Modelled Economic Analysis for Dacomitinib-A Cost Effectiveness Analysis in Treating Patients With EGFR-Mutation-Positive Non-Small Cell Lung Cancer in China.

OBJECTIVES: To establish the cost-effectiveness of dacomitinib compared to gefitinib from the Chinese healthcare system perspective. PATIENTS: Advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. METHODS: Partitioned survival analysis was undertaken to examine the cost-effectiveness of dacomitinib utilising individual patient data (IPD) from the pivotal randomised controlled trial (RCT) (ARCHER 1050). The three health states modelled were progression-free, post-progression, and death. Parametric survival distributions were fitted to IPD against the Kaplan-Meier survival curves corresponding to progression-free survival (PFS) and overall survival (OS) outcomes by randomised groups. Costs included drug acquisition and administration, outpatient management (outpatient consultation and examinations), and best supportive care costs. Utility weights were sourced from the pivotal trial and other published literature. The incremental cost-effectiveness ratio (ICER) was calculated with costs and quality-adjusted life years (QALYs) discounted at an annual rate of 5%. Both deterministic and probabilistic sensitivity analyses were undertaken. RESULTS: In the base case, dacomitinib (CNY 265,512 and 1.95 QALY) was associated with higher costs and QALY gains compared to gefitinib (CNY 247,048 and 1.61 QALYs), resulting in an ICER of CNY 58,947/QALY. Using the empirical WTP/QALY threshold, dacomitinib is a cost-effective treatment strategy for patients with EGFR-mutation-positive advanced NSCLC. The probabilistic sensitivity analysis suggested that dacomitinib had a 97% probability of being cost-effective. CONCLUSIONS: Dacomitinib is a cost-effective treatment strategy in treating patients with EGFR-mutation-positive NSCLC from the Chinese healthcare system perspective. The uncertainty around the cost-effectiveness of dacomitinib could be reduced if long-term survival data become available. CLINICAL TRIAL REGISTRATION: NCT01024413.

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.

Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment.

BACKGROUND: Several clinical trials showed that erlotinib was effective after the failure of gefitinib in advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of erlotinib treatment after the failure of gefitinib based on the data from our hospital. METHODS: The clinical data of 20 patients with advanced NSCLC who were admitted to Shanghai Chest Hospital from August 2007 to December 2008 were retrospectively analyzed. All of the patients were given erlotinib treatment after the failure of gefitinib. Survival analysis was made by Kaplan-Meier method. The Cox regression model was performed to analyze the relationship between the influential factors and the erlotinib progression-free survival (PFS). RESULTS: Five patients had a partial response (PR), nine patients had stable disease (SD) and six patients had progressive disease (PD) with gefitinib treatment. The median PFS was 277 days (95% CI 0- 566). No patient had a PR, seven had SD and fourteen PD with the erlotinib therapy. The median PFS was 31 days (95% CI 9.1- 52.9). The response rate (RR) was 0, and the disease control rate (DCR) was 35% (7/20). Cox regression analysis demonstrated that sex (P = 0.96), age (P = 0.89), smoking history (P = 0.78), performance status (PS) (P = 0.98), gefitinib efficacy (P = 0.90) and whether chemotherapy was applied between using the two drugs (P = 0.45) had no significant correlation with erlotinib PFS. Fifteen patients had epidermal growth factor receptor (EGFR) mutation status determined. There were five cases got SD with the erlotinib treatment in ten mutation negative (wild-type) patients. No SD was recorded in the five mutation positive patients. CONCLUSIONS: The efficacy of erlotinib treatment after gefitinib failure was limited. However, the patients who are EGFR mutation negative can probably benefit from erlotinib treatment after gefitinib failure.

Maintenance Therapy for NSCLC: Consensus and Controversy.

Nowadays, advanced non-small cell lung cancer (NSCLC) is still an incurable disease. However, recent researches on maintenance therapy have led to considerable progress. Recently, pemetrexed and erlotinib have been approved for maintenance chemotherapy by both the U.S. Food and Drug Administration and European Medicines Agency. However, there are not adequate data to support the maintenance therapy as the standard treatment for advanced NSCLC and there has been no conclusive predictor of who will get benefit from maintenance chemotherapy and what type of maintenance, continuation or switch, is preferred. This article reviews the main studies on maintenance therapy of advanced NSCLC and discusses the results available to date.

A cost-effectiveness analysis of docetaxel versus pemetrexed in second-line chemotherapy for stage IIIb or IV non-small cell lung cancer in China.

BACKGROUND: To study the cost-efficacy of docetaxel and pemetrexed as single agents versus platinum-based combination agents in second-line treatment of stage IIIb or IV non-small cell lung cancer (NSCLC) patients by evaluating chemotherapeutic indexes and medical costs. METHODS: Treatment responses were evaluated by progression-free survival (PFS), overall survival (OS), hematological and gastrointestinal toxicities. RESULTS: Two hundred and seven stage IIIb or IV NSCLC patients were recruited to this clinical observation retrospective study. Thirty-four subjects were treated with docetaxel (group A), 98 with platinum-based doublet chemotherapy with docetaxel (group B), 42 with pemetrexed (group C), and 33 patients with platinum-based doublet combination therapy with pemetrexed (group D). The average PFS of groups A and B was 3.28 and 4.58 months, respectively (p = 0.042). The mean PFS of groups C and D was 3.1 and 4.98 months, respectively (p = 0.017). The mean OS of these groups was 12.88, 13.17, 12.40 and 13.04 months, respectively, without significant differences. The total medical costs in these four groups amounted to USD 5,533, 7,745, 8,569 and 15,291, respectively. CONCLUSIONS: Platinum-based doublet chemotherapy with docetaxel or pemetrexed could significantly increase PFS, however, without significant OS improvement in comparison with using them as single agents. The medical expenses associated with doublet therapy were much higher than those associated with single therapy with a significant portion of the medical expenses spent on treating hematological and gastrointestinal toxicity.

Discrepancy of biologic behavior influenced by bone marrow derived cells in lung cancer.

Disseminated cancer cells may initially require local nutrients and growth factors to thrive and survive in bone marrow. However, data on the influence of bone marrow derived cells (BMDC, also called bone stromal cells in some publications) on lung cancer cells is largely unexplored. This study explored the mechanism of how bone stromal factors contribute to the bone tropism in lung cancer. The difference among lung cancer cell lines in their abilities to metastasize to bone was found using the SCID animal model. Supernatant of bone marrow aspiration (BM) and condition medium from human bone stromal cells (BSC) were used to study the activity of bone stromal factors. We found bone stromal factors significantly increased the proliferation, invasion, adhesion and expression of angiogenosis-related factors, and inhibited the apoptosis for high bone metastasis H460 lung cancer cells. These biologic effects were not seen in SPC-A1 or A549 cells, which are low bone metastasis lung cancer cells. Adhesion of H460 cells to surface coated with bone stromal cells can activate some signal transduction pathways, and alter the expression of adhesion associated factors, including integrin ß 3 and ADAMTS-1, two potential targets related with bone metastasis. We concluded that bone marrow derived cells had a profound effect on biological behavior of lung cancers, therefore favoring the growth of lung cancer cells in bone.

[Comparison of single-agent docetaxel versus docetaxel plus platinum combination agent in second-line treatment for advanced non-small cell lung cancer].

OBJECTIVE: To compare the therapeutic efficacies and toxicities of single-agent docetaxel or docetaxel plus platinum combination agent in patients with advanced non-small cell lung cancer (NSCLC) so as to provide rationales for standard second-line chemotherapy. METHODS: The clinical data from 152 patients with NSCLC who were admitted into Chest Hospital Affiliated to Shanghai Jiaotong University, from January 2004 to May 2008 were retrospectively analyzed. Forty patients were treated with single-agent docetaxel (single-agent group, 16 and 24 patients with stages IIIb and IV disease respectively; 32 patients with PS score 0-1 before treatment and 8 patients with PS score 2 before treatment), and 112 patients were treated with docetaxel plus platinum combination agent (combination group, 29 and 83 patients with stage IIIb and IV disease respectively; 98 patients with PS score 0-1 before treatment and 14 patients with PS score 2 before treatment). Primary end point was overall survival (OS), and secondary end point were progression-free survival time (PFS), disease control rate (DCR), one-year survival, and drug toxicity. Survival analysis was evaluated by Kaplan-Meier. Single factor analysis and Cox regression model were done to analyze the relationship between the influencing factors and the prognosis of disease. RESULTS: The median PFS of the single-agent group was 3.0 months, significantly shorter than that of the combination group (4.2 months, P = 0.048). However, no statistical differences were found in OS, DCR or one-year survival between the two groups (all P > 0.05). The most common grade 3 to 4 toxicities were leukopenia (32.5% for single-agent group, and 56.2% for combination group, P = 0.000), and gastro-intestinal toxicity (0 for single-agent group, and 4.5% for combination group, P = 0.000). Single factor analysis showed that the factors including radiotherapeutic history, operative history, PS score before treatment, clinical stage, and response to second-line treatment influenced the prognosis of NSCLC (all P < 0.05). Cox regression analysis demonstrated operative history (HR = 0.428, 95% CI: 0.261-0.701), PS score before treatment (HR = 1.919, 95% CI: 0.999-3.685), clinical stage (HR = 2.297, 95% CI: 1.427-3.696) and response to second-line treatment (HR = 0.318, 95% CI: 0.177-0.571) had effects on survival. CONCLUSIONS: To those well-selected patients, docetaxel plus platinum combination agent as the second-line treatment of advanced NSCLC significantly prolongs the progression-free survival. But such a regimen is more toxic and does not improve the response rate and overall survival.

The effects of cetuximab alone and in combination with endostatin on vascular endothelial growth factor and interleukin-8 expression in human lung adenocarcinoma cells.

BACKGROUND: Angiogenesis, the growth of new blood vessels, plays an important role in tumor growth and metastasis. Both cetuximab and endostatin have been found to reduce the expression of endothelial-stimulating growth factors such as vascular endothelial growth factor (VEGF) and interleukin (IL)-8. However, the effects of cetuximab alone or in combination with endostatin on human lung adenocarcinoma cell growth remain unclear. OBJECTIVE: The aim of this study was to evaluate the cellular and molecular effects of cetuximab alone and in combination with endostatin on human lung adenocarcinoma cell lines HI 299, SPC-A1, and H460 in vitro. Methods The epidermal growth factor receptor (EGFR) status of a panel of human lung adenocarcinoma cell lines was characterized using Western blot analysis. We used a modified tetrazolium salt assay to evaluate the growth-inhibitory effects of cetuximab and endostatin alone and in combination on the cell lines. We also determined the effects of these 2 drugs on VEGF and IL-8 expression using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Cells were treated for 4 days with cetuximab 12.5 µ/mL, endostatin 25 µ/mL, or cetuximab 12.5 µg/mL + endostatin 25 µg/mL. Untreated cells cultured for 4 days served as controls. RESULTS: EGFR expression in the H1299 cells was higher than in the SPC-A1 and H460 cells. Varying concentrations of cetuximab alone were associated with a significant growth-inhibitory effect on all 3 cell lines in a dose-dependent manner after 4 days of exposure compared with controls (all, P < 0.05). Compared with controls, varying concentrations of endostatin alone were not associated with significant inhibition of cell growth in any of the 3 cell lines. The inhibitory ratio of cetuximab + endostatin at varying concentrations was significantly greater than that of cetuximab alone (all, P < 0.05). On ELISA, either drug alone was associated with significant reductions in secreted VEGF and IL-8 in the HI 299, SPC-A1, and H460 cell lines (all, P < 0.05), with the exception of IL-8 concentration in the H460 cells. Mean (SD) VEGF expression with combination treatment in the H1299 and SPC-A1 cell lines (687 [21] and 629 [23] pg/mL, respectively) was significantly lower than with cetuxi-mab alone (878 [31] and 708 [20] pg/mL; both, P < 0.001); in the H460 cell line, combination treatment was not associated with a significant further reduction in VEGF expression. IL-8 concentrations with cetuximab in the H1299, SPC-A1, and H460 cell lines were 628 (20), 484 (29), and 532 (28) pg/mL, respectively, while the IL-8 concentrations with the combination treatment were 516 (20), 480 (18), and 467 (30) pg/mL. An enhanced effect of endostatin on IL-8 was observed in the H1299 and H460 cell lines (P < 0.001 and P = 0.018, respectively); however, no enhanced effect in the SPC-A1 line was observed. Similar results for VEGF and IL-8 expression were found using Western blot analysis. CONCLUSIONS: The results from this in vitro study suggest that cetuximab treatment might both inhibit human lung adenocarcinoma cell line growth and reduce the expression of VEGF and IL-8, which are the biomarkers of angiogenesis. Endostatin was not associated with inhibition of human lung adenocarcinoma cell line growth directly. Findings with the combination of cetuximab + endostatin suggest that endostatin might enhance the antiangiogenic and antitumor activity of cetuximab through an apparent effect on VEGF expression and, to a lesser degree, on IL-8 expression.

[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.