Stage IIIA Non-small Cell Lung Cancer Patients Research Articles

Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer

ObjectiveAccurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) remains clinically challenging. In this study, we investigate the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase II trial. MethodsBlood samples were prospectively collected from 45 stage IIIA (N2) NSCLC patients undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the CT-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. ResultsAt baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 Muts/Mb was associated with significantly higher MPR rates (77.8% vs. 38.5%, p = 0.042), and longer disease-free survival (DFS, p = 0.043), but not overall survival (p = 0.131), compared to bTMB < 11 Muts/Mb in 35 patients with bTMB available. The developed DL model achieved an area under the curve (AUC) of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an AUC of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathological response and survival. Compared to ctDNA residual, ctDNA clearance before surgery was associated with significantly higher MPR rates (88.2% vs. 11.1%, p < 0.001) and improved DFS (p = 0.010). ConclusionsThe integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

NEOADJUVANT CHEMORADIOTHERAPY IN THE MULTIMODALITY TREATMENT OF STAGE IIIA(N2) NON-SMALL CELL LUNG CANCER (NSCLC)

Summary. The choice of optimal treatment for stage IIIA(N2) non-small cell lung cancer (NSCLC) remains controversial, since the five-year survival rate of this category of patients cannot meet modern medical requirements and patient expectations even after radical surgery and chemotherapy (CT). Accordingly, the analysis of available clinical data and the search for the most effective multimodal treatment option are constantly ongoing. The main treatment strategy for stage IIIA(N2) NSCLC is surgery with induction CT. As part of a comprehensive clinical approach, neoadjuvant CT (NCT) is used to eliminate distant micrometastases, leading to increased survival in an independent operation. Meanwhile, induction with concurrent chemoradiotherapy (CRT) followed by surgery resulted in a 30% to 40% improvement in 5-year survival. Aim: to evaluate the results of treatment of patients with stage IIIA(N2) NSCLC after the use of various methods of neoadjuvant and adjuvant therapy in case of surgical intervention. Object and methods: the effect of NCRT was performed in 37 patients with stage IIIA(N2) NSCLC in selected tumors of the lungs and the middle of the National Cancer Institute. This group of patients was planned for multimodal treatment, which included 3 or 4 cycles of chemotherapy with platinum-based drugs following the regimens of cisplatin + docetaxel or carboplatin + paclitaxel with one-hour radiotherapy (RT), consisting of sessions in the or classical fractionation with a single dose of 2 Gy, SOD up to 50 Gy with subsequent surgery. The number of CT cycles (3 or 4) depended on the result of the control observation of the dynamics of regression of the tumor process. In the core of the vicoristan group, there was the first control group of stage IIIA(N2) NSCLC patients with NCT (n = 194). This group of patients was given 3 or 4 courses of CT using a regimen similar to the main group: cisplatin / carboplatin + docetaxel / paclitaxel, and in the second control group – similar to the number of courses and drugs, neoadjuvant CT and RT in SOD 50 Gy in adjuvant regimen (n = 60) with further surgical treatments. All patients, depending on the prevalence of the tumor process, underwent radical surgery in the form of lobectomy, bilobectomy or pneumonectomy with mediastinal lymphodissection. Results: median survival in the main group was 30.12 months, in the first control group (NCT) – 23.68 months and the second control group (NCT + adjuvant RT) – 23.23 months, respectively. In the main group, 5 (14.7%) patients were diagnosed with a complete morphological response of the primary tumor and a complete morphological response of the tumor tissue in the regional lymph nodes. In addition to the complete morphological response of the primary tumor and metastatic mediastinal lymph nodes (tumor cells were not detected in histological preparations), in 5 (14.7%) cases, a pronounced morphological response of a highly differentiated tumor was detected (residual viability of tumor tissue to 12±5%). These patients had a higher median survival (45 and 39 months, respectively) compared to controls. Conclusion: the treatment regimen with NCRT is more promising for increasing patient survival.

Rates of surgery and adjuvant chemotherapy use in patients with stage IB to IIIA non-small cell lung cancer: A provincial population-based study.

134 Background: The current standard of treatment for early-stage (IB to IIIA) non-small cell lung cancer (NSCLC) include surgery and adjuvant chemotherapy. The objective of this study is to identify rates of adherence to guideline recommended surgery and adjuvant chemotherapy treatment for early-stage NSCLC for patients living in Ontario, the most populous province of Canada. Methods: A retrospective population-based study using linked administrative data through ICES was completed that included all adult patients with a diagnosis of stage IB to IIIA NSCLC made from 2010 to 2020 in Ontario. Rates of surgery and chemotherapy completion were calculated using available OHIP (Ontario Health Insurance Plan) billing codes. Logistic multivariate regressions were completed to assess for any predictors for completion of surgery and chemotherapy. Results: A total of 24,237 eligible patients were included. By cancer staging, there were 6,495 (26.8%) stage IB, 7,156 (29.5%) stage II, and 10,586 (43.7%) stage IIIA NSCLC patients. Within 180 days of diagnosis, surgery was completed for 9,929 (41.0%) of patients, by cancer staging were 4090/6495 (63.0%), 3719/7156 (52.0%), and 2120/10586 (20.0%) for IB, II, and IIIA respectively. The median time from diagnosis to surgery was 49 days (IQR 23-77 days). Amongst patients who completed surgery, 3344/9929 (33.7%) underwent at least 1 cycle of adjuvant chemotherapy within 180 days. Having advanced age (p&lt;0.001), high Charlson comorbidity score (p&lt;0.001), and low income (p&lt;0.001) are predictors for poor uptake for both chemotherapy and surgery. Being male also reduces the likelihood of undergoing surgery (p&lt;0.001). Conclusions: In our population-based study, less than half of the patients with early-stage (IB-IIIA) NSCLC underwent surgical resection and chemotherapy. These low treatment rates are concerning and may be contributing to suboptimal outcomes. Our findings indicate that elderly individuals with multiple comorbidities and those with low incomes are at the highest risk of not receiving appropriate chemotherapy and surgery. Our data highlight the need for quality improvement strategies aimed at identifying and enhancing treatment uptake within this patient population.

Sociodemographic factors affecting survival in stage IIIA NSCLC treated with surgery-based treatment or definitive chemoradiation with immunotherapy consolidation: An NCDB analysis.

e18555 Background: Stage IIIA non-small cell lung cancer (NSCLC) is a heterogeneous disease treated by surgery-based approach or definitive chemoradiation (CRT) and immunotherapy (ICI) consolidation. Studies have shown that black patients in general are diagnosed at advanced stages, are less likely to receive ICI, and have lower overall survival (OS) compared to whites. Importantly, ICI was shown to impart similar or even better OS among advanced-stage black NSCLC patients, compared to whites. Geographical location and socioeconomic status have also been shown to affect outcomes. There are no studies on sociodemographic factors affecting survival in stage IIIA NSCLC in the ICI era. Methods: We used National Cancer Database (NCDB) to identify 23,110 patients with clinical stage IIIA NSCLC treated with either surgery-based approach or definitive CRT followed by ICI during 2017-2019, and surgery-based treatment or CRT during 2014-2016. We analyzed age, race, sex, insurance type, income, geographic location, Charlson Comorbidity Index (CCI) and education. Kaplan-Meier (KM) plots were used to examine survival curves and descriptive analysis was performed to examine the characteristics of sociodemographic variables by the two treatment modalities. Cox regression analysis was used to identify factors associated with OS. Results: ICI maintenance improved the OS of all stage IIIA NSCLC patients after CRT during 2017-2019 compared to CRT only in 2014-2016. On multivariate analysis of surgical and CRT-ICI cohorts, blacks had slightly better OS compared to whites (HR, 95%CI, p-value) (0.89, 0.84-0.95, &lt; 0.001) but lower than other races including Asians (0.77, 0.69-0.87, &lt; 0.001). While there was no OS difference in the surgical arm (0.94, 0.83-1.07, p = 0.356) between black and white patients, better survival was seen in blacks in the CRT-ICI arm (0.88, 0.82-0.94, &lt; 0.001). No significant interaction between race and CRT-ICI was identified which indicates the benefit of CRT-ICI is independent of the race effect. Other factors associated with lower OS were older age with age &gt; 75 HR 1.00, ages 19-39 (0.47, 0.35-0.64) ages 40-64 (0.71, 0.67-0.75), ages 65-74 (0.79, 0.76-0.83), median quartile income &lt; $40,227 (1.07, 1.01-1.14), non-metro location (1.12, 1.07-1.17), non-academic facility (1.09, 1.05-1.14), and male sex (1.24, 1.20-1.29). Insurance status had no effect on OS. Conclusions: Our study indicates that there is no survival difference between white and black patients treated with surgery, but blacks had better survival when treated with CRT-ICI. Racial disparity in NSCLC survival depends on stage and access to care. Treatment modality, income, metro location, and access to an academic center are more significant predictors of survival than race. Interestingly, health insurance had no impact on OS.

The Validation of Predictive Risk Scoring Model of Radiation Pneumonitis (RP) in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> In our previous research, pulmonary emphysema (PE) was reported as a risk factor of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC). Subclinical interstitial lung disease (SILD) was associated with severe RP in small cell lung cancer patients. A predictive risk scoring model of RP was developed in stage IIIA or Stage IIIB NSCLC patients receiving radical radiotherapy. The risk score has not been validated using an independent dataset. The aim of this study was to validate the predictive risk score which established in our previous study and evaluate the predictive value of the model. <h3>Materials/Methods</h3> From January 2019 to October 2021,129 lung cancer patients were recruited in study which included in validation group. Those patients were received thoracic radiotherapy with ≥50Gy total radiotherapy dose. The risk scoring model in our previous research as follow: PRS=5 (if subclinical ILD grade≥1) + 3 (if age >68 years) + 3 (if PE grade >1). According to the risk score, the cases in validation group were scored, predictive value of this model were evaluated by receiver operator characteristic curve (ROC) using statistical software. The decision curve analysis was constructed using Stata 17.0 software. <h3>Results</h3> In 129 eligible patients, 13(10.08%, 13/129) developed grade 1 RP, 15(11.62%, 15/129) developed grade 2 RP, grade 3 and grade 4 RP were not observed. 23 (16.60%, 23/129) had PE grade >1. Risk scores of all patients were calculated according to the risk score, 37 had 3 points which incidence of RP ≥2 grade was 13.50%, 2 had 5 points which incidence of RP ≥2 grade was 100.0%, 3 had 6 points which incidence of RP ≥2 grade was 33.33%. ROC curve was plotted according to the risk score of all patients, the area of ROC curve (AUC) was 0.695 (95%CI: 0.541-0.849, P < 0.05). The decision curve indicated that the net benefit of the model was higher in the high-risk threshold of 0.2-0.3. <h3>Conclusion</h3> The previous predictive risk scoring model indicated good discrimination and clinical application value, which can be used in clinical treatment.

Molecular Markers for Long-term Survival in Stage IIIA (N2) NSCLC Patients.

Survival rates among non-small cell lung cancer (NSCLC) stage IIIA (N2) patients are generally low and depend on the treatment. We aimed to identify predictive markers for long term survival in responders and non-responders to chemotherapy, analyzing tumour and non-tumour samples by microarray (n=35) and whole exome sequencing (WES, n=25). WES data showed correlation of overall survival of all patients with rs9905892 in the SLFN12L gene. High frequency of mutations (4/6, 66.7%) was identified in members of SWI/SNF complex in responder patients and in patients that were alive after seven years. Microarray data for immune components showed that VISTA (VSIR) was down-regulated in tumoral tissue. Our research suggests that mutations in SWI/SNF complex associate with long term survival after multimodal treatment, while down-regulation of VISTA might indicate its immunomodulatory role in NSCLC stage III (N2) patients.

Importance of tumour volume and histology in trimodality treatment of patients with Stage IIIA non-small cell lung cancer-results from a retrospective analysis.

OBJECTIVESChemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT.METHODSIn a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting.RESULTSFrom a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume.CONCLUSIONSPatients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT.

Abstract 2606: A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer

Abstract Background: 80% of non-small cell lung cancer (NSCLC) cases are diagnosed at stages IIIB-IV and have a dismal prognosis with a median life expectancy that does not exceed 2 years. In contrast, patients diagnosed at early and locally advanced stages (I-IIIA) can undergo surgery and have the potential to be totally cured. Imaging technologies often detect lung nodules of unknown significance that pose a diagnostic challenge; some patients with benign nodules are submitted to unnecessary surgical interventions while others with small tumors are just kept in observation, risking a significant delay for treatment. A diagnostic test that could differentiate between benign and malignant masses would be of great help in this setting. Methods: Circulating-free RNA (cfRNA) was isolated from the plasma of healthy individuals (N=21), early(I-II) stage (N=22) and stage IIIA (N=12) NSCLC patients, using an automatic extraction method(Qiasymphony, Qiagen). Purified cfRNA was quantified using Qubit, retrotranscribed and pre-amplified (14cycles) using the Low RNA Input Amplification kit (NanoString Technologies). Gene expression analysis was performed on the nCounter platform using the PanCancer IO360TM (NanoString Technologies), which can detect 770 transcripts related to tumor biology, micro-environment and the immune system. Results: Gene expression analysis revealed differential patterns for some cf-mRNAs from localized stage NSCLC patients versus healthy controls. A bioinformatics recursive feature elimination algorithm selected a 16-gene mRNA signature that was able to distinguish between localized NSCLC and control samples with an area under the ROC curve of 0.91 to 0.95. Furthermore, the signature scores derived from the algorithm were significantly different between the two cohorts. Conclusions: We have found an 16-gene signature that can differentiate between cfRNA of localized stages NSCLC patients and control individuals. Our results warrant validation studies in larger cohorts. Citation Format: Ana Giménez Capitán, Jillian Bracht, Nicolas Potie, María González-Cao, Santiago Viteri, Alejandro Martínez-Bueno, Carlos Cabrera-Gálvez, Pablo Rubinstein, Clara Mayo-de-las-Casas, Joselyn Valarezo, Chung-Ying Huang, Carlos Pedraz, Richard Boykind, Sarah Warren, Rafael Rosell, Miguel Ángel Molina-Vilaa, Andrés Aguilar-Hernández. A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2606.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BackgroundImmunotherapy is being tested in early‐stage non‐small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment‐related changes to find biomarkers associated to CPR.MethodsBlood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed.ResultsNeoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p‐value <.05. CPR patients had significantly higher levels of CD4+PD‐1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+CD56–CTLA‐4+ cells, CD14++CD16+CTLA‐4+ cells, CTLA‐4 expression on T CD56 cells and lower levels of b‐NGF, NT‐3, and VEGF‐D in plasma compared to non‐CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4‐1BB, MCSF, and PARC and lower levels of MPIF‐1 and Flt‐3L in plasma compared to non‐CPR.ConclusionsPatients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non‐CPR responses.

The safety and efficacy of neoadjuvant programmed death 1 inhibitor therapy with surgical resection in stage IIIA non-small cell lung cancer.

BackgroundLung cancer ranks as the most prevalent solid cancer in the world. The non-small-cell lung cancer (NSCLC) histological subtype accounts for the largest proportion of lung cancers. Even though neoadjuvant therapy has shown encouraging efficacy for resectable NSCLC, there is a lack of clinical data on the treatment of stage IIIA NSCLC patients. Therefore, we carried out an evaluation of the safety and efficacy of programmed cell death 1 (PD-1) inhibitor as an addition to neoadjuvant chemotherapy.MethodsThis prospective study involved 72 treatment-naive adult subjects with stage IIIA NSCLC between September 2019 and July 2020. Two circles PD-1 inhibitor with chemotherapy (Albumin paclitaxel 100 mg/m2 d1,8 + Carboplatin AUC 5 d1) were administered intravenously every 3 weeks. The patients were operated on between 3 and 5 weeks following the second cycle. Feasibility and safety served as the primary endpoints for this study. The rates of pathologic complete response, complete resection, response rate, and operative and postoperative complications among the patients were also analyzed.ResultsSeventy-two patients with untreated stage IIIA NSCLC were enrolled. The postoperative pathological specimens of 21 (29.1%) and 47 (65.2%) patients suggested pathologic complete response and partial remission, respectively. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side effect profile, and none of the subjects withdrew from the study preoperatively due to disease progression or toxicity. According to Response Evaluation Criteria in Solid Tumors (RESIST), responses evaluated by CT scan before surgery, 21 and 47 patients achieved complete response (CR) and partial response (PR), respectively, and a single patient was evaluated as stable disease (SD). There were no postoperative deaths.ConclusionsThe outcomes of PD-1 inhibitor with chemotherapy as a novel treatment for stage IIIA NSCLC in the neoadjuvant setting are satisfactory with respect to the high R0 resection rate and low toxicity profile. Prospective comparative and longer follow-up trials are needed to confirm the long-term outcomes of this novel treatment and to reach definitive conclusions.

Clinical impact of the tumor immune microenvironment in completely resected stage IIIA(N2) non-small cell lung cancer based on an immunoscore approach.

Background:Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) comprises a heterogeneous population according to discrepancies in survival prognosis. Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs) are clinically significant, despite a lack of consensus regarding the immunoscore (IS) in NSCLC. Here, we determined the prognostic value of the immune microenvironment as an IS in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.Methods:Consecutive patients with pathologically confirmed stage IIIA(N2) NSCLC and who underwent complete resection (2005–2012) were retrospectively reviewed. Tissue microarrays (TMAs) were constructed from surgical paraffin-embedded primary lung tumor specimen. For each case, two representative regions from the tumor center (CT) and two from the invasive margin (IM) containing the highest density of lymphocytes were selected. Densities of CD3+, CD45RO+, and CD8+ lymphocytes were assessed using immunohistochemistry (IHC) by specialized pathologists according to predefined scoring scales. Patients were classified according to IS definition based on TIL type, density, and distribution, and relationships between IS and prognosis were evaluated.Results:Patients (N = 288) with complete IHC-based TMA spots were included. Univariate analyses showed that CD3+ T cell density was associated with neither overall survival (OS) nor distant metastasis-free survival (DMFS), whereas CD45RO+ T cell density in the IM was a significant prognostic factor for DMFS (p = 0.02) and was predictive of OS (p = 0.05). Combined CD45RO+ and CD8+ cell infiltration in tumor regions (CT and IM) significantly improved IS prognostic impact. Multivariate analyses revealed IS as an independent prognostic predictor for both DMFS (p = 0.001) and OS (p = 0.002).Conclusion:The proposed IS might provide valuable prognostic information, including prediction of DMFS and OS in stage IIIA(N2) NSCLC patients. Larger patient cohorts are needed to validate this IS classification, which might assist with accurate risk stratification and treatment decisions.

Variation Between Multidisciplinary Tumor Boards in Clinical Staging and Treatment Recommendations for Patients With Locally Advanced Non-small Cell Lung Cancer

BackgroundAccurate diagnosis and staging are crucial to ensure uniform allocation to the optimal treatment methods for non-small cell lung cancer (NSCLC) patients, but may differ among multidisciplinary tumor boards (MDTs). Discordance between clinical and pathologic TNM stage is particularly important for patients with locally advanced NSCLC (stage IIIA) because it may influence their chance of allocation to curative-intent treatment. We therefore aimed to study agreement on staging and treatment to gain insight into MDT decision-making.Research QuestionWhat is the level of agreement on clinical staging and treatment recommendations among MDTs in stage IIIA NSCLC patients?Study Design and MethodsEleven MDTs each evaluated the same 10 pathologic stage IIIA NSCLC patients in their weekly meeting (n = 110). Patients were selected purposively for their challenging nature. All MDTs received exactly the same clinical information and images per patient. We tested agreement in cT stage, cN stage, cM stage (TNM 8th edition), and treatment proposal among MDTs using Randolph’s free-marginal multirater kappa.ResultsConsiderable variation among the MDTs was seen in T staging (κ, 0.55 [95% CI, 0.34-0.75]), N staging (κ, 0.59 [95% CI, 0.35-0.83]), overall TNM staging (κ, 0.53 [95% CI, 0.35-0.72]), and treatment recommendations (κ, 0.44 [95% CI, 0.32-0.56]). Most variation in T stage was seen in patients with suspicion of invasion of surrounding structures, which influenced such treatment recommendations as induction therapy and type. For N stage, distinction between N1 and N2 disease was an important source of discordance among MDTs. Variation occurred between 2 patients even regarding M stage. A wide range of additional diagnostics was proposed by the MDTs.InterpretationThis study demonstrated high variation in staging and treatment of patients with stage IIIA NSCLC among MDTs in different hospitals. Although some variation may be unavoidable in these challenging patients, we should strive for more uniformity.

Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes

Patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) with no progression after induction chemotherapy are usually selected for surgery. Nowadays, response to chemotherapy is not predictable. We aimed to identify genomic predictive markers for response to induction chemotherapy in stage IIIA (N2) NSCLC patients. Whole-exome sequencing (WES) was performed on samples from 11 patients with no response after induction chemotherapy and 6 patients with documented pathological response, admitted to the Hotel Dieu Hospital, Paris or Allegemeines Krakenhaus University, Vienna. A higher alternative allele frequency was found on SENP5, rs63736860, rs1602 and NCBP2, rs553783 in the non-responder group, and on RGP1, rs1570248, SLFN12L, rs2304968, rs9905892, and GBA2, rs3833700 in the responder group. These polymorphisms contribute to inter-individual sensibility to chemotherapy response. Interrogation of these genetic variations may have potential applicability when deciding the treatment strategy for patients with stage III NSCLC (N2).

Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (&lt; 10% viable tumour) and incomplete response (&gt; 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.

Outcomes following lobectomy and pneumonectomy in stage IIIA non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiation.

e20042 Background: INT 0139 study showed that patients who received surgery after neoadjuvant chemoradiation did not have an overall survival (OS) benefit as compared to chemoradiation alone. Moreover, patients who underwent right sided pneumonectomy had non-significantly worse overall survival than chemoradiation alone. Methods: We sought to compare the survival outcomes in patients who received surgery after neoadjuvant chemoradiation based on the surgery type and the laterality of the disease using National Cancer Data Base (2004-15). Kaplan-Meier estimates were used to compare OS between the groups. Results: A total of 2881 and 499 patients had lobectomy and pneumonectomy after neoadjuvant chemoradiation, respectively. We found no difference in median OS in the patients who had left vs right lobectomy (Table). However, 30-, 90-day morality was higher in right lobectomy patients (p = 0.03). Similar trend was seen in the 30-, 90-day mortality and median OS in right and left pneumonectomies (Table). Total number of patients that got right pneumonectomy after neo-adjuvant chemoradiation before and after INT 0139 study (2009) did not change (49% vs 45%, p = 0.33). Conclusions: The short-term mortality was higher in right sided stage IIIA NSCLC patients in our cohort who received surgery irrespective of type of surgery. Interestingly, we did not notice any decrease in pneumonectomy rates since 2009. [Table: see text]

Trimodally treatment for stage IIIa NSCLC patients increases survival while not effecting surgical mortality or complexity

IntroductionAdvanced non-small cell lung cancer (NSCLC) is still a therapeutic challenge as the 5-year survival is under 30%. The optimal treatment regimen is still under debate.HypothesisNeo adjuvant (NA) treatment given pre-pneumonectomy does not increase surgical complexity or peri-OP mortality while it has a potential to increase long term survival.MethodsWe have conducted a retrospective study of 169 patients who underwent a pneumonectomy for NSCLC between January 2005 to December 2015 and focused on stage IIIa patients; a cohort of 51 patients, 30 which received neo adjuvant chemo-radiation (NA group) prior to pneumonectomy and 21 patients who had undergone pneumonectomy followed by adjuvant treatment (Adjuvant group). Surgical complexity and short- and long-term survival were evaluated. Surgical complexity was assessed by surrogates as surgery duration, hospitalization length and interdepartmental transfer.ResultsWhile no statistically significant differences were found in surgery duration, hospitalization length, morbidity in the 1st year post-OP and the peri-OP mortality; The long term beneficiary effect among the neo adjuvant patients was clear; while 30% of the NA patients were alive 8 years post-OP, there were no survivors in the adjuvant group 5.5 years post-OP.ConclusionWe conclude that while NA treatment has no effect on operation complexity, peri-OP mortality or post-OP morbidity; its impact on long term survival is protuberant, therefore, we believe that NA treatment should be considered as the treatment of choice in advanced NSCLC in need for pneumonectomy.

Induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) non-small cell lung cancer: a systematic review and meta-analysis.

Non-small cell lung cancer (NSCLC) accounts for 85% to 90% of lung cancer cases. At diagnosis, around 30% of NSCLC patients are already at stage IIIA (N2). One standard treatment for this stage is induction chemotherapy followed by surgery, whether induction chemoradiotherapy is superior to induction chemotherapy remains uncertain. We therefore performed a systematic review and meta-analysis of published randomized control trials to evaluate the therapeutic efficacy and toxicity of induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) NSCLC. We systematically searched for relevant studies in PubMed, Embase, Web of Science and Cochrane Library from the inception of each database to September 10, 2017. The primary endpoints were objective response rate (ORR), pathological complete response (pCR) rate of mediastinal lymph nodes, toxicity (grade 3-4 adverse events, i.e., nausea and vomiting, infections, leukopenia and anemia), overall survival (OS) and progression-free survival (PFS). Statistical analyses were performed using Review Manager v5.3. Four studies, containing 461 patients in total, were included for meta-analysis. Our analyses suggest that compared with induction chemotherapy, induction chemoradiotherapy improved ORR [odds ratio (OR) =1.97, 95% confidence interval (CI): 1.25-3.10, P<0.05] and pCR rate of mediastinal lymph nodes (OR =1.97, 95% CI: 1.00-3.86, P=0.05); but it did not significantly improve OS [hazard ratio (HR) =0.91, 95% CI: 0.73-1.14, P=0.42] or PFS (HR =1.01, 95% CI: 0.81-1.26, P=0.91); also it did not exacerbate the toxicity. Induction chemoradiotherapy may have limited value concerning tumor response and pCR of mediastinal lymph nodes. However, current evidence does not support that addition of radiotherapy to induction chemotherapy followed by surgery can bring significant benefits to operable stage IIIA (N2) NSCLC patients. More studies are required to draw a better conclusion.

Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy

BackgroundTo evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients.MethodsTwo groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re-planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test.ResultsBoth SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V20, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST.ConclusionsThis study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice.

The application of preoperative neoadjuvant chemotherapy in patients with stage IIIA non-small cell lung cancer

Objective To analyze the clinical efficacy of neoadjuvant chemotherapy in patients with stage ⅢA non-small cell lung cancer (NSCLC). Methods From March 2008 to October 2015, there were 92 cases of stage ⅢA NSCLC patients received 2 cycles of neoadjuvant chemotherapy and underwent radical surgery for lung cancer 3-4 weeks late (observation group), and another group of 65 cases of stage ⅢA NSCLC patients (control group) underwent surgery for lung cancer without preoperative chemotherapy. The clinical data as well as early and meddle term surgical outcome of both groups were analyzed retrospectively. Results The neoadjuvant chemotherapy effective rate was 73.9% in the observation group. All surgeries for lung cancer patients were undertaken either with video-assisted thoracotomy or traditional thoracotomy. No operative mortality and the postoperative pathology findings were in accordance with NSCLC. The bleeding amount and operation time of two groups were similar; the resection rate of the observation group was greater than that of the control group. All patients were followed up at least 3 years, and the 2 years and 3 years survival rate of the observation group was slightly higher than that of the control group. Conclusions Preoperative neoadjuvant chemotherapy in patients with NSCLC can improve the resection rate and prolong the survival time, which is worthy of clinical application. Key words: Chemotherapy, adjuvant; Carcinoma, non-small-cell lung/TH

Neoadjuvant and adjuvant therapy for Stage III non-small cell lung cancer.

The treatments for advanced non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the 5-year survival of patients with Stage III NSCLC who underwent surgical resection alone has been dismal. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy is considered to be an appropriate treatment approach for Stage IIIA NSCLC patients; although, optimal treatment strategies are still evolving. When N2 nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy confers an overall survival benefit. The addition of postoperative radiotherapy might be considered for patients with nodal metastases. Although definitive chemoradiation remains a standard of care for cN2 NSCLC, alternative approaches such as induction chemotherapy or chemoradiotherapy and surgery can be considered for a selective group of patients. When surgical resection can be performed after induction therapy with low risk and a good chance of complete resection, the outcome may be optimal. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection.