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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.)

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 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: This study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy., Patients and Methods: In this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life., Results: This trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46-0.98; P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14-0.57; P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56-1.16; P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild., Conclusion: In patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.)

Background: The role of matrix metalloproteinase 9 (MMP-9) expression in non-small cell lung cancer (NSCLC) remains controversial. We performed a systematic review of the literature with meta-analysis., Methods: Electronic databases were used to identify published studies before December 1, 2011. Pooled hazard ratio (HR) with 95% confidence interval (95% CI) was used to estimate the strength of the association between MMP-9 expression survival of NSCLC patients. Heterogeneity and publication bias were also assessed., Results: The final analysis of 2029 NSCLC cases from 17 studies is presented. The combined HR of 1.84 (95% CI: 1.62-2.09) suggested that MMP-9 over-expression had a poor prognosis in patients with NSCLC. Subgroup analyses also detected significant association. Heterogeneity and publication bias was absent in current meta-analysis. Sensitivity analyses suggested that the summary statistics obtained should approximate the actual average., Conclusion: High MMP-9 expression is associated with a poor prognosis in patients with NSCLC., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the association between various cytokine gene polymorphisms and lung cancer (LC) susceptibility. We searched Pubmed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, Google scholar. Totally, 20 studies involving 6,467 cases and 8,320 controls were included in the meta-analysis. The effects of eight polymorphisms, i.e. TNF-α 308G/A, IL-6 174G/C, IL-1β 31T/C, IL-1β 511C/T, COX-2 8473T/C, IL-10 1082G/A, IL-10 819C/T, and IL-10 592C/A were evaluated. The combined odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the strength of the association in a fixed or random effect model. Heterogeneity and publication bias were also assessed. We found a significant association between IL-10 polymorphism and LC. For IL-10 1082G/A, the overall ORs (95% CI) of the G versus A, GG versus AA, and GG/GA versus AA were 2.35 (1.16-4.76), 2.07 (1.16-3.70) and 3.17 (1.31-7.68), respectively. For IL-10 819C/T, the pooled ORs (95% CI) of the C versus T and CC versus TT were 1.27 (1.01-1.58) and 2.27 (1.32-3.89). For IL-10 592C/A, the comparison of subjects in the CC or CC/CA genotype versus AA homozygotes showed significant results (OR = 2.00, 95% CI: 1.24-3.23; OR = 1.80, 95% CI: 1.28-2.54). But, other gene polymorphisms did not reach statistical associations. IL-10 1082G/A, 819C/T and 592C/A polymorphisms might be risk factors for LC. TNF-α 308G/A, IL-6 174G/C, IL-1β 31T/C, IL-1β 511C/T, COX-2 8473T/C polymorphisms were not detected to be related to the risk for LC. Due to the limitation of the number of the studies, we should take the conclusion with caution. While, further studies are necessary for more precise association.