Early-stage Non-small Cell Lung Carcinoma Research Articles

STK11/LKB1 alterations worsen the poor prognosis of KRAS mutated early-stage non-squamous non-small cell lung carcinoma, results based on the phase 2 IFCT TASTE trial

BackgroundSTK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). Patients and methodsSurgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. ResultsAmong 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1–3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2–4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5–10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6–5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. ConclusionThis analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

Objective improvement in dexterity for trainees undergoing a video-assisted thoracoscopic surgery simulation program, a prospective single center study.

Video-assisted thoracoscopic surgery (VATS) is the recommended approach for the management of early-stage operable non-small cell lung carcinoma as well as for other pathologies of the thoracic cavity. Although VATS approaches have been largely adopted in Europe and North America, teaching the technique to novice thoracic surgery trainees remains challenging and non-standardized. Our objective was to assess the impact of a VATS simulation training program on the dexterity of thoracic surgery residents in a prospective single institution study. We developed a 6-month VATS simulation training program on two different dry-lab simulators (Johnson & Johnson Ethicon Stupnik® lobectomy model; CK Surgical Simulation® Crabtree perfused lobectomy model) and assessed the skills of first year thoracic surgery residents (study group, n=7) before and after this program using three standardized exercises on the Surgical Science Simball® Box (peg placement on a board, rope insertion in loops, precision circle cutting). The results were compared to those of last-year medical students who performed the same Simball® Box exercises at a 6-month interval without undergoing a training program (control group, n=5). For each participant, the travel distances of instruments, operation time and absences of periods of extreme motion were assessed for each exercise by the use of the computer-based evaluation of the Simball® Box. After the 6-month VATS training program, all residents revealed a significant increase of their performance status with respect to instrument travel distances operation times and absence of periods of extreme motion in all three exercises performed. The performance of the control group was not different from the study group prior to the training program and remained unchanged 6 months later, for all exercises and parameters assessed. Our results suggest that the implementation of a VATS simulation training program objectively increases the dexterity of thoracic surgery residents and could be an interesting training tool for their surgical education.

Percutaneous ablation treatment in metastatic lung tumors: a single-center experience

In recent years, many studies have proven that percutaneous thermal ablation is an effective second-line treatment method with low complication rates in early-stage non-small cell lung carcinoma and lung metastases. Radiofrequency ablation and microwave ablation are commonly used for this purpose. To evaluate the factors affecting the success of the percutaneous thermal ablation treatment with technical success, complication rates, and long-term follow-up results in metastatic lung lesions. Computed tomography (CT)-guided percutaneous ablation was performed for 70 metastatic lung lesions in 35 patients (22 men, 13 women; mean age = 61.34 years; age range = 41-75 years). Radiofrequency ablation was performed in 53/70 (75.7%) lesions and microwave ablation in 17/70 (24.3%) lesions. The technical success rate was 98.6%. Median overall survival, progression-free survival, and local recurrence-free survival of the patients were 33.9 months (range=25.6-42.1 months), 12 months (range=4.9-19.2 months), and 24.2 months (range=8.2-40.1 months), respectively. One- and two-year overall survival rates were 84% and 74%, respectively. Median progression-free survival times were 20.3 months and 11.4 months, respectively, according to the number of metastatic lung lesions being single and multiple, and the difference was statistically significant (P = 0.046). According to the number of lesions ≤3 and >3, the difference was also found statistically significant (P = 0.024) (14.3 months and 5.7 months, respectively). In conclusion, CT-guided percutaneous thermal ablation is a safe and effective treatment method in metastatic lung lesions. The number of lesions is the most important factor in predicting treatment success.

The use of minimal residual disease in thoracic oncology: Gaps between promises and the on-the-ground reality of daily practice.

The assessment of minimal residual disease (MRD) from blood samples of patients with resected non-small cell lung carcinoma (NSCLC) is promising and opens up many opportunities for the optimisation of patient care in daily practice. Notably, this includes the potential for escalation or de-escalation of adjuvant therapies. Thus, the evaluation of MRD status can directly contribute to an increase in the overall survival of early stage NSCLC patients and/or limit therapeutic but also "financial" toxicity. Therefore, several clinical trials recently evaluated MRD in early stage NSCLC by integrating and retrospectively comparing the results of MRD assessments. In this context, there is an urgent need to close the gap between clinical research and the use of the evaluation of MRD in routine daily practice. Further action needs to be taken, particularly in evaluating the pertinence of the detection of MRD in prospective interventional clinical studies. This may be done in part by comparing different parameters, such as the techniques used, the different time points and the cutoffs of MRD assessments. This article investigates the assessment of MRD in non-small cell lung cancers, with a special focus on the issues associated with the various assays and the limitations of using circulating free DNA analyses for MRD assessment in early stage lung cancer. Recommendations and tips for the optimisation of MRD evaluation in non-small cell lung cancers are provided.

Role of circulating-tumor DNA in the early-stage non-small cell lung carcinoma as a predictive biomarker.

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer.

Planning Tumor Volume and Local Control Following Stereotactic Body Radiation Therapy of Early-Stage NSCLC

<h3>Purpose/Objective(s)</h3> Stereotactic body radiation therapy (SBRT) is often used to treat primary early-stage non-small cell lung carcinoma (NSCLC) as an alternative to surgical management. The planning methods used for delivering SBRT differs across institutions with various planning target volume (PTV) margins utilized. The purpose of this study is to evaluate the impact of PTV margin and other factors on local control following SBRT. <h3>Materials/Methods</h3> A total of 283 patients with single lesion early-stage NSCLC treated with SBRT at our institution between 2017-2019 were included in this retrospective analysis. The median age was 75 years, with 57% female gender. Of the treated tumors, 68.6% were peripheral while 31.4% were central. Adenocarcinoma was the most common histology at 35.3% followed by 27.2% squamous cell carcinoma with other/unknown histology in the remaining 37.5% of patients. Mean gross tumor volume (GTV) was 9.7 cc (0.3-92.1) and mean PTV was 33.5 cc (5.3-170). The most common fractionation scheme used was 54 Gy in 3 fractions followed by 48 Gy in 4 fractions with mean biologically effective dose at α/β=10 (BED10) of 149.5 Gy. Local recurrence was based on recurrence of the treated lesion on follow-up imaging, defined as either significant enlargement not consistent with post-treatment radiation fibrosis or significant residual FDG-avidity if a PET/CT scan was obtained. Univariate analysis was performed via Kaplan-Meier analysis to analyze the association of local control with GTV volume, ratio of PTV to GTV volume, BED10, histology, and tumor location. <h3>Results</h3> The median follow-up was 1.6 years. Overall, 30 of the 283 patients (10.6%) developed a local recurrence. Kaplan-Meier analysis of local control and patients with a PTV to GTV ratio greater than the median of 4.74 showed statistically significant better local control at 3-years of 90.9% versus 67.7% (p=0.004). Local control was also significantly associated with GTV volume with 3-year local control of 91.9% for tumors <5 cc versus 67.7% for those >5 cc (p=0.007). The BED10 was significantly associated with local control with a 3-year local control of 82.2% for >150 Gy BED10 versus 78.3% for 100-150 Gy BED10 (p=0.016). Local control was not associated with histology (p=0.146) or central versus peripheral location (p=0.25). <h3>Conclusion</h3> Larger PTV to GTV ratio, smaller tumor volume, and a BED10 of greater than 150 Gy were significantly associated with better local control in patients treated with SBRT for early-stage NSCLC. These factors should be considered when treatment planning for SBRT in these patients.

Prognostic value of postoperative decrease in serum albumin on surgically resected early-stage non-small cell lung carcinoma: A multicenter retrospective study.

Preoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC. We analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb - postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC. Patients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (p<0.0001) in the TC, and pT1b (p = 0.0169) and non-adenocarcinoma (p = 0.0251) in the VC. Multivariable analysis identified ΔAlb as an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both cohorts (VC: DFS, HR = 1.9, 95%CI: 1.10-3.15, p = 0.0197; OS, HR = 2.0, 95%CI: 1.13-3.45, p = 0.0173). Moreover, subgroup analysis demonstrated that the prognostic value of ΔAlb was consistent for age, sex, smoking history, surgical procedure, and histological type. We demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes.

EGFR Status Assessment for Better Care of Early Stage Non-Small Cell Lung Carcinoma: What Is Changing in the Daily Practice of Pathologists?

The recent emergence of novel neoadjuvant and/or adjuvant therapies for early stage (I-IIIA) non-small cell lung carcinoma (NSCLC), mainly tyrosine kinase inhibitors (TKIs) targeting EGFR mutations and immunotherapy or chemo-immunotherapy, has suddenly required the evaluation of biomarkers predictive of the efficacy of different treatments in these patients. Currently, the choice of one or another of these treatments mainly depends on the results of immunohistochemistry for PD-L1 and of the status of EGFR and ALK. This new development has led to the setup of different analyses for clinical and molecular pathology laboratories, which have had to rapidly integrate a number of new challenges into daily practice and to establish new organization for decision making. This review outlines the impact of the management of biological samples in laboratories and discusses perspectives for pathologists within the framework of EGFR TKIs in early stage NSCLC.

Can reducing planning safety margins broaden the inclusion criteria for lung stereotactic ablative body radiotherapy?

IntroductionStereotactic ablative body radiotherapy (SABR) is currently indicated for inoperable, early‐stage non‐small cell lung carcinoma (NSCLC). Advancements in image‐guidance technology continue to improve treatment precision and enable reductions in planning safety margins. We investigated the dosimetric benefits of margin reduction, its potential to extend SABR to more NSCLC patients and the factors influencing plan acceptability.MethodsThis retrospective analysis included 61 patients (stage IA–IIIA) treated with conventional radiotherapy. Patients were ineligible for SABR due to tumour size or proximity to organs at risk (OAR). Using Pinnacle auto‐planning, three SABR plans were generated for each patient: a regular planning target volume margin plan, a reduced margin plan (gross tumour volume GTV+3 mm) and a non‐margin plan. Targets were planned to 48Gy/4 or 50Gy/5 fractions depending on location. Plans were compared in terms of target coverage, OAR doses and dosimetric acceptability based on local guidelines. Predictors of acceptability were investigated using logistic regression analysis.ResultsCompared to regular margin plans, both reduced margin and non‐margin plans resulted in significant reductions to almost all dose constraints. Dose conformity was significantly worse in non‐margin plans (P < 0.05) and strongly correlated with targets’ surface area/volume ratio (R 2 = 0.9, P < 0.05). 26% of reduced margin plans were acceptable, compared to 54% of non‐margin plans. GTV overlap with OARs significantly affected plan acceptability (OR 0.008, 95% CI 0.001–0.073).ConclusionMargin reduction significantly reduced OAR doses enabling acceptable plans to be achieved for patients previously excluded from SABR. Indications for lung SABR may broaden as treatment accuracy continues to improve; further work is needed to identify patients most likely to benefit.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

A prognosis-related molecular subtype for early-stage non-small lung cell carcinoma by multi-omics integration analysis

BackgroundEarly-stage non-small cell lung carcinoma (NSCLC) accounts for more than 80% of lung cancer, which is a kind of cancer with high heterogeneity, so the genetic heterogeneity and molecular subtype should be explored.MethodsPartitioning Around Medoid algorithm was used to acquire the molecular subtype for early-stage NSCLC based on prognosis-related mRNAs and methylation sites. Random forest (RF) and support vector machine (SVM) were used to build prediction models for subtypes.ResultsSix prognosis-related subtypes for early-stage NSCLC, including 4 subtypes for lung squamous cell carcinoma (LUSC) and 2 subtypes for lung adenocarcinoma (LUAD), were identified. There were highly expressed and hypermethylated gene regions for LUSC-C1 and LUAD-C2, highly expressed region for LUAD-C1, and hypermethylated regions for LUSC-C3 and LUSC-C4. Molecular subtypes for LUSC were mainly determined by DNA methylation (14 mRNAs and 362 methylation sites). Molecular subtypes for LUAD were determined by both mRNA and DNA methylation information (143 mRNAs and 458 methylation sites). Ten methylation sites were selected as biomarkers for prediction of LUSC-C1 and LUSC-C3, respectively. Nine genes and 1 methylation site were selected as biomarkers for LUAD subtype prediction. These subtypes can be predicted by the selected biomarkers with RF and SVM models.ConclusionsIn conclusion, we proposed a prognosis-related molecular subtype for early-stage NSCLC, which can provide important information for personalized therapy of patients.

The development and external validation of an overall survival nomogram in medically inoperable centrally located early-stage non-small cell lung carcinoma

Background and purposeCurrent nomograms predicting survival prognosis after stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) are based on peripherally located tumors. However, patients with a central lung tumor tend to be older, the tumor is often larger and fraction-schedules are risk-adapted. Therefore, we developed and externally validated a nomogram to predict overall survival (OS) in patients having centrally located early-stage NSCLC treated with SBRT. Materials and methodsPatients who underwent SBRT for centrally located NSCLC were identified and baseline characteristics were obtained. A nomogram was built to predict 6-month, 1-, 2- and 3-year OS using Cox proportional hazards model. The model building procedure was validated using bootstrap sampling. To determine generalizability, external validation was performed on a cohort of patients with central NSCLC treated with SBRT from another center. Discriminatory ability was measured with the concordance index (C-index) and calibration plots were used to compare Kaplan–Meier-estimated and nomogram-predicted OS. ResultsThe nomogram was built on data of 220 patients and consisted of the following variables: PTV, age, WHO performance status, tumor lobe location and ultracentral location. The C-index of the nomogram (corrected for optimism) was moderate at 0.64 (95% confidence interval (CI) 0.59–0.69). Calibration plots showed favorable predictive accuracy. The external validation showed acceptable validity with a C-index of 0.62 (95% CI 0.61–0.64). DiscussionWe developed and externally validated the first nomogram to estimate the OS-probability in patients with centrally located NSCLC treated with SBRT. This nomogram is based on 5 patient and tumor characteristics and gives an individualized survival prediction.

High diagnostic value of miRNAs for NSCLC: quantitative analysis for both single and combined miRNAs in lung cancer

Background MicroRNAs (miRNAs) are good candidates as biomarkers for Lung cancer (LC). The aim of this article is to figure out the diagnostic value of both single and combined miRNAs in LC. Methods Normative meta-analysis was conducted based on PRISMA. We assessed the diagnostic value by calculating the combined sensitivity (Sen), specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) and the area under the curve (AUC) of single and combined miRNAs for LC and specific subgroups. Results A total of 80 qualified studies with a total of 8971 patients and 10758 controls were included. In non-small cell lung carcinoma (NSCLC), we involved 20 single-miRNAs and found their Sen, Spe and AUC ranged from 0.52-0.81, 0.66-0.88, and 0.68-0.90, respectively, specially, miR-19 with the maximum Sen, miR-20 and miR-10 with the highest Spe as well as miR-17 with the maximum AUC. Additionally, we detected miR-21 with the maximum Sen of 0.74 [95%CI: 0.62-0.83], miR-146 with the maximum Spe and AUC of 0.93 [95%CI: 0.79-0.98] and 0.89 [95%CI: 0.86-0.92] for early-stage NSCLC. We also identified the diagnostic power of available panel (miR-210, miR-31 and miR-21) for NSCLC with satisfying Sen, Spe and AUC of 0.82 [95%CI: 0.78-0.84], 0.87 [95%CI: 0.84-0.89] and 0.91 [95%CI: 0.88-0.93], and furtherly constructed 2 models for better diagnosis. Conclusions We identified several single miRNAs and combined groups with high diagnostic power for NSCLC through pooled quantitative analysis, which shows that specific miRNAs are good biomarker candidates for NSCLC and further researches needed.

A prognostic model for overall survival of patients with early-stage non-small cell lung cancer: a multicentre, retrospective study

SummaryBackgroundIntratumoural heterogeneity has been previously shown to be related to clonal evolution and genetic instability and associated with tumour progression. Phenotypically, it is reflected in the diversity of appearance and morphology within cell populations. Computer-extracted features relating to tumour cellular diversity on routine tissue images might correlate with outcome. This study investigated the prognostic ability of computer-extracted features of tumour cellular diversity (CellDiv) from haematoxylin and eosin (H&E)-stained histology images of non-small cell lung carcinomas (NSCLCs).MethodsIn this multicentre, retrospective study, we included 1057 patients with early-stage NSCLC with corresponding diagnostic histology slides and overall survival information from four different centres. CellDiv features quantifying local cellular morphological diversity from H&E-stained histology images were extracted from the tumour epithelium region. A Cox proportional hazards model based on CellDiv was used to construct risk scores for lung adenocarcinoma (LUAD; 270 patients) and lung squamous cell carcinoma (LUSC; 216 patients) separately using data from two of the cohorts, and was validated in the two remaining independent cohorts (comprising 236 patients with LUAD and 335 patients with LUSC). We used multivariable Cox regression analysis to examine the predictive ability of CellDiv features for 5-year overall survival, controlling for the effects of clinical and pathological parameters. We did a gene set enrichment and Gene Ontology analysis on 405 patients to identify associations with differentially expressed biological pathways implicated in lung cancer pathogenesis.FindingsFor prognosis of patients with early-stage LUSC, the CellDiv LUSC model included 11 discriminative CellDiv features, whereas for patients with early-stage LUAD, the model included 23 features. In the independent validation cohorts, patients predicted to be at a higher risk by the univariable CellDiv model had significantly worse 5-year overall survival (hazard ratio 1·48 [95% CI 1·06–2·08]; p=0·022 for The Cancer Genome Atlas [TCGA] LUSC group, 2·24 [1·04–4·80]; p=0·039 for the University of Bern LUSC group, and 1·62 [1·15–2·30]; p=0·0058 for the TCGA LUAD group). The identified CellDiv features were also found to be strongly associated with apoptotic signalling and cell differentiation pathways.InterpretationCellDiv features were strongly prognostic of 5-year overall survival in patients with early-stage NSCLC and also associated with apoptotic signalling and cell differentiation pathways. The CellDiv-based risk stratification model could potentially help to determine which patients with early-stage NSCLC might receive added benefit from adjuvant therapy.FundingNational Institue of Health and US Department of Defense.

Abstract 399: Tertiary lymphoid structures features associate with outcome in non-small cell lung carcinoma

Abstract Introduction: Tertiary lymphoid structures (TLS) are ectopic lymphoid structures organized in a nodular pattern secondary to chronic inflammation. The presence of TLS has been associated with efficacious response to immune checkpoint blockade in a wide array of tumor types, including Non-Small Cell Lung Carcinoma (NSCLC). At early stages of NSCLC, TLS are observed in up to 70% of primary tumors where they are also associated with effective anti-tumor immune-responses and response to anti-PD-1 therapy. Despite complete surgical resection, however, up to 50% of patients with early stage NSCLC will eventually relapse. A systematic histomorphologic analysis of TLS and their association with relapse has not been well characterized. Design: Serial sections from Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens from 33 patients with stage I NSCLC were obtained (23 adenocarcinomas and 10 squamous cell carcinomas). Slides were stained with hematoxylin and eosin (H&amp;E), immunohistochemistry for Vimentin, and 2 multiplex immunofluorescence (mIF) panels (Panel 1: cytokeratin (CK), CD3, CD8, CD68, PD-1, PD-L1 and DAPI Panel 2: CK, CD3 CD8, CD45RO, FOXP3, Granzyme B and DAPI). TLS were classified based on the H&amp;E and Vimentin analysis into lymphoid aggregates (LA), immature TLS (iTLS), and mature TLS (mTLS). Morphometric analysis (number, area, and distance to nearest malignant cell) of intratumoral (IT) and peritumoral (PT) TLS was performed. mIF slides were scanned and IT representative areas were selected for cell densities and percentage quantification of immune-phenotypes. Morphometric analysis of TLSs was correlated with clinical outcomes, and tumor infiltrating immune cells. Results: Patients who recurred had fewer IT mTLS (1.8 vs 6; p=0.02) and smaller area of mTLS (64541.7μm2 vs 149870.5 μm2; p=0.004) compared with patients who did not recurr.The cell density of IT antigen-experienced cytotoxic T-lymphocytes (CTLs), regulatory T-cells, memory CTLs, and memory CTLs expressing FOXP3 were inversely correlated with the mTLS area (r=-0.6, p≤0.02). Antigen-experienced CTLs (r=-0.61; p≤0.05) and non-CTLs (r=-0.63; p≤0.05) were inversely correlated with the number of IT mTLS. Conclusion: Detailed morphometric analysis of mTLS offers relevant prognostic information for recurrence at stage I of NSCLC. mTLSs are associated with reduced IT infiltration by PD-1+ TILs. Taken together, germinal center development in mTLSs might convey a protective immune response due to immuno-dominant neoantigen presentation. Supported in part by CPRIT RP160668 grant and UT Lung SPORE. Citation Format: Rossana Natalia Lazcano Segura, Andre Catao, Luisa M. Solis, Mei Jiang, Auriole Tamegnon, Junya Fujimoto, Jaime Rodriguez-Canales, Chi-Wan B. Chow, Carmen Behrens, Neda Kalhor, Annika Weissferdt, John Heymach, Stephen Swisher, Boris Sepesi, Jack Lee, Cesar Moran, Andrew Futreal, Jianjun Zhang, Edwin R. Parra, Ignacio I. Wistuba, Michael T. Tetzlaff, Alejandro Francisco-Cruz. Tertiary lymphoid structures features associate with outcome in non-small cell lung 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 399.

Prognostic impact of solid tumor component diameter in early-stage non-small cell lung carcinoma treated with intensity-modulated fractionated radiotherapy: a retrospective analysis impact of solid tumor component diameter in NSCLC treated with IMRT.

Objective:To investigate the suitability of the new diameter-based subgroupings of the eighth edition Tumor Node Metastasis (TNM) classification system regarding radiotherapy treatment for early-stage non-small-cell lung cancer (NSCLC), we retrospectively re-analyzed the clinical data of patients treated with intensity-modulated radiotherapy using non-coplanar beams (ncIMRT) for Stage I NSCLC.Methods:Between March 2011 and March 2018, 92 patients with 94 tumors who were diagnosed with Stage I NSCLC according to the seventh edition TNM classification system were enrolled and underwent ncIMRT of 75 Gy in 30 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were retrospectively investigated according to the T-classification subdivisions of the eighth edition and maximal solid tumor component diameter.Results:The median follow-up period was 32.5 months. The median maximum tumor and solid tumor component diameters were 22 mm and 18 mm, respectively. 3-year LC, PFS, and OS rates were 84.1%, 69.4%, and 85.3%, respectively. The 3-year LC rates were 91.0 and 76.8% in the groups with tumor diameter ≤2 cm and >2 cm, corresponding to the T1c and T1b subdivisions of the eighth edition, respectively (p = 0.24). In the ≤2 cm and >2 cm solid tumor component groups, the 3 year LC rates were 93.6 and 63.2%, respectively, which were significantly different (p = 0.007).Conclusion:LC rates after radiotherapy in patients with Stage I NSCLC were correlated with solid tumor component diameter. High LC rates in patients with solid tumor components <2 cm in diameter were associated with high PFS and OS rates.Advances in knowledge:This study suggests that the eighth edition TNM classification system, which focuses on solid tumor components rather than tumor diameter, can be applied to radiotherapy.

Combination of FDG-PET and FMISO-PET as a treatment strategy for patients undergoing early-stage NSCLC stereotactic radiotherapy

BackgroundWe investigated the prognostic predictive value of the combination of fluorodeoxyglucose (FDG)- and fluoromisonidazole (FMISO)-PET in patients with non-small cell lung carcinoma (NSCLC) treated with stereotactic body radiation therapy (SBRT).Patients and methodsWe prospectively examined patients with pathologically proven NSCLC; all underwent FDG and FMISO PET/CT scans before SBRT. PET images were acquired using a whole-body time-of-flight PET-CT scanner with respiratory gating. We classified them into recurrent and non-recurrent groups based on their clinical follow-ups and compared the groups' tumor diameters and PET parameters (i.e., maximum of the standardized uptake value (SUVmax), metabolic tumor volume, tumor-to-muscle ratio, and tumor-to-blood ratio). We performed univariate analysis to evaluate the impact of the PET variables on the patients' progression-free survival (PFS). We divided the patients by thresholds of FDG SUVmax and FMISO SUVmax obtained from receiver operating characteristic analysis for assessment of recurrence rate and PFS.ResultsThirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled. All received SBRT. At the study endpoint, 23 patients (71.9%) were non-recurrent and nine patients (28.1%) had recurrent disease. Significant between-group differences were observed in tumor diameter and all the PET parameters, demonstrating that those were significant predictors of the recurrence in all patients. In the 22 patients with tumors > 2 cm, tumor diameter and FDG SUVmax were not significant predictors. Thirty-two patients were divided into three patterns from the thresholds of FDG SUVmax (6.81) and FMISO SUVmax (1.89); A, low FDG and low FMISO (n = 14); B, high FDG and low FMISO (n = 8); C, high FDG and high FMISO (n = 10). No pattern A patient experienced tumor recurrence, whereas two pattern B patients (25%) and seven pattern C patients (70%) exhibited recurrence. A Kaplan-Meier analysis of all patients revealed a significant difference in PFS between patterns A and B (p = 0.013) and between patterns A and C (p < 0.001). In the tumors > 2 cm patients, significant differences in PFS were demonstrated between pattern A and C patients (p = 0.002).ConclusionThe combination of FDG- and FMISO-PET can identify patients with a baseline risk of recurrence and indicate whether additional therapy might be performed to improve survival.

IBS19.02 Novel Radiotherapy Approaches in Small Cell Lung Carcinoma – Has SABR and Radionuclide Therapy Got a Role to Play?

Thoracic radiotherapy has been shown in to increase overall survival when added to systemic therapy in patients with small cell lung carcinoma (SCLC) and M0 stage. The dose, fractionation, treatment time and timing issues have not been fully resolved. A recent study did not show the superiority of 66Gy in 33 daily fractions over 6.5 weeks over twice-daily radiotherapy to a dose of 45 Gy in 30 fractions over 3 weeks twice daily [1]. For stage I non-small cell lung carcinoma (NSCLC), stereotactic ablative body radiotherapy (SABR) has been clearly shown to be superior to conventional fractionation [2]. Given the clear benefit seen in early stage NSCLC, it is postulated that SABR may have a role to play in early stage SCLC. A recent multi-institutional cohort study has reported favourable outcomes in this setting [3]. However, randomised data of equivalence or indeed superiority are lacking. Furthermore, questions remain as the timing and role of systemic therapy and prophylactic cranial irradiation when SABR is used in this setting. In advanced SCLC, many tumors display neuroendocrine clinical and cytological features and many SCLC tumors express somatostatin receptor and this can be imaged using radiolabeled somatostatin analogs such as 68Ga-DOTATATE [4]. Given the uptake by some SCLC tumors of 68Ga-DOTATATE, higher doses of the tracer have been used in an attempt to provide radiolabelled radiotherapy treatment in metastatic disease in what has been described as peptide receptor radionuclide therapy (PRRT) [5]. This molecularly target radiotherapy is a potentially exciting therapeutic approach, but the ideal positioning of such therapy in tumors which are suitable for treatment with PRRT and the safety of PRRT with systemic therapy have yet to be determined. 1. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116–1125. https://doi.org/10.1016/S1470-2045(1730318-2) 2. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small cell lung cancer (TROG 09.02. CHISEL): a phase 3, open-label, randomised controlled trial. The Lancet. 2019; 20: 494-503 3. Verma V, Simone CB, 2nd, Allen PK, et al. Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017;97:362-71 4. Sollini M, Farioli D, Froio A, et al. Brief Report on the Use of Radiolabeled Somatostatin Analogs for the Diagnosis and Treatment of Metastatic Small-Cell Lung Cancer Patients. J Thor Oncol 2013;8(8):1095-1101. 5. Lapa C, Hänscheid H, Wild V, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. 2016 Apr 12;7(15):20033-40. SCLC, SABR, radiotherapy

Combined anesthesia shows better curative effect and less perioperative neuroendocrine disorder than general anesthesia in early stage NSCLC patients.

ObjectivesWe aimed to compare the effects of general anesthesia with combined epidural and general anesthesia in patients with early-stage non-small cell lung carcinoma (NSCLC).MethodsPatients scheduled to undergo tumor resection with adjuvant chemoradiotherapy were eligible. Patients in the control group received general anesthesia during surgery, and those in the observation group received combined epidural and general anesthesia. The hemodynamic factors mean arterial pressure (MAP), heart rate, end-tidal carbon dioxide, and oxygen saturation were measured. Serum levels of pro-inflammatory cytokines interleukin (IL)-1, IL-8, high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor (TNF)-α as well as β-endorphin were measured by enzyme-linked immunosorbent assay. Serum malondialdehyde (MDA) was measured using the thiobarbituric acid method.ResultsThe incidence of specific adverse events was reduced and overall and disease-free survival were improved in the observation group compared with the control group. MAP was generally lower in the observation group compared with the control group, as were the serum levels of IL-1, IL-8, hs-CRP, TNF-α, and MDA.ConclusionsCompared with general anesthesia, combined epidural and general anesthesia may inhibit the occurrence of short-term adverse events and improve long-term outcomes by inhibiting inflammatory responses in patients with early-stage NSCLC after tumor resection.

Differential inflammatory response dynamics in normal lung following stereotactic body radiation therapy with protons versus photons

Background and purposeTo compare time-dependent changes in lung parenchyma of early-stage non-small cell lung carcinoma (NSCLC) patients after stereotactic body radiation therapy with protons (SBPT) or photons (SBRT). Materials and methodWe retrospectively identified NSCLC patients treated with SBPT and matched each one with a SBRT patient by patient, tumor, and treatment characteristics. Lung parenchyma on serial post-treatment chest computer tomography (CT) scans was deformably registered with the treatment plan to analyze lung density changes as function of dose, quantified by Houndsfield Unit (HU)/Gy. A thoracic radiologist also evaluated the CTs using an established grading system. ResultsWe matched 23 SBPT/SBRT pairs, including 5 patients treated with both modalities (internally matched cohort). Normal lung response following SBPT significantly increased in the early time period (CTs acquired <6 months, median 3 months) post-treatment, and then did not change significantly in the later time period (CTs acquired 6–14 months, median 9 months). For SBRT, the normal lung response was similar to SBPT in the early time period, but then increased significantly from the early to the late time period (p = 0.007). These differences were most pronounced in sensitive (response >6 HU/Gy) patients and in the internally matched cohort. However, there was no significant difference in the maximum observed response in the entire cohort over all time periods, median 3.4 [IQR, 1.0–5.4] HU/Gy (SBPT) versus 2.5 [1.6–5.2] HU/Gy (SBRT). Qualitative radiological evaluation was highly correlated with the quantitative analysis (p < 0.0001). ConclusionWhile there was no significant difference in maximum response after SBPT versus SBRT, dose-defined lung inflammation occurred earlier after proton irradiation. Further investigation is warranted into the mechanisms of inflammation and therapeutic consequences after proton versus photon irradiation.