Efficacy of erlotinib in previously treated patients with advanced non-small cell lung cancer: analysis of the Chinese subpopulation in the TRUST study.

OBJECTIVE: This study is to analyze the data of Chinese subpopulation in the Tarceva Lung Cancer Survival Treatment Study (TRUST-China) which was a global Phase IV study designed to provide erlotinib to previously treated patients with Stage IIIB/IV non-small cell lung cancer. METHODS: Patients with pathologically confirmed, unresectable Stage IIIB/IV non-small cell lung cancer who were previously failed on or unsuitable for chemotherapy or radiotherapy were given erlotinib (150 mg/day, oral) until disease progression, intolerable toxicity or death. Efficacy and toxicity of the agent were evaluated. RESULTS: In total, 519 patients Chinese patients were analyzed. The TRUST-China had similar baseline characteristics to TRUST-Global except the greater percentage of adenocarcinoma and non-smoker cases. The response rate and disease control rate were 24.7 and 75.3%, respectively. Median progression-free survival and overall survival were 6.4 and 15.4 months in the general Chinese population in the TRUST, and 10.2 and 18.9 months in non-smokers with adenocarcinoma (n = 254). Median progression-free survival and overall survival were significantly longer in non-smokers with adenocarcinoma than those in other groups (P ≤ 0.0001 and P ≤ 0.0001, respectively). Eastern Cooperative Oncology Group Performance Status (≥ 2 vs. ≤ 1, hazard ratio = 1.746, P < 0.0001) and histology (squamous cell carcinoma vs. adenocarcinoma, hazard ratio = 1.595, P = 0.0008) were independent risk factors that affected survival according to Cox regression multivariate analysis. CONCLUSIONS: We confirmed the efficacy and safety of erlotinib in Chinese patients. Non-smoking patients with adenocarcinoma histology had the best clinical benefits. (NCT00949910).

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

BACKGROUND: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). METHODS: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. FINDINGS: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). INTERPRETATION: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. FUNDING: Boehringer Ingelheim.

Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial.

BACKGROUND: The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. METHODS: In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779. FINDINGS: From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). INTERPRETATION: Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. FUNDING: F Hoffmann-La Roche.

Clinical analysis of postoperative venous thromboembolism risk factors in lung cancer patients.

BACKGROUND AND OBJECTIVES: The objective of this study is to explore clinical risk factors for venous thromboembolism (VTE) in postoperative lung cancer patients in order to provide a basis for the prevention and treatment of postoperative VTE. METHODS: A total of 1,001 lung cancer patients were retrospectively analyzed. Each patient was confirmed with surgical pathology diagnosis and had a complete clinical and follow-up record. VTE was identified in a combination of spiral computed tomography (CT), pulmonary angiography, and color Doppler ultrasound. We used life table method to create an occurrence frequency curve of thrombosis. We also searched for high risk factors for postoperative VTE with Cox multivariate regression model and created frequency curves of thrombosis against different risk factors using Kaplan-Meier method. RESULTS: As of July 31, 2011, the median follow-up time is 25.73 ± 0.11 months (19.23-31.37). The cumulative frequency of VTE among 1,001 lung cancer patients is 2%, 3%, 4%, 5%, and 5.3% over 1, 3, 6, 12, and 30 months after the surgery. COX regression analysis showed that the hazard ratio of VTE occurrence in patients with incomplete resection relative to ones with complete resection is 9.867 (95% CI: 5.275-18.459, P = 0.000). And the hazard ratio of VTE occurrence is 3.472 (95% CI: 1.761-6.845, P = 0.000) in patients with anti-angiogenesis treatment compared to patients without such treatment. The hazard ratio of VTE occurrence is 2.808 (95% CI: 1.439-5.479, P = 0.002) in patients with EGFR-TKI treatment relative to patients without the treatment, and 7.520 (95% CI: 3.968-14.250, P = 0.000) in patients with an increase in D-dimer level relative to normal ones CONCLUSIONS: The highest incidence of VTE is within 1 month after lung cancer surgery. High risk factors for VTE include incomplete surgical resection, postoperative use of anti-angiogenesis drugs, EGFR-TKI application and an increase in preoperative D-dimer level.

[Efficacy and safety of gefitinib or docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had failed previous platinum-based first-line chemotherapy].

OBJECTIVE: To compare the efficacy and safety of gefitinib or docetaxel in Chinese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had failed previous platinum-based first-line chemotherapy. METHODS: We retrospectively reviewed 222 Chinese NSCLC patients in the subgroup of INTEREST (gefitinib versus docetaxel in previously treated non-small cell lung cancer) study. Survival analysis was evaluated by Kaplan-Meier method, and Functional Assessment of Cancer Therapy-Lung (FACT-L) was used to compare the quality of life between gefitinib group and docetaxel group. RESULTS: A total of 222 patients were analyzed in this subgroup study. 107 patients were treated with gefitinib, and 115 patients treated with docetaxel. There were all balanced between the two groups in terms of sex, age, staging and pathology in patient characteristics. The median overall survival in the two groups was similar (11 months in the gefitinib group vs. 14.0 months in the docetaxel group, P = 0.783). The progression-free survival (PFS) was also similar between the two groups (median PFS: 3.4 months in gefitinib group vs. 3.8 months in docetaxel group, P = 0.214). The response rate in gefitinib group was significantly higher than that in the docetaxel group (21.9% vs. 9.1%, P = 0.016). CONCLUSION: The efficacy of gefitinib is similar with that of docetaxel in pretreated patients with locally advanced or metastatic NSCLC, however, gefitinib is more favorable in the tolerance and quality of life improvement.

Functional roles of PC-PLC and Cdc20 in the cell cycle, proliferation, and apoptosis.

Phosphatidylcholine-specific phospholipase C (PC-PLC) is the major enzyme in the Phosphatidylcholine (PC) cycle and is involved in many long-term cellular responses such as activation, proliferation, and differentiation events. Cell division cycle 20 homolog (Cdc20) is an essential cell-cycle regulator required for the completion of mitosis. Our previous studies identified the interaction between PC-PLC and Cdc20. Through the interaction, Cdc20 could mediate the degradation of PC-PLC by Cdc20-mediated ubiquitin proteasome pathway (UPP). In this study, we found that PC-PLC might not be involved in cancer metastasis. Inhibition of PC-PLC by D609 could cause cell proliferation inhibition and apoptosis inhibition in CBRH-7919 cells. Inhibition of PC-PLC could also influence the cell cycle by arresting the cells in G1 phase, and Cdc20 might be involved in these processes. Taken together, in this report, we provided new evidence for the functional roles of PC-PLC and Cdc20 in the cell cycle, proliferation, and apoptosis in CBRH-7919 cells.

[Efficacy and safety of Erlotinib in the treatment for advanced non-small cell lung cancer in Chinese patients].

OBJECTIVE: To observe the efficacy and the adverse effects of erlotinib in the treatment for advanced non-small cell lung cancer (NSCLC) in Chinese patients. METHODS: From November 2005 to March 2009, a total of 519 patients with unresectable, local advanced, relapsed or metastatic NSCLC were enrolled in the trial. All the patients were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity or for other reasons. The response rate, time to disease progression, overall survival and toxicity were analyzed. RESULTS: Of these 519 patients, 1 case had complete response, 127 cases had partial response and 263 cases had stable disease, resulting in an overall response rate (CR + PR) of 26.7%, disease stable rate of 54.9% and disease control rate (CR + PR + SD) of 81.6%. The median time to progression was 6.44 months and median overall survival was 15.37 months. The major erlotinib treatment-related adverse events (AE) were mild (CTC AE 1/2), only 3 cases had severe adverse effect, 1 case had interstitial lung disease and died of respiratory failure. CONCLUSION: The study presents excellent response rates, time to progression and overall survival of erlotinib treatment for advanced NSCLC in Chinese patients, and its adverse events are tolerable.

First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

Non-small-cell lung cancer (NSCLC) is an increasing global challenge, especially in low-income countries. Most guidelines for the management of advanced-stage NSCLC have limited effect in countries with resource constraints. Following a systematic literature search, we present an overview of the management of advanced-stage NSCLC in the first-line setting, discuss resources required for systemic therapy, and provide treatment recommendations stratified to four resources levels. Treatment guidelines appropriate for different resource levels offer a realistic approach to management of advanced-stage NSCLC, by recognising the limitations of a particular health-care system. Although there are many barriers to cancer control in low-resource countries, these can be overcome by using measures that are culturally appropriate, economically feasible, and evidence-based. Initiatives include strategic planning, tobacco control, training of health-care workers, access to therapeutic agents, acquisition of information, public education, and alliances with established institutions and international organisations.

Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.

BACKGROUND: Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy. METHODS: We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (>/=one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m(2) intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388. FINDINGS: 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1.020, 96% CI 0.905-1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1.09, 95% CI 0.78-1.51; p=0.62; median survival 8.4 vs 7.5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common. INTERPRETATION: INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.

Value of folate receptor-positive circulating tumour cells in the clinical management of indeterminate lung nodules: A non-invasive biomarker for predicting malignancy and tumour invasiveness.

BACKGROUND: Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR+-CTCs) in combination with maximum tumour diameter (MTD) determines, before surgery, the invasiveness of small-sized, indeterminate solitary pulmonary nodules (SPNs). METHODS: A total of 382 patients with suspicious lung adenocarcinoma on computed tomography who were expected to undergo lung resection were enrolled in this study at three participating institutes and randomly assigned into training and validation cohorts. Before surgery, 3 mL peripheral blood was collected from all participants. FR+-CTCs were analyzed using immunomagnetic leukocyte depletion and quantitated by ligand-targeted PCR method. After surgery, the resected tissues were diagnosed by pathologists according to IASLC/ATS/ERS classification. FINDINGS: FR+-CTC levels in the peripheral blood can differentiate benign from malignant nodules with a sensitivity of 78·6%-82·7% and a specificity of 68·8%-78·4%. Both FR+-CTC and MTD are independent predictive indices of invasive tumours for lung adenocarcinoma ≤2 cm based on multivariate analyses. Further, FR+-CTC count in combination with MTD can differentiate non-invasive cancers from invasive cancers with a sensitivity of 63·6%-81·8% and a specificity of 71·4%-89·7%. INTERPRETATION: Detection of FR+-CTC is a reliable method to differentiate malignancy of indeterminate SPNs. Combining of FR+-CTC count and MTD could possibly enhance preoperative determination of the invasiveness of lung nodules and guide surgeons to select limited lung resection and avoid overtreatment for patients with non-invasive lesions. FUND: None.

Synergistic inhibitory activity of zoledronate and paclitaxel on bone metastasis in nude mice.

Zoledronic acid (Zometa, ZOL) and cytotoxic chemotherapy agents have been reported to have synergistic antitumor activities. However, there is limited data on the effects of combination therapies on the development of bone metastasis in animal models of lung cancer. The purpose of this study was to establish a human lung adenocarcinoma cell line with high bone metastatic potential in an immunodeficient mouse model and to evaluate the synergistic inhibitory activity of zoledronate and paclitaxel (P) on bone metastasis in nude mice. A human lung adenocarcinoma cell line with high bone metastatic potential (SPC-A1-BM) was established by 10 rounds of in vivo selection. Cells were inoculated into the cardiac ventricle of NIH-BNX mice, which were treated 8 days later with: ZOL (0.2 mg/kg s.c. twice weekly) alone, P (6.0 mg/kg every week, i.p.) alone, P + ZOL, or vehicle (10 mice per group). Tumor growth was evaluated with bone scans, X-rays and in situ immunohistochemistry. Serum n-telopeptide of type I collagen (NTX) was measured by ELISA. Survival was assessed using the Kaplan-Meier method. Bone scan, radiographic and histological assessments revealed fewer bone metastases in all treatment groups vs. vehicle, with P + ZOL significantly reducing the incidence of bone metastases detected by bone scans (P=0.020) and X-rays (P=0.036). A histological analysis revealed marginal differences in the number of bone metastases between P + ZOL and vehicle (P=0.058). There was a trend towards differences in survival between the groups (P=0.1511) and survival was significantly longer for the P + ZOL group vs. vehicle (P=0.022). Compared with vehicle and ZOL alone, cancerous cells in the bone of mice treated with P + ZOL expressed higher levels of Bax and lower levels of Bcl-2 and Bcl-xl. ZOL produced a trend towards reduced NTX levels vs. vehicle and P + ZOL produced a profound reduction in NTX vs. vehicle (P=0.022). The results of this study indicated that zoledronate enhanced the efficacy of paclitaxel synergistically, by reducing the incidence of bone metastasis from lung cancer and prolonging survival in a mouse model of non-small cell lung cancer with a high potential for metastasis to bone.

Gemcitabine and cisplatin treatment over a 3-week versus a 4-week dosing schedule: a randomized trial conducted in Chinese patients with nonsmall cell lung cancer.

BACKGROUND: Gemcitabine plus cisplatin is a standard treatment for stages IIIB and IV nonsmall cell lung cancer (NSCLC). This randomized phase II study evaluated a 3-week versus a 4-week schedule of gemcitabine-cisplatin as first line treatment for Chinese patients with advanced NSCLC. METHODS: Patients were randomized to receive cisplatin 75 mg/m(2) on day 1 plus either gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle (3-week group) or gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle (4-week group). RESULTS: One hundred patients were enrolled in this study. The response rate was 24% (12/51 patients) in the 3-week group and 27% (13/49 patients) in the 4-week group. There were no statistically significant differences between the two treatment groups in survival (hazard ratio: 1.19; 95% CI: 0.68 - 2.09) with a median survival of 12.1 months and 13.8 months in the 3-week group and the 4-week group respectively. The rate of grade 3/4 toxicity in the 3-week group was 55% compared with 86% in the 4-week group (P = 0.001). The difference in the incidence of grade 3/4 haematological toxicities did not reach statistical significance (3-week: 37%, 4-week: 57%), however grade 3/4 drug related neutropenia (3-week: 27%, 4-week: 51%) and thrombocytopenia (3-week: 8%, 4-week: 31%) were significantly lower in the 3-week group. Grade 3/4 nonhaematological toxicities were less in the 3-week group (33% cf 63%; P = 0.005). CONCLUSIONS: The differences in the efficacy endpoints were all in favour of the 4-week schedule of gemcitabine plus cisplatin, however these differences did not reach statistical significance. Fewer grade 3/4 toxicities were observed in the 3-week group compared with the 4-week group.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.

[Incidence, time trend, survival, and predictive factors of lung cancer in Shanghai populations].

OBJECTIVE: To investigate the incidence, survival, and influential factors of lung cancer in the Shanghai populations. METHODS: Data of individual cases of lung cancer 2000 - 2004 were obtained from the Shanghai Cancer registry System. The annual prevent change (APC) of incidence of lung cancer from 1972 to 2004 was calculate by crude and standardized rates so as to analyze the time trends. Cox proportional risk model was used to analyze the factors influencing the survival. RESULTS: 23,196 new cases of lung cancer were diagnosed 2002 - 2004. The crude incidence rate of lung cancer in the females was 33.73/100,000, and the age-adjusted rate was 30.90/100,000. The crude incidence rate of lung cancer and the age-adjusted rate for the males were 81.65/100,000 and 33.73/100,000 respectively, both higher than those of females. The APC values of crude incidence 2004 for both the males and females increased by 1.723% and 2.036% respectively in comparison with the values 1972 (both P < 0.01). The age-adjusted APC of standardized incidence rate for the males in the city center was -0.605% (P < 0.01), showing a tendency to reduce; while the age-adjusted APC of standardized incidence rate for the females in the city center was -0.136 (P > 0.05). The proportion of stage IV cases in the females was 47.5%, significantly higher than that in the males (40.0%, P < 0.05). The proportion of adenocarcinoma in the females was 86.1%, significantly higher than that in the males (47.8%, P < 0.05). The 3-year survival rate and median survival time of adenocarcinoma in the females were 30.38% and 1.48 years respectively, both significantly higher than those in the males (22.66% and 0.98 years, both P < 0.01). Female gender, being younger, living in urban area, squamous cancer, early stage, visit to higher-grade hospital were the factors beneficial to the prognosis of lung cancer. CONCLUSION: The age adjusted incidence rate of lung cancer in Shanghai is much closer to that of Western Europe and North America. The beneficial factors for higher survival rate are female, younger age, urban residency, squamous cell lung cancer, earlier stage of diagnosis, and higher grade hospital for treatment. Women have statistically better outcomes than men in different stages of disease.

Endostar in combination with postoperative adjuvant chemotherapy prolongs the disease free survival of stage IIIA NSCLC patients with high VEGF expression.

PURPOSE: The aim of this study is to compare the therapeutic effect between endostar plus adjuvant chemotherapy and adjuvant chemotherapy alone in the patients with completely resected non-small cell lung cancer (NSCLC) at stage IB to IIIA. EXPERIMENTAL DESIGN: This is an open, multicenter, randomized (1:1) study with 250 NSCLC patients. Completely resected NSCLC patients at stages IB to IIIA were randomized to receive adjuvant NP plus endostar (Vinorelbine 25 mg/m2 on day 1 and day 8 plus Cisplatin 75 mg/m2 on day 1, and plus endostar 7.5 mg/m2 per day iv for consecutive 14 days) or NP regimen alone. Every 21 days were set as one cycle for 4 cycles. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety. RESULTS: The two groups had no significant difference in the incidence of toxicity reaction. Endostar plus NP prolonged the DFS of patients with completely resected NSCLC at stage IIIA (19.33±3.73 vs 17.10±9.68 months) but with no statistical difference compared to NP alone. In the endostar plus NP group, those cases with high expression of vascular endothelial growth factor (VEGF) showed a significantly better DFS than those with low VEGF expression (48.45±3.52 vs 40.18±4.54 months, P<0.05). CONCLUSIONS: Vascular targeted therapy with endostar plus NP prolongs the DFS of patients with complete resectable NSCLC in stage IIIA and significantly extends the DFS of NSCLC patients with high VEGF expression, but does not show benefits in OS for stage IB-IIIA.

XBP1-LOX Axis is critical in ER stress-induced growth of lung adenocarcinoma in 3D culture.

Rapid growth of tumor cells needs to consume large amounts of oxygen and glucose, due to lack of blood supply within the tumor, cells live in an environment that lack of oxygen and nutrients. This environment results in endoplasmic reticulum (ER) stress and activates the UPR (unfolded protein response). More and more evidence suggests UPR provides a growth signal pathway required for tumor growth. In the present study, we investigated the relationship between XBP1, one transcription factor in UPR, and the expression of LOX. We found that ER stress induces high expression of XBP1, one transcription factor in UPR, in both 2D culture and 3D culture; but only promotes growth of lung adenocarcinoma cells in in vitro 3D culture other than 2D culture. In 3D culture, we further showed that knockdown XBP1 expression can block Tm/Tg-induced cell growth. LOX genes may be key downstream effector of XBP1. Knockdown LOX expression can partially block XBP1-induced cell growth. Then we showed XBP1 suppressed by RNA interference (RNAi) can reduce the expression of LOX. For the first time, it is being shown that XBP1 can regulate the expression of LOX to promote cell growth.

Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment.

Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003-14. ©2017 AACR.

A consensus on liquid biopsy from the 2016 Chinese Lung Cancer Summit expert panel.

The diagnosis and treatment of lung cancer have evolved into the era of precision medicine. Liquid biopsy, a minimally invasive approach, has emerged as a promising practice in genetic profiling and monitoring of lung cancer. Translating liquid biopsy from bench to bedside has encountered various challenges, including technique selection, protocol standardisation, data analysis and cost management. Regarding these challenges, the 2016 Chinese Lung Cancer Summit expert panel organised a trilateral forum involving oncologists, clinicians, clinical researchers, and industrial expertise on the 13th Chinese Lung Cancer Summit to formally discuss these controversies. Six consensuses were reached to guide the use of liquid biopsy and perform precision medicine in both clinic and research.

[A primary study of immunotherapy with carcinoembryonic antigen peptide-pulsed, autologous human cultured dendritic cells in patients with advanced non-small cell lung cancer].

BACKGROUND: Dendritic cell (DC)-based immunotherapy is a new approach and effective for some malignant tumors. The aim of this study is to observe the efficacy and toxicity of immunotherapy with carcinoembryonic antigen (CEA) peptide-pulsed DCs in patients with refractory advanced lung cancer. METHODS: Lung cancer patients with high CEA expression were enrolled into this project. Autologous DCs were generated from patients' plastic-adherent peripheral blood mononuclear cells and loaded with CEA 5 days later. Cytokine-induced killer cells (CIK) were cultured from non-adherent peripheral blood mononuclear cells. DCs and CIK were transfused to patients. Responses and toxicities were observed. RESULTS: A total of 22 patients with lung cancer received DCs immunotherapy. DCs doses were 2.5×106-9.6×107 (5.03×106). CIK doses were 3.4×108-46×108. CD3, CD8, NK and IFN-γ levels obviously increased after treatment (P < 0.05). The 1-year survival rate was 68.2% (15/22). Main toxicities were fever and rash. CONCLUSIONS: DCs-based immunotherapy is feasible and safe to patients with lung cancer.