13/35 patients, 7 of whom received durvalumab. Four plasma cytokines were most consistently associated with pneumonitis: GMCSF, E selectin, sIL6R (soluble Interleukin-6 Receptor), and SCF (stem cell factor). Higher baseline GMCSF and sIL6R (HR 2.1-4.2, p=0.01-0.03) were correlated with pneumonitis. Higher mid-CRT GMCSF, sIL6R and E selectin (HR 1.6-3.2, p=0.02-0.05), along with decline in mid-CRT SCF (HR 0.2, p=0.02), were associated with pneumonitis. The 4-cytokine signature at mid-CRT predicted for subsequent pneumonitis incidence (cross-validated AUC=0.84). Since GMCSF and SCF are linked to monocyte development, and sIL6R and E selectin are both associated with monocyte function, we performed single cell functional assay (Isocode chips) of mid-CRT peripheral monocytes from two patients with different pneumonitis status. A patient who subsequently developed grade 3 pneumonitis showed higher peripheral monocyte function (5.7% producing MIP1b) relative to a patient who did not develop pneumonitis (0% producing MIP1b). CONCLUSIONS: Our results show it may be possible to predict development of pneumonitis after chemoradiation in patients with LA-NSCLC, with mid-treatment assessment of 4 plasma cytokines: GMCSF, E selectin, sIL6R, and SCF. Changes in these cytokines may be related to monocyte function. These biomarkers need to be validated in other independent patient populations. Citation Format: Jing Zeng, Ramesh Rengan, Rafael Santana-Davila, Daniel S. Hippe, Ashley M. Houghton, Paul E. Kinahan, Hubert J. Vesselle, Paul Lampe, Stephen R. Bowen. Early assessment of liquid biomarkers to predict pneumonitis after chemoradiation in patients with locally advanced non-small cell lung cancer (LA-NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6497.

Abstract 1671: Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma

Abstract Non-small cell lung carcinoma (NSCLC) represents ~ 85% of lung cancer, and ~1/3 of these patients present with locally-advanced, unresectable/medically-inoperable disease. Patients who present with locally-advanced NSCLC are commonly treated with definitive chemoradiation. Even though an initial response to concurrent chemoradiation is commonly observed, disease relapse in the radiation fields occurs in 1/3 of cases, likely driven by therapy-resistant tumor cells. However, the underlying molecular mechanisms of chemoradiation resistance of NSCLC remains largely unknown. We herein report that upregulation of mTOR signaling plays an important role in the chemoradiation resistance of NSCLC. Patient-derived xenograft (PDX) models of lung squamous cell carcinoma (LUSC) were established in the flanks of NOD-SCID gamma (NSG) mice. Chemoradiation resistant tumor models were developed by treating the tumors with a regimen of 2-4 weeks of chemoradiation (20, 30 or 40 Gy at 2 Gy per day, concurrent with cisplatin). Recurrent tumor models were collected and subjected to functional proteomics using reverse phase protein analysis (RPPA). Several LUSC tumors recurred in the 20 Gy+cisplatin, and 40 Gy+cisplatin groups. RPPA analysis of the recurrent and parental (untreated) PDX tumors showed that there were enhanced mTOR signaling in the chemoradiation resistant 20 Gy+cisplatin and 40 Gy+cisplatin tumors compared to that in the control tumors. Of note, phospho-AKT-S473, phospho-AKT-S308, phospho-S6-S235/6 and phospho-GSK3β-S9/21 were the highest upregulated signaling and were validated by immunoblotting. Consistently, pharmacological inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. Our results demonstrate that utilization of PDX models is a useful method to elucidate the molecular mechanisms of chemoradiation resistance of NSCLC and deregulation of mTOR signaling contributes to the chemoradiation resistance of NSCLC. Our findings suggest that clonal selection of subpopulations with high mTOR signaling in heterogeneous NSCLC tumors might contribute to the relapse of NSCLC after chemoradiation and that mTOR kinase inhibitors are promising agents for the upfront treatment of NSCLC patients in combination with chemoradiation. Citation Format: Changxian Shen, Duan-Liang Shyu, Min Xu, Linlin Yang, Wenrui Duan, Terence M. Williams. Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1671.

Functional lung volume mapping with perfusion Single-Photon Emission Computed Tomography scan for radiotherapy planning in patients with locally advanced nonsmall cell lung cancer

Radical chemotherapy-radiotherapy represents the standard treatment for locally-advanced nonsmall cell lung cancer (NSCLC). Conventional radiotherapy achieves limited local tumor control, but dose escalation to the primary tumor is prevented by radiotherapy-induced toxicity. The aim of this study was to evaluate feasibility of tailored intensity-modulated radiotherapy (IMRT) planning based on lung single-photon emission computed tomography (SPECT) perfusion data and to compare functional and conventional dose-volume parameters. A total of 21 patients were prospectively enrolled. Patients underwent IMRT treatment with 2 Gy/fraction (median total dose of 60 Gy). Lung perfusion SPECT images were acquired before radiotherapy and 3 and 6 months after radiotherapy completion. SPECT and planning computed tomography images were co-registered using MIM-MAESTRO software with 3D-PET Edge algorithm. Lung volumes were defined anatomically as total lung and functionally as total not functional lung and total functional lung. Dose-volume histograms were calculated using QUANTEC constraints [mean lung dose (MLD)<20 Gy, V20<20%]. For each patient, conventional and functional radiotherapy plans were generated and compared. A total of 19 of 21 patients with NSCLC were included (mean age 66 years, 11 stage IIIA, 8 stage IIIB), 12/19 patients completed the 6-months follow-up. A significant reduction of mean V20 was observed in functional radiotherapy planning compared to conventional plan (405.9 cc, P < 0.001). Mean MLD was also lower in the SPECT-based plans, but the difference was not statistically relevant (0.8 Gy, P = 0.299). G2 radiation pneumonitis was observed in two patients. Functional radiotherapy planning allowed to decrease functional lung irradiation compared to conventional planning. The possibility to limit radiotherapy-induced toxicity could allow us to perform an effective dose-escalation to target volume.

Incidence of hippocampal metastases in non‐small‐cell lung cancer

Patients with locally advanced non-small-cell lung cancer (LA-NSCLC) develop brain metastases in 25-50% of cases during the course of their disease. Data on the incidence of metastases occurring in the hippocampus/perihippocampal zones are limited. This is important when considering hippocampal-sparing brain radiation (HS-BR), a method that could potentially reduce the neurocognitive impact of such treatment. The aim of this study was to assess the incidence of hippocampal/perihippocampal metastases in a cohort of patients with advanced NSCLC treated at our institution. This retrospective cohort study included NSCLC patients discussed at our institutional lung cancer multidisciplinary meeting between 2000 and 2016. MRI and contrast-enhanced CT (ceCT) brain images were reviewed to assess the incidence of hippocampal/perihippocampal metastases including metastases within the hippocampal subgranular zone and a 5mm margin (hippocampal avoidance region) defined as per the RTOG 0933 study. Of 2146 patients reviewed, 357 (16.6%) had brain metastases. A total of 335 patients had available MRI/ceCT brain images for review. Thirty (9%) patients had brain metastases in the hippocampal avoidance region, 8 (2.4%) with hippocampal metastases and 22 (6.6%) with perihippocampal metastases. Univariate analyses did not show an association between developing metastases in the hippocampal avoidance region and age (P=0.75), gender (P=0.91) and tumour type (P=0.298). The incidence of metastases in the hippocampal avoidance region in our large cohort of patients was 9%. With low rates of metastases in this region, HS-BR can be considered a feasible option in the management of patients with advanced NSCLC.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints

PurposeThe dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. Methods and MaterialsIn the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. ResultsThe multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. ConclusionsIn addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.