Inoperable Locally Advanced Non-small Cell Lung Cancer Research Articles

A validation study on the lung immune prognostic index for prognostic value in patients with locally advanced non–small cell lung cancer

BackgroundBaseline lung immune prognostic index (LIPI) was reported as a potential predictive biomarker of immune checkpoint inhibitor treatment and a prognostic biomarker for metastatic non-small cell lung cancer (NSCLC). However, it remains unclear whether LIPI is associated with outcomes in locally advanced NSCLC (LA-NSCLC). Materials/methodsPatients with LA-NSCLC receiving radiotherapy between 2000 to 2017 were retrospectively reviewed. Based on pretreatment dNLR and LDH level made up LIPI per previous publications, patients were divided into good group (0 score) and intermediate-poor group (1 or 2 scores). Propensity score matching (PSM) was conducted to balance confounding variables. ResultsA total of 1079 patients were eligible for analysis. Patients with intermediate-poor pretreatment LIPI had inferior overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) than those with good LIPI. Multivariate analysis suggested that LIPI was an independent prognostic marker for OS (hazard ratio [HR] = 1.19, 95% CI: 1.02–1.40), PFS (HR = 1.18, 95% CI: 1.02–1.36), and LRRFS (HR = 1.22, 95% CI: 1.05–1.41) in patients with inoperable LA-NSCLC. PSM analysis further verified that intermediate-poor LIPI was an independent prognostic factor for shorter survivals (OS, PFS and LRRFS). ConclusionsLIPI is a simple and promising prognostic marker for patients with unresectable LA-NSCLC. Further prospected studies are warranted to validated these findings.

Efficacy comparison of concurrent chemoradiotherapy with nedaplatin and cisplatin in inoperable locally-advanced non-small cell lung cancer

Objective： To compare the efficacy and safety of concurrent chemoradiotherapy with nedaplatin and cisplatin in inoperative locally-advanced non-small cell lung cancer（NSCLC）.Methods： Eighty patients with locally-advanced NSCLC treated in Guanyun County People’s Hospital，Lianyungang，Jiangsu Province，from January 2015 to January 2019 were enrolled as study subjects，and were randomly divided into the nedaplatin group and the cisplatin group，each consisting of 40 patients.The patients in the 2 groups were treated with linear accelerator 6 MV high energy X-ray and 3D-CRT，5 times a week for a succession of 6 weeks，with a total dosage of 55-66 Gy.Then，the patients were given paclitaxel（155 mg/m2） intravenously for 3 hours in the first day after radiotherapy，and the patients in the cisplatin group were treated with cisplatin（80 mg/m2） intravenously for 3 to 4 days，and the patients in the nedaplatin group were given nedaplatin（80 mg/m2） intravenously also for 3 to 4 days.The efficacy，the levels of such serum tumor markers as carcinoembryonic antigen（CEA），carbohydrate antigen 125（CA125），neuron specific enolase（NSE） and cytokeratin fragment antigen 21-1（CYFRA21-1），as well as the rate of adverse drug reactions（ADRs） were compared between the 2 groups.Results： There was no statistical significance in remission rate and disease control rate，when comparisons were made between the 2 groups（P>0.05）.After treatment，CEA，CA125，NSE and CYFRA21-1 levels in the 2 groups were significantly lower than those before treatment（P<0.05）.There were no significant differences in CEA and CA125 levels，when comparisons were made between the 2 groups（P>0.05）.However，NSE and CYFRA21-1 levels in the patients of the nedaplatin group were significantly lower than those of the cisplatin group（P<0.05）.The rates of leucopenia，neutropenia，nausea and vomiting，constipation or diarrhea，increase of blood urea nitrogen or creatinine，and weight loss in the nedaplatin group were significantly lower than those in the cisplatin group（P<0.05）.Conclusion： Nedaplatin has similar efficacy as cisplatin in the treatment of inoperable locally-advanced NSCLC，with higher safety，meanwhile it could decrease the levels of NSE and CYFRA21-1.For this reason，it is worthy further clinical promotion.

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.

Multiple immune features based signature for predicting recurrence and survival of inoperable la-NSCLC patients.

e21066 Background: The immune status of 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. Methods: In this study, 100 patients who were diagnosed as inoperable LA-NSCLC between January 2005 and January 2016 were analyzed. A 5-immune feature-based signature was then constructed using the nested repeat 10-fold cross validation with LASSO Cox regression model. Nomograms were then established for predicting prognosis. Results: Immune signature combining 5 immuno-features were significantly associated with OS and PFS (P = 0.002 and P = 0.014, respectively) in patients with inoperable LA-NSCLC, and at a cutoff of -0.198 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. Using immune signature, we proposed immune signature nomograms, which 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 immune signature plays a complementary role in the prognosis prediction of patients with inoperable LA-NSCLC. Conclusions: Multiple 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.

Prognostic value of PD-L1 expression on tumor cells combined with CD8+ TIL density in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

Background/aimmmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT).Patients and methodWe retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0–40% vs. 41–100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated.ResultsMedian OS was 14 months (range: 3–167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1neg/CD8low) and type IV (PD-L1pos/CD8low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively.ConclusionAssessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.

Prognostic Value of Delta Inflammatory Biomarker-based Nomograms in Patients with Inoperable Locally Advanced NSCLC

Inflammation plays critical roles in tumor growth and progression, and can be adversely affected by chemotherapy and radiotherapy. However, there have been few studies on the prognostic value of delta (Δ) inflammatory biomarkers before and after chemoradiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). In this study, pre/post-treatment and Δ inflammatory biomarkers of 370 patients who were diagnosed as having inoperable LA-NSCLC in Shandong Cancer Hospital between January 2005 and January 2016 were analyzed. Nomograms were then established for predicting prognosis. Median overall survival (OS) and progression free survival (PFS) for all patients were 28.1 (range 1.9–129.0) months and 11.1 (range 1.7–58.7) months, respectively. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) significantly increased and the lymphocyte-to-monocyte ratio (LMR) significantly decreased during the concurrent chemoradiotherapy course (P<0.001, P<0.001, and P<0.001, respectively). Multivariate analysis revealed that pre-LMR, ΔNLR, and minimum absolute lymphocyte counts were independent predictors of OS (P=0.027, P=0.012, and P=0.015, respectively) and post-LMR, post-NLR, and ΔNLR were independent predictors of PFS (P=0.014, P=0.001, and P=0.036, respectively). Nomograms for OS and PFS were established by combining all significant inflammatory markers and clinicopathological characteristics. The concordance indexes for OS and PFS were 0.709 and 0.688, respectively. Post-treatment and Δ inflammatory biomarkers may have more prognostic significance than baseline measurements of inflammatory biomarkers in LA-NSCLC patients. The proposed nomograms based on the dynamic inflammatory biomarkers and clinicopathological factors are practical and widely available for evaluating the prognosis of patients with inoperable LA-NSCLC.

Prognostic value of delta inflammatory biomarker-based nomograms in patients with inoperable locally advanced NSCLC

ObjectiveInflammation plays critical roles in tumor growth and progression, and can be adversely affected by chemotherapy and radiotherapy. However, there have been few studies on the prognostic value of delta (Δ) inflammatory biomarkers before and after chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). MethodsIn this study, pre/post-treatment and Δ inflammatory biomarkers of 370 patients who were diagnosed as having inoperable LA-NSCLC in Shandong Cancer Hospital between January 2005 and January 2016 were analyzed. Nomograms were then established for predicting prognosis. ResultsMedian overall survival (OS) and progression free survival (PFS) for all patients were 28.1 (range 1.9–129.0) months and 11.1 (range 1.7–58.7) months, respectively. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) significantly increased and the lymphocyte-to-monocyte ratio (LMR) significantly decreased during the concurrent chemoradiotherapy course (P < 0.001, P < 0.001, and P < 0.001, respectively). Multivariate analysis revealed that pre-LMR, ΔNLR, and minimum absolute lymphocyte counts were independent predictors of OS (P = 0.027, P = 0.012, and P = 0.015, respectively) and post-LMR, post-NLR, and ΔNLR were independent predictors of PFS (P = 0.014, P = 0.001, and P = 0.036, respectively). Nomograms for OS and PFS were established by combining all significant inflammatory markers and clinicopathological characteristics. The concordance indexes for OS and PFS were 0.709 and 0.688, respectively. ConclusionPost-treatment and Δ inflammatory biomarkers may have more prognostic significance than baseline measurements of inflammatory biomarkers in LA-NSCLC patients. The proposed nomograms based on the dynamic inflammatory biomarkers and clinicopathological factors may be practical and widely available for evaluating the prognosis of patients with inoperable LA-NSCLC.

The efficacy analysis of simultaneous integrated boost intensity-modulated radiotherapy for locally advanced non-small cell lung cancer

Objective To investigate the clinical efficacy and toxicity in the use of simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) for inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Methods Between February 2012 and July 2015, 58 pathologically diagnosed inoperable LA-NSCLC patients treated with SIB-IMRT were analyzed. A radiation dose of 50-64 Gy was administered in 1.8-2.2 Gy/fraction (26-30 fractions) to the planning target volume (PTV). Simultaneously, 60-70 Gy was administered in 2.0-2.35 Gy/fraction (26-30 fractions) to the planning gross tumor volume (PGTV). Results The median follow-up time was 28.0 months (ranging from 6.0 to 40.0 months). The median overall survival (OS) and progress-free survival (PFS) were 25.0 (95% CI: 23.8-26.2) and 15.0 (95% CI: 11.3-18.7) months, respectively. The 1-, 2-year OS were 91.4% and 51.7%, respectively. The 1-, 2-year PFS were 56.9% and 22.7%, respectively. None of the patients developed grade 4 or 5 pneumonitis and esophagitis. In addition, in the subgroup analysis, the patients with N3 have a higher incident of ≥ grade 2 esophagitis compared with N0-N2, the incident are 29.2% and 20.6%, respectively (P<0.05). Conclusions SIB-IMRT is feasible and well-tolerated for inoperable LA-NSCLC patients. It remains to be further evaluated in a large sample size prospective clinical trial. Key words: Radiotherapy, intensity-modulated; Carcinoma, non-small-cell lung/RT

P2.02-012 Long-Term Survival of Phase II of Full-Dose Oral Vinorelbine Combined with Cisplatin &amp; Radiotherapy in Locally Advanced NSCLC

Chemo-radiotherapy is the standard of care for the treatment of inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Cisplatin (P) plus vinorelbine is one of the chemotherapy (CT) regimens widely used concurrently with radiotherapy (RT). Since oral vinorelbine (oV) has achieved comparable results to the IV formulation, the optimal dose for the oV administration with P and concurrent RT is still being investigated. The aim of this study is to evaluate the efficacy and safety of full-dose oV combined with P and radical RT for LA-NSCLC patients (pts). Untreated pts between 18-70 years (y), with histologically proven inoperable LA-NSCLC (supraclavicular lymph node involvement excluded), V20<30%, adequate bone marrow, respiratory, hepatic and renal function, and ECOG PS0-1; received 4 cycles (cy) of oV 60 mg/m2 D1 & 8 plus P 80 mg/m2 D1, every 3 weeks, plus 2Gy/day of RT started on D1 of 2nd cy (total dose 66Gy). Primary endpoint was overall response rate (ORR) by RECIST 1.1. Secondary endpoints were: progression free survival (PFS), overall survival (OS) & safety profile. To guarantee a type-1 (□) error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint, a sample size of 45 eligible pts was planned. EudraCT 2009-010436-17. Forty-eight pts were included between 02/2010-12/2011. Median age 61y [34-72], male 90%, PS1 58%; smokers 52%; squamous 63%; stage IIIB 54%. Main G3-4 toxicities (% cy) were: neutropenia 33%, febrile neutropenia 14.6%, anemia 12.5%, thrombocytopenia 16.6%, & esophagitis 12.5%. Two treatment-related deaths during the 1st cy. RT was administered to 87.5% of pts; 7.1% received less than 60Gy and 23.8% had delays due to adverse events. The ORR was 77.3% (2 complete responses). With a median follow-up of 28.2 months (m) [0.5-70.6], 33 pts (68.8%) have progressed and 32 (66.7%) have died. Median PFS and OS were 11.8m (CI95% 7.2-16.5) and 29.8m (CI95% 21.4-38.1), respectively. PFS at 1y was 48.8% pts (CI95% 33.9-63.7%). OS at 1 and 2y were 72.7% (CI95% 60-85.4%) and 57.3% (CI95% 43-71.6%), respectively. This long-term analysis confirms the good efficacy results of the administration of full doses of oral vinorelbine combined with cisplatin and concurrent RT in patients with LA-NSCLC.

The effect of consolidation chemotherapy after concurrent chemoradiotherapy on the survival of patients with locally advanced non-small cell lung cancer: a meta-analysis.

Whether consolidation chemotherapy (CCT) after chemoradiotherapy (CRT) helps in the treatment of locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. The aim of this meta-analysis was to evaluate the impact of CCT on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities in patients with inoperable LA-NSCLC. PubMed, Embase, The Cochrane Library, WanFang, VIP, and CNKI were searched to identify any relevant publications. After screening the literature and completing quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software. Ultimately, 5 eligible studies with a total of 1036 patients were selected for the present meta-analysis. The results of the analysis indicated that treatment of LA-NSCLC patients with CRT followed by CCT improved OS (pooled HR0.85; 95% CI 0.73-0.99; P=0.03), but did not improve PFS (pooled HR0.78; 95% CI 0.60-1.02; P=0.07) and ORR (P=0.26). Although it could increase the risk of grade ≥3 infection (P=0.04), it may not increase the risk of grade ≥3 radiation pneumonitis (P=0.09) during the CCT period. CCT after concurrent CRT may provide additional benefits in the treatment of LA-NSCLC. Although this therapeutic strategy did not prolong PFS, further assessment is warranted.

Regimens for inoperable locally advanced non-small cell lung cancer

Concurrent chemoradiotherapy is the optimal regimen for patients with inoperable locally advanced non-small cell lung cancer (LA-NSCLC).The application of new technologies such as positron emission tomography (PET)/CT and four dimensional CT (4D-CT) enhances the accuracy of radiotherapy and decreases adverse reaction.Induction chemotherapy and consolidation chemotherapy do not show benefit to survival.The targeted therapy and immunotherapy have the potential of improving the outcomes of inoperable LA-NSCLC. Key words: Carcinoma, non-small-cell lung; Radiotherapy; Drug therapy

SU-FF-J-141: Volumetric Response Analysis During Chemoradiation as Predictive Tool for Optimizing Treatment Strategy in Locally Advanced Unresectable NSCLC

Background In the treatment of locally advanced non‐small cell lungcancer (LANSCLC) there is a trend towards concurrent chemoradiation because of the advantage on local control and survival (Auperin et al, IASLC 2007). Chemoradiation however is burdened by a marked increase in toxicity. This calls for a more patient‐tailored approach, trying to identify those patients that benefit from a more aggressive approach. We studied the feasibility of measuring volumetric changes in the primary tumor on tomotherapy MVCT, correlating with local response to assess its usefulness in reliable, early detection of patients with poor local therapy outcome. Methods Fifteen consecutive patients with stage III, inoperable LANSCLC were treated using helical tomotherapy. They were monitored for acute toxicity and evaluated with daily MVCT imaging. The tumor volume was delineated daily in a standardized way and the volumetric changes were fitted to a negative exponential resulting in a regression coefficient (RC). Local response evaluation was done using PET‐scan. Results The mean volume decrease (±standard deviation) was 77% (±18%). With a mean treatment time of 42 days this treatment schedule resulted in a mean decrease of 1.83%/day. Out of the 13 evaluable patients 7 developed a metabolic complete remission (MCR). The mean RC of the patients with MCR is 0.050 versus a mean RC of 0.023 in non‐responders (p=0.0074). Using a proposed cut‐off value for the RC of 0.03 80% of the non‐responders will be detected correctly while misclassifying 16.4% of patients who eventually achieve a MCR. Conclusions The RC derived from volumetric analysis of daily MVCT is prognostic and predictive for local response in patients treated with chemoradiation for a locally advanced NSCLC. Because of the possible toxicity of chemoradiation, MVCT can be a tool for the implementation of patient‐individualized treatment strategies.

Phase II study of induction chemotherapy with cisplatin (Cis) and gemcitabine (Gem) followed by concomitant Cis-Gem and thoracic radiation (RTX) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC)

7550 Background: In the CALGB Study Cis with Gem followed by concomitant chemoradiation for inoperable LA-NSCLC was effective, however with significant toxicity (E. Vokes et al; JCO 20: 2002). The aim of this study was to improve tolerability by reducing the Gem dose during radiotherapy and adding one cycle of induction chemotherapy. Methods: Patients with histological proven stage IIIA and IIIB NSCLC were included in this study from 8/04 to 9/07. All patients were to receive 3 induction cycles (21 days) of Cis 80 mg/m2 d1 plus Gem 1250 mg/m2 over 30 minutes d1, 8. After a 3 weeks rest period, 2 cycles of concomitant chemoradiation Cis 80 mg/m2 d1, Gem 300 mg/m2 d1, 8 and RTX (about 60 Gy; 5 times 1,8 Gy fractions / week) were given. Results: A total of 49 patients, median age 63.4 yrs, 73.5% male, with Karnofsky performance status 80/85/90/100: 16.3% / 2.0% / 49.0% / 32.7% were entered. Disease stage IIIA/IIIB: 28.6% / 71.4%. Median dose intensity during chemoradiation Gem 98.4%, Cis 99.0% and radiation median total dose was 63 Gy. Number of grade 3/4 toxicities during induction chemotherapy (N=49): neutropenia 9/9, thrombocytopenia 4/1. Acute grade 3/4 toxicities during chemoradiation phase (N=31): neutropenia 4/0, thrombocytopenia 5/1, radiation esophagitis 4/0 and radiation pneumonitis 1/0. No toxic death. Tumor Response Rate of enrolled patients was 22 (44.9%) (95% CI: 30.7–59.8). Conclusions: Concurrent Cis Gem chemoradiation after Cis Gem induction is an active treatment for LA-NSCLC with managable toxicity. [Table: see text]