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Background: As the main executor of immunotherapy, T cells significantly affect the efficacy of immunotherapy. However, the contribution of the T cell proliferation regulator to the prognosis of lung adenocarcinoma (LUAD) and immunotherapy is still unclear., Methods: Based on T cell proliferation regulators, LUAD samples from The Cancer Genome Atlas (TCGA) were divided into two different clusters by consensus clustering. Subsequently, the T cell proliferation regulator (TPR) signature was constructed according to the prognostic T cell proliferation regulators. Combined with clinical information, a nomogram for clinical practice was constructed. The predictive ability of the signature was verified by the additional Gene Expression Omnibus (GEO) dataset. We also analyzed the differences of tumor microenvironment (TME) in different subgroups and predicted the response to immunotherapy according to the TIDE algorithm. Finally, we further explored the role of ADA (Adenosine deaminase) in the lung adenocarcinoma cell lines through the knockdown of ADA ., Results: According to the consensus clustering, there were differences in survival and tumor microenvironment between two different molecular subtypes. T cell proliferation regulator-related signature could accurately predict the prognosis of LUAD. The low-risk group had a higher level of immune infiltration and more abundant immune-related pathways, and its response to immunotherapy was significantly better than the high-risk group (Chi-square test, p<0.0001). The knockdown of ADA inhibited proliferation, migration, and invasion in lung adenocarcinoma cell lines., Conclusion: T cell proliferation regulators were closely related to the prognosis and tumor microenvironment of LUAD patients. And the signature could well predict the prognosis of LUAD patients and their response to immunotherapy. ADA may become a new target for the treatment of LUAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chang, Li, Cheng, He, Ou and Wang.)

Background: Zinc is a key mineral element in regulating cell growth, development, and immune system. We constructed the zinc metabolism-related gene signature to predict prognosis and immunotherapy response for lung adenocarcinoma (LUAD)., Methods: Zinc metabolism-associated gene sets were obtained from Molecular Signature Database. Then, the zinc metabolism-related gene signature (ZMRGS) was constructed and validated. After combining with clinical characteristics, the nomogram for practical application was constructed. The differences in biological pathways, immune molecules, and tumor microenvironment (TME) between the different groups were analyzed. Tumor Immune Dysfunction and Exclusion algorithm (TIDE) and two immunotherapy datasets were used to evaluate the immunotherapy response., Results: The signature was constructed according to six key zinc metabolism-related genes, which can well predict the prognosis of LUAD patients. The nomogram also showed excellent prediction performance. Functional analysis showed that the low-risk group was in the status of immune activation. More importantly, the lower risk score of LUAD patients showed a higher response rate to immunotherapy., Conclusion: The state of zinc metabolism is closely connected to prognosis, tumor microenvironment, and response to immunotherapy. The zinc metabolism-related signature can well evaluate the prognosis and immunotherapy response for LUAD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chang, Li, Ou and Wang.)

Introduction: In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective., Methods: A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results., Results: PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained., Conclusion: PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited., Methods: This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years., Results: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months., Conclusions: These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC., Lay Summary: The utility of serial circulating tumor DNA (ctDNA) monitoring for predicting disease recurrence and survival for early-stage non-small cell lung cancer (NSCLC) has not been well characterized. The detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence and long-term patient outcomes for resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than routine radiologic imaging. ctDNA analyses can detect minimal residual disease for resectable NSCLC and thus can facilitate early intervention., (© 2021 American Cancer Society.)

We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity in stage III NSCLC. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data., Methods: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I 2 test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively., Results: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p = 0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p = 0.002) and BM-free survival (HR 0.82 [0.69-0.97] p = 0.02). The number of patients with high-grade (≥3) toxicity was 6.4% (21/330) for PCI., Conclusion: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chemotherapy is applied to treat non-small cell lung cancer (NSCLC), but often limited due to its unstable therapeutic effects and adverse reactions (ADRs). Ginseng and its main ingredients (ginsenosides and polysaccharides) have been clinically used as adjuvants to chemotherapy. However, their efficacies were based on individual trials with relatively small sample sizes, and it is difficult to draw a valid conclusion. In this study, eligible randomized controlled trials (RCTs) were searched in six international and Chinese databases (PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese VIP Information and Wanfang). The outcomes of the objective response rate (ORR), disease control rate (DCR), ADRs, quality of life (QOL), survival rates and immunity were extracted using standard data extraction forms. The efficacies of ginseng and its ingredients as adjuvants to chemotherapy in NSCLC were investigated and compared by meta-analysis and subgroup meta-analysis, respectively. A total of 28 RCTs including 2503 subjects were enrolled, and most of the eligible studies were of low-to-moderate quality. For the evaluation of ginseng and its ingredients as adjuvants to chemotherapy, the risk ratio (RR) or standardized mean difference (SMD) and 95% confidence intervals (CI) of the ORR, DCR, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity, nausea and vomiting, diarrhea, CD4+/CD8+ and one- and two-year survival rates, and QOL were 1.35 (1.21,1.50), 1.20 (1.14,1.28), 0.59 (0.50, 0.70), 0.53 (0.37, 0.76), 0.30 (0.17, 0.53), 0.67 (0.52, 0.87), 0.67 (0.53, 0.86), 0.42 (0.19, 0.96), 1.39 (0.63, 2.16), 1.35 (1.13, 1.60), 3.21 (1.51, 6.81) and 1.31 (1.22, 1.41) with significant differences. Subgroup analysis showed that ginseng enhanced nausea and vomiting and QOL, ginsenosides increased ORR, DCR, QOL, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity, diarrhea, CD4+/CD8+, and one- and two-year survival rates, while polysaccharides improved ORR, DCR, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity and nausea and vomiting during chemotherapy. In conclusion, ginseng and its ingredients facilitated the therapeutic effects of chemotherapy on NSCLC patients. Ginseng had beneficial effects on alleviating ADRs and enhancing QOL, ginsenosides demonstrated beneficial effects on enhancing therapeutic effects, reducing ADRs, improving immunity, prolonging survival rates and promoting QOL, while polysaccharides showed beneficial effects on promoting therapeutic effects and reducing ADRs.

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs., Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles., Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort ( n = 232) and the testing cohort ( n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts ( P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts., Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients., (Copyright © 2020 Chen, Zhou, Cao, Sun, Su, Deng, Lin, Xiao, Chen, Wang and Lin.)

Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), has proven to be effective and safe for treating patients with advanced gastric cancer after second-line chemotherapy failure. As VEGFR-2 targeted therapy has made encouraging progress for the treatment of a broad range of malignancies, we explored the efficacy and safety of apatinib for the treatment of advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy., Methods: We retrospectively analyzed the data of 34 patients (11 with squamous carcinoma and 23 with adenocarcinoma) who were treated with apatinib alone in a daily oral dose of 250 mg in the second-line or third-line setting from January 2016 to July 2017. The primary endpoint was progression-free survival (PFS)., Results: EGFR mutation or amplification was detected in 15 patients. The median PFS of the whole group was four months (95% confidence interval 0.3-7.7). A partial response was observed in 2 patients (5.88%) and stable disease in 19 (55.88%). The disease control rate was 61.76%. Common side effects of apatinib were hypertension (n = 12), hand-foot syndrome (n = 8), and proteinuria (n = 5), which accounted for 35.30%, 23.53%, and 14.71%, respectively, and no grade 3/4 adverse reactions occurred. Apatinib toxicity was controllable and tolerable., Conclusions: Apatinib appears to be effective and safe for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: Brain metastases remain lethal in lung cancer patients. The impacts of epidermal growth factor receptor (EGFR) mutations and EGFR tyrosine kinase inhibitors (TKIs) on the incidence of brain metastases in patients with advanced non-squamous non-small cell lung cancer (NSCLC) are still uncertain., Patients and Methods: A total of 1672 patients with advanced non-squamous NSCLC with a definitive report on EGFR mutation status between January 2005 and June 2013 were retrospectively analyzed. The impacts of EGFR mutation status and EGFR TKIs use on the incidence of brain metastases and survival were investigated., Results: Of the 1672 patients, 465 (27.8%) had an EGFR mutation, and 1207 (72.2%) did not. Four hundred and eighteen (25.0%) patients had baseline brain metastases. The cumulative incidence of brain metastases for patients in EGFR+ group was significantly higher than patients in EGFR- group (HR, 1.27; 95% CI 1.06-1.52; P=0.008). The cumulative incidence of brain metastases was also higher for patients who received an EGFR-TKI as their first-line treatment than those who received other first-line treatment (HR, 1.36; 95% CI 1.14-1.64; P=0.001). Patients harboring EGFR mutations had prolonged overall survival (OS) than patients with wild-type EGFR (HR, 0.47; 95% CI 0.41-0.54; P<0.001; median, 25.2 vs. 12.9 months)., Conclusions: Both the EGFR mutation-positive status and the use of a TKI are associated with higher incidence of brain metastases for patients with advanced non-squamous NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The prognostic values of preoperative neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) have been previously described. This study assessed the prognostic values of other pretreatment complete blood cell parameters in Chinese patients with curatively resected NSCLC., Methods: A total of 1466 consecutive NSCLC patients who received curative surgery from January 1, 2005 to December 31, 2009 with complete data from pretreatment blood tests were enrolled in this retrospective study. Correlations between each blood test parameter and overall survival were examined by Kaplan-Meier method or Cox proportional hazards regression, followed by a stratification analysis of significant variables., Results: Optimal cut-off values of 0.55 for neutrophil/white blood cell ratio (NWR), 0.28 for lymphocyte/white blood cell ratio (LWR), 0.09 for monocyte/white blood cell ratio (MWR), 2.06 for NLR, 0.35 for MLR, 204.00 for PLR, and 38.25 for platelet/white blood cell ratio (PWR) were identified using X-tile software. Univariate analysis suggested that NWR ≥ 0.55, LWR < 0.28, MWR ≥ 0.09, NLR ≥ 2.06, MLR ≥ 0.35, and PLR ≥ 204.00 predicted a poor prognosis in NSCLC patients. However, only NWR and MLR were identified as independent significant prognostic factors in multivariable analysis, especially in tumor node metastasis stage I and I/II/III NSCLCs., Conclusion: Pretreatment NWR, MWR, LWR, NLR, MLR, and PLR values are associated with poor overall survival for patients with curatively resected NSCLC. NWR and MLR are independent prognostic factors in curatively resected NSCLC., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: This study aimed to investigate the association of epidermal growth factor receptor (EGFR) mutation status with treatment outcome for patients with stage 3 non-small cell lung cancer (NSCLC) who had undergone a complete (R0) resection., Methods: The study identified 3445 NSCLC patients tested for EGFR mutations between September 2001 and December 2011 at the Sun Yat-Sen University Cancer Center. Of these patients, 224 were stage 3 patients who had undergone R0 resections., Results: These 224 R0-resected, pathologic stage 3A and 3B patients included 150 patients with wild-type EGFR and 74 patients with EGFR mutations. During a median follow-up period of 42 months (range, 4-133 months), pathologic stage was shown to be the only prognostic factor. The 3-year overall survival (OS) rates did not differ significantly from the OS rates for the wild-type and mutant EGFR groups (62.0 vs 67.2 %; p = 0.789). Multivariate analyses indicated that the patients in the mutant EGFR group with EGFR exon 19 mutations had a better OS rate (73.0 vs 61.1 %; p = 0.026)., Conclusions: Cancer stage remained the significant prognostic factor in R0-resected stage 3 NSCLC patients. The presence of an EGFR mutation is more likely to be a predictive marker for the response to treatment with tyrosine kinase inhibitors. In the EGFR mutant group, the patients with an exon 19 mutation had better 3-year OS rates. These findings might be considered in future study designs.

Background: The objective of this phase 2 trial was to assess the efficacy and safety of induction bevacizumab plus chemotherapy followed by surgery in patients with unresectable stage III lung adenocarcinoma., Methods: The authors investigated induction bevacizumab (7.5 mg/kg) plus pemetrexed (500 mg/m(2) and carboplatin (area under the receiver operating characteristic curve = 5) followed by surgery for patients with unresectable stage III lung adenocarcinoma ages 18 to 65 years. The patients received neoadjuvant therapy every 3 weeks for 4 cycles. Surgery was scheduled 3 to 4 weeks after the last neoadjuvant therapy; then, the medical team assessed each patient's resectability status. The primary endpoint was the resectability rate., Results: From April 2012 to April 2014, 42 patients were enrolled and received bevacizumab plus pemetrexed and carboplatin. Grade 3 or 4 induction-related AEs included fatigue in 5 patients, neutropenia in 4 patients, hypertension in 1 patient, anemia in 1 patient, and thrombocytopenia in 1 patient. One patient achieved a complete response, 22 achieved a partial response, 17 had stable disease, and 2 had progressive disease. After neoadjuvant therapy, 31 patients (73.8%) underwent surgery, including 11 who underwent pneumonectomy. Complete (R0) resection was achieved in 22 patients (52.4%). Reoperation was required in 1 patient because of a bleeding intercostal artery. No perioperative thromboembolic events or wound-healing problems were observed. The median event-free survival was 15.4 months, and the 1-year event-free survival rate was 56.1%., Conclusions: Treatment with neoadjuvant bevacizumab in combination with pemetrexed and carboplatin followed by surgery appears to be feasible and safe in patients with unresectable stage III lung adenocarcinoma. Cancer 2016;122:740-747. © 2015 American Cancer Society., (© 2015 American Cancer Society.)

Background: Bilirubin levels have been associated with risk of several malignancies. The association between pretreatment serum bilirubin levels and survival of curatively resected non-small-cell lung cancer (NSCLC) is unclear., Methods: This analysis was performed retrospectively in a cohort of 1617 consecutive patients with bilirubin levels within the range considered normal, who received curative resection for NSCLC. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off points. The significance of pretreatment serum total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels in the prognosis of patients with curatively resected NSCLC was investigated., Results: The cutoff points of serum TBIL, DBIL and IBIL were 9.50μmol/L, 3.45μmol/L and 6.95μmol/L, respectively. High TBIL was observed in 65.2% of entire patient population, high DBIL 50%, and high IBIL 56.8%. The high-TBIL group had significantly lengthened overall survival (OS; hazard ratio [HR], 0.73; 95% confidence interval [CI] 0.63-0.84; P<0.001), disease-free survival (DFS; HR, 0.72; 95% CI 0.64-0.82; P<0.001) and distant metastasis-free survival (DMFS; HR, 0.74; 95% CI 0.60-0.91; P=0.004). Similarly, high-DBIL and high-IBIL levels were associated with longer OS, DFS, and DMFS with significant differences. In multivariable analysis, IBIL level was identified as an independent significant prognostic factor., Conclusions: Moderately elevated pretreatment bilirubin levels are associated with longer OS, DFS, and DMFS for patients with curatively resected NSCLC. IBIL is an independent prognostic factor in curative resected NSCLC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show great efficacy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of gefitinib following adjuvant chemotherapy in patients with EGFR mutation are unknown., Methods: In this open-label, phase II study, patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations (either exon 19 deletion or L858R point mutation) were assigned randomly to receive pemetrexed (500 mg/m(2)) and carboplatin (AUC = 5), administered every 21 days for 4 cycles, followed with or without gefitinib (250 mg/day) for 6 months. The primary end point was disease-free survival (DFS)., Results: From August 2008 to September 2011, 60 patients were included in our center. DFS was significantly longer among those who received pemetrexed and carboplatin (PC)-gefitinib than among those who received PC alone [hazard ratio (HR), 0.37; 95 % confidence interval (CI) 0.16-0.85; P = 0.014; median, 39.8 vs. 27.0 months]. The rates of 2-year DFS were 78.9 % in the PC-gefitinib group and 54.2 % in the PC alone group. The rates of 2-year overall survival (OS) were 92.4 % in the PC-gefitinib group and 77.4 % in the PC alone group (HR, 0.37; 95 % CI 0.12-1.11, P = 0.076). The most common adverse event was rash (43.3 %, 13/30) in the PC-gefitinib group and the administration of gefitinib following chemotherapy was well tolerated., Conclusions: The administration of gefitinib following PC adjuvant therapy shows significant improvement in DFS in patients with resected stage IIIA-N2 NSCLC harbouring EGFR mutations.

Background: The current study was undertaken to investigate the efficacy and safety of erlotinib versus pemetrexed as second-line therapy for patients with advanced epidermal growth factor receptor (EGFR) wild-type and EGFR fluorescence in situ hybridization (FISH)-positive lung adenocarcinoma., Methods: In this open-label, randomized, phase 2 study, patients with EGFR wild-type and EGFR FISH-positive adenocarcinoma who had developed disease progression after 1 prior platinum-based chemotherapy were randomly assigned (1:1) to receive erlotinib or pemetrexed until the time of disease progression or death, unacceptable toxicity, or a request for discontinuation by the patient. The primary endpoint was progression-free survival (PFS)., Results: A total of 123 patients were enrolled (61 in the erlotinib arm and 62 in the pemetrexed arm). The median PFS was 4.1 months (95% confidence interval [95% CI], 1.6 months-6.6 months) in the erlotinib group versus 3.9 months (95% CI, 2.7 months-5.1 months) in the pemetrexed group. The difference in PFS between the 2 treatment groups was not significant (hazard ratio, 0.92; 95% CI, 0.62-1.37 [P= .683]). The objective response rate appeared to be higher among patients receiving erlotinib compared with those receiving pemetrexed (19.7% vs 8.1%; P= .062). The 3 most commonly recorded adverse events were rash (54.1%), fatigue (19.7%), and diarrhea (16.4%) in the erlotinib group and fatigue (25.8%), nausea (24.2%), and anorexia (14.5%) in the pemetrexed group., Conclusions: There were no significant differences noted with regard to efficacy between erlotinib and pemetrexed in the second-line setting for patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Both regimens appear to be effective treatment options for these patients., (© 2014 American Cancer Society.)

Introduction: This study was to assess the association of epidermal growth factor receptor (EGFR) mutation status and efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 non-small-cell lung cancer (NSCLC)., Materials and Methods: Tumor samples (n = 150) from patients with IIIA-N2 NSCLC who either had or had not received paclitaxel plus carboplatin or vinorelbine plus carboplatin doublet adjuvant chemotherapy were analyzed for EGFR mutations. The association of the presence of EGFR mutations and survival was assessed., Results: Mutations were identified in 43 (28.7%) patients (n = 25 in the no chemotherapy [observation] arm and n = 18 in the chemotherapy arm). Patients with EGFR mutations had statistically significant improved disease-free survival (41 months [95% CI, 25.1-56.9 months] vs. 20 months [95% CI, 15.0-25.0 months]; 2P = .005) and overall survival (50 months [95% CI, 37.6-62.4 months] vs. 25 months [95% CI, 20.8-29.2 months]; 2P = .001), regardless of treatment. The patients with wild-type EGFR had greater overall survival with chemotherapy compared with no adjuvant therapy (hazard ratio [HR] 4.748 [95% CI, 2.844-7.928]; 2P < .001). In contrast, in patients with EGFR mutation in the observation group compared with the chemotherapy group had longer median disease-free survival (49 months [95% CI, 35.1-62.9 months] for the observation arm vs. 30 months [95% CI, 23.8-36.2 months] for the chemotherapy arm, 2P = .195) and overall survival (59 months [95% CI, 43.9-74.1 months] vs. 33 months [95% CI, 24.7-41.3 months]; 2P = .050)., Conclusions: In this exploratory study, the status of EGFR mutations was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC. Further studies are required to confirm that a patient's adjuvant treatment may be customized to their EGFR mutational status., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Estrogen receptor (ER) and progesterone receptor (PR) play important roles in breast cancer. Similarly, there have been several reports of ER and PR expression in lung cancers, but the results have not been consistent. The aim of this study was to investigate the association between hormone receptor expression and clinicopathologic factors and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC)., Methods: We evaluated 316 resected NSCLC specimens for ER-α, PR, human epidermal growth factor receptor 2, and aromatase (n=272) expression using immunohistochemical methods. EGFR mutations were evaluated with polymerase chain reaction (PCR)., Results: ER-α and PR were detected in 36.1% and 44.9% of all patients, respectively. The expression of ER-α was observed mostly in cytoplasm (94.7%) and the expression of PR was observed mostly in nucleus (95.8%). Aromatase was detected in the cytoplasm of 64.0% of patients. ER-α expression was significantly associated with female gender (p=0.004). The expression of PR was significantly associated with better clinicopathologic features. ER-α expression showed a positive correlation with PR (r=0.275; p<0.001) and aromatase (r=0.244; p<0.001) expression levels. EGFR mutation was independently associated with the female gender (p=0.001), negative expression of PR (p<0.001), and negative expression of aromatase (p=0.027)., Conclusions: The expression of ER-α and PR distinguish a subset of NSCLC that has defined clinicopathologic features. Negative expression of PR and aromatase correlate with EGFR mutation., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Instruction: We determined whether adjuvant vinorelbine/paclitaxel plus carboplatin prolonged overall survival among patients with completely resected stage IIIA-N2 non-small cell lung cancer (NSCLC)., Methods: We randomly assigned patients with completely resected stage IIIA-N2 NSCLC to a control group or to a treatment group with vinorelbine/carboplatin or paclitaxel/carboplatin doublet adjuvant chemotherapy. The primary endpoint was overall survival; secondary endpoints were disease-free survival and the toxicity and safety of the regimen., Results: This trial was terminated before accumulation of the planned numbers for registration because of the results of bigger clinical trial. Finally, 150 patients underwent randomization to vinorelbine/paclitaxel plus carboplatin (79 patients) or observation. In the chemotherapy group, 38 patients received vinorelbine plus carboplatin and 41 patients received paclitaxel plus carboplatin. In both groups, the median age was 57 years, 73% were men, and 28% had squamous carcinoma. Chemotherapy caused neutropenia in 82% of the patients (including grade 3 and 4 neutropenia in 42%), and there were no treatment-related deaths in this trial. After a median follow-up of 29 months (range, 1-110 months), the overall survival was significantly prolonged in the chemotherapy group, when compared with the observation group (33 months [95% confidence interval {CI}, 27.4-38.6] versus 24 months [95% CI, 15.8-32.2], p = 0.037), as was disease-free survival (32 months [95% CI, 21.3-42.7] versus 20 months (95% CI, 13.1-26.9), p = 0.020). The 5-year overall survival rates were 31.1% and 19.1%, respectively., Conclusions: Although with limitations, this clinical trial showed that adjuvant vinorelbine/paclitaxel plus carboplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected stage IIIA-N2 NSCLC.

Background: Adjuvant cisplatin-based chemotherapy benefits selected patients with stages II and III non-small cell lung cancer (NSCLC). However, carboplatin being tolerated better than cisplatin, carboplatin-based adjuvant therapy may have better chemotherapy compliance. This study aimed to investigate the feasibility and toxicity of adjuvant carboplatin and docetaxel in patients with completely resected locally advanced NSCLC., Methods: Eighty patients with completely resected locally advanced NSCLC were enrolled in this trial. Adjuvant chemotherapy was initiated between 1 and 4 weeks after surgery, and consisted of four cycles of carboplatin (AUC=5), and docetaxel (Taxotere, 75mg/m(2)) every 3 weeks, after which patients received prophylactic G-CSF supportive therapy., Results: Patient demographics were: Median age 55 years (range 34-73): gender ratio was 56.3% male/43.7% female: 72.5% of the patients were at stage IIIA and 27.5% were at stage IIIB. The two most common histologies were adenocarcinoma (62.5%) and squamous cell carcinoma (17.5%). Sixty-six patients (82.5%) received four cycles of therapy over a 12-week period. Fourteen patients (17.5%) did not complete therapy due to: patient refusal (n=12), severe adverse events (n=1) and bone metastases during chemotherapy (n=1). No treatment related deaths were observed and the primary adverse events were hematologic toxicity, alopecia, fatigue and gastointestinal reaction (nausea, vomiting and diarrhea)., Conclusion: Combination therapy with carboplatin and docetaxel with the use of G-CSF supportive therapy has an acceptable toxicity profile such that the majority of patients completed four cycles of therapy in 12 weeks., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Cerebral metastases are the main determining factor in the failure of locally advanced non-small-cell lung cancer (NSCLC) management. Our study assessed the risk factors of brain metastases in patients with postoperative, locally advanced NSCLC. Implications for PCI treatment are discussed., Methods: Two hundred twenty-three patients treated with surgical resection for stage III-N2 NSCLC were retrospective analyzed to elucidate risk factors for development of brain metastases, and to establish a mathematical model., Results: Median survival time for this patient population was 29.5 months. Frequency of brain metastases in the entire patient population was 38.1% (85/223). Frequency of brain metastases in patients with single mediastinal lymph-node region with metastases at 1, 2, and 3 years was 5.6%, 14.0%, and 19.0%, respectively. The frequency of brain metastases in patients with multiple mediastinal lymph-node regions with metastases was 31.8%, 60.3%, 68.0%, respectively (P<0.001). The frequency of brain metastases among patients with mediastinal metastasis number less than 4, 4-6, and more than 6 was significantly different (P<0.001). There were also significant differences in brain metastases frequency between patients with complete versus incomplete resection (P=0.001), and patients with non-squmous versus squamous (P=0.029), and patients administered adjuvant chemotherapy versus none (P=0.032)., Conclusion: A mathematical model to predict brain metastases risk was developed. It can aid in selection of patients with locally advanced NSCLC for PCI in clinical trails.

Objective: To investigate the prognostic effect of mediastinal lymph node dissection in patients with stage I non-small cell lung cancer (NSCLC)., Methods: The clinical data of 330 patients with stage I NSCLC who were treated with curative resection from January 1994 to December 2003 were reviewed retrospectively. According to the extent of mediastinal lymph node dissection and the pathology report, the patients were assigned to lung resection combined with mediastinal lymph node dissection (LND) group or with lymph node sampling (LNS) group. The Kaplan-Meier method was used for survival analysis. COX proportional hazards model was used for multivariate analysis., Results: There were 233 (70.6%) male patients and 97 (29.4%) female patients. The median age was 60 years old. Ninety-eight patients were in stage IA and 233 in stage IB. One hundred and forty patents were in group LND and 190 in group LNS. The mean number of removed lymph nodes in group LND and group LNS were (13.3 +/- 4.7) and (5.2 +/- 3.0) (P < 0.01), respectively. The mean of mediastinal lymph node station sampled in group LND and group LNS were (3.7 +/- 0.9) and (1.3 +/- 1.1) (P < 0.01), respectively. The 5-year and 10-year survival rates of patients in group LND were 72.0% and 66.1%, while in group LNS were 65.9% and 43.0% (P < 0.05), respectively. Other prognostic factors included symptom, staging, visceral pleura invasion and tumor size. LND was disclosed as a favourable prognostic factor at COX multivariate analysis, together with absence of symptom at diagnosis., Conclusion: As compared with LNS, LND can improve survival in stage I NSCLC.

Objective: To evaluate the potential reconsideration of curative operative treatment for patients with unresectable stage IIIA (N2) non-small-cell lung cancer (NSCLC)., Methods: From Jan. 1999 to Dec. 2002, 76 patients with unresectable stage IIIA (N2) NSCLC were entered in this study. They had all been proved by chest CT, chest film and fiberobronchoscopy. Twenty-one (27.6%) patients were examined by mediastinoscopy. All the patients received two cycles of chemotherapy with NVB (25 mg/m(2), D1, D5) and carboplatin (300 mg/m(2), D1). All the patients were staged again three weeks after induction chemotherapy. Sixty-four patients who achieved partial response (PR) or complete response (CR) were allowed to undergo surgery. Twelve patients who did not responde to chemotherapy received radiotherapy instead. Of the 64 surgically treated patients, 56 (84.7%) had a complete resection and then received 2 cycles of chemotherapy using the same regime, 8 patients had an incomplete resection and then received radiotherapy for the residual tumor., Results: The median survival for these 76 patients with unresectable stage IIIA (N2) NSCLC treated by either surgery or radiation after induction chemotherapy was 18.6 months with 1-, 2-, 3-year survival rate of 64.2%, 39.4% and 25.6%, respectively. The median survival for the 56 patients with a complete resection was 28.2 months with 1-, 2-, 3-year survival rate of 70.4%, 52.5% and 38.6%, respectively., Conclusion: Preoperative induction chemotherapy with NVB plus carboplatin should be seriously considered for the patients with unresectable stage IIIA (N2) NSCLC, It is suggested that, whenever possible, surgery should be taken as the first choice for the patients who show down-staged benefits that complete resection can be attempted.

Background & Objective: The metastasis status of regional lymph node is an important prognostic factor of non-small cell lung cancer (NSCLC). Sentinel lymph node (SLN) mapping and biopsy is a quick and high efficient technique to intraoperatively detect occult micrometastatic disease, however, its application in NSCLC is immature. This study was designed to investigate the feasibility of detecting SLN in patients with NSCLC during radical surgery, and to evaluate its accuracy of predicting metastasis status of regional lymph node., Methods: Fifty patients with NSCLC underwent SLN detection. During radical operation, 4 ml of 1% isosulfan blue was injected into the lung tissue around the tumor at 3, 6, 9, and 12 o'clock sites. Location and number of blue dyed SLNs were recorded, and compared with pathologic results to calculate the accuracy and false negative rate of SLN detection., Results: Blue dyed SLNs were seen in 33 patients with a detection rate of 66.0%. SLNs located in N1 lymph node of 24 patients (72.7%), in N2 lymph node of 6 patients (18.2%), in both N1 and N2 lymph nodes of 3 patients (9.1%). Approved by pathology, the accuracy of SLN detection was 87.9% (29/33), the sensibility was 73.3% (11/15), the false negative rate was 26.7% (4/15)., Conclusion: SLN detection is valuable for predicting hilar and mediastinal lymph nodes metastases in NSCLC.

Purpose: We conducted a randomized trial to investigate whether systematic nodal dissection (SND) is superior to mediastinal lymph nodal sampling (MLS) in surgical treatment of non-small cell lung cancer (NSCLC)., Methods: The patients resectable clinical Stage I-IIIA NSCLC were randomly assigned to lung resection combined with SND or lung resection combined with MLS. After postoperative pathological re-staging, eligible cases were followed up until 30 November 2000. The Kaplan-Meier method was used for survival analysis. COX proportional hazards model was used for prognostic analysis., Results: Of the 532 patients who were enrolled in the study, 268 patients were assigned to lung resection combined with SND and 264 were assigned to lung resection combined with MLS. After surgical restaging only 471 cases were eligible for follow-up. The median survival was 59 months in the group given SND and 34 months in the group given MLS (P=0.0000 by the log rank test). There was significant difference in survival in Stage I (5-year survival 82.16 vs. 57.49%) and Stage IIIA (26.98 vs. 6.18%) by the log rank test and Breslow test. There was no significant yet marginal difference in survival by log rank test (10-year survival 32.04 vs. 26.92%, P=0.0523) but significant difference in survival by Breslow test (5-year survival 50.42 vs. 34.05%, P=0.0284) in Stage II. Types of mediastinal lymph node dissection, pTNM stage, tumor size and number of lymph node metastasis were four factors that influenced long-term survival rate by multivariate analysis., Conclusions: As compared with MLS, lobectomy (pneumonectomy) combined with SND can improve survival in resectable NSCLC.