Lung cancer survival and mortality in Taiwan following the initial launch of targeted therapies: an interrupted time series study.

OBJECTIVES: Two oral targeted therapies, gefitinib and erlotinib, were first approved and then launched into the market for treatment of late-stage non-small cell lung cancer (NSCLC) in Taiwan in 2003 and 2006, respectively. The aim of this study were to determine the trends in lung cancer burden and examine changes in lung cancer-related survival rates and mortality following the launch of these new drugs. SETTING: Yearly lung cancer-related data (1994-2013), including incidence, number of newly diagnosed patients, survival rate and mortality, were retrieved from the Taiwan Cancer Registry Database. DESIGN AND OUTCOME MEASURES: Using a time series design with autoregressive integrated moving average model, we investigated and projected trends in the incidence and early diagnosis of lung cancer in Taiwan. We also estimated the changes in survival rates and mortality following the launch of targeted therapies using interrupted time series and segmented regression models. RESULTS: The age-standardised incidence of lung cancer increased from 22.53 per 100 000 people in 1994 to 34.09 in 2013, and it was projected to reach 38.98 by 2020. The rate of early-stage NSCLC at diagnosis increased from 12.63% in 2004 to 23.99% in 2013, and it was projected to reach 32.95% by 2020. The 2-year lung cancer survival increased by 19.81% (95% CI 14.90% to 24.71%) 3 years following the launch of gefitinib. Lung cancer mortality declined by 5.97% (95% CI -8.20% to -3.73%) 3 years following the launch of gefitinib. CONCLUSIONS: Lung cancer survival rate increased and mortality decreased significantly following the launch of gefitinib and erlotinib in Taiwan.

Effects of removing reimbursement restrictions on targeted therapy accessibility for non-small cell lung cancer treatment in Taiwan: an interrupted time series study.

INTERVENTIONS: Targeted therapies have been proven to provide clinical benefits to patients with metastatic non-small cell lung cancer (NSCLC). Gefitinib was initially approved and reimbursed as a third-line therapy for patients with advanced NSCLC by the Taiwan National Health Insurance (NHI) in 2004; subsequently it became a second-line therapy (in 2007) and further a first-line therapy (in 2011) for patients with epidermal growth factor receptor mutation-positive advanced NSCLC. Another targeted therapy, erlotinib, was initially approved as a third-line therapy in 2007, and it became a second-line therapy in 2008. OBJECTIVES: This study is aimed towards an exploration of the impacts of the Taiwan NHI reimbursement policies (removing reimbursement restrictions) related to accessibility of targeted therapies. SETTING: We retrieved 2004-2013 claims data for all patients with lung cancer diagnoses from the NHI Research Database. DESIGN AND OUTCOME MEASURES: Using an interrupted time series design and segmented regression, we estimated changes in the monthly prescribing rate by patient number and market shares by cost following each modification of the reimbursement policy for gefitinib and erlotinib for NSCLC treatment. RESULTS: Totally 92 220 patients with NSCLC were identified. The prescribing rate of the targeted therapies increased by 15.58%, decreased by 10.98% and increased by 6.31% following the introduction of gefitinib as a second-line treatment in 2007, erlotinib as a second-line treatment in 2008 and gefitinib as as first line treatment in 2011, respectively. The average time to prescription reduced by 65.84% and 41.59% following coverage of erlotinib by insurance and gefitinib/erlotinib as second-line treatments in 2007-2008 and following gefitinib as the first-line treatment in 2011. CONCLUSIONS: The changes in reimbursement policies had a significant impact on the accessibility of targeted therapies for NSCLC treatment. Removing reimbursement restrictions can significantly increase the level and the speed of drug accessibility.

Synthesis and SAR studies of novel 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives for anticancer activity.

BACKGROUND AND PURPOSE: 4-Phenylquinolin-2(1H)-one (4-PQ) derivatives can induce cancer cell apoptosis. Additional new 4-PQ analogs were investigated as more effective, less toxic antitumour agents. EXPERIMENTAL APPROACH: Forty-five 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives were synthesized. Antiproliferative activities were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide assay and structure-activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute-60 human cancer cell line panel. Hoechst 33258 and Annexin V-FITC/PI staining assays were used to detect apoptosis, while inhibition of microtubule polymerization was assayed by fluorescence microscopy. Effects on the cell cycle were assessed by flow cytometry and on apoptosis-related proteins (active caspase-3, -8 and -9, procaspase-3, -8, -9, PARP, Bid, Bcl-xL and Bcl-2) by Western blotting. KEY RESULTS: Nine 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives (7e, 8e, 9b, 9c, 9e, 10c, 10e, 11c and 11e) displayed high potency against HL-60, Hep3B, H460, and COLO 205 cancer cells (IC50 < 1 µM) without affecting Detroit 551 normal human cells (IC50 > 50 µM). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G2/M arrest, polyploidy and apoptosis via the intrinsic and extrinsic signalling pathways. Activation of JNK could play a role in TRAIL-induced COLO 205 apoptosis. CONCLUSION AND IMPLICATIONS: New quinolone derivatives were identified as potential pro-apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.