Wu Y.-L.,Guangdong General Hospital and Guangdong Academy of Medical science |
Zhou C.,Tongji University |
Liam C.-K.,University of Malaya |
Wu G.,Wuhan University of Science and Technology |
And 18 more authors.
Annals of Oncology | Year: 2015
Background: The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Patients and methods: Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m2 i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m2 i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety. Results: A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP. Conclusion: These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965). © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study)
Shen L.,Peking University |
Li J.,Fudan University |
Xu J.,Beijing 307 Hospital |
Pan H.,Shao Yifu Hospital |
And 12 more authors.
Gastric Cancer | Year: 2015
Background: In the AVAGAST study, fluoropyrimidine and cisplatin plus bevacizumab did not significantly improve overall survival (OS) versus fluoropyrimidine and cisplatin plus placebo in patients with advanced gastric cancer. Geographic differences in efficacy were observed in AVAGAST, but the study only included 12 Chinese patients. AVATAR, a study similar in design to AVAGAST, was a randomized, double-blind, phase III study conducted in Chinese patients with advanced gastric cancer.Methods: Patients more than 18 years of age with gastric adenocarcinoma were randomized 1:1 to capecitabine–cisplatin plus either bevacizumab or placebo. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and safety.Results: In total, 202 patients were included (placebo n = 102; bevacizumab n = 100). Baseline characteristics were well balanced. The primary analysis result did not show a difference in OS for the bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95 % CI, 0.79–1.56); P = 0.5567]. Median PFS was also similar in both arms. Bevacizumab plus capecitabine–cisplatin was well tolerated. Grade 3–5 adverse events (AEs) occurred in 60 % of bevacizumab-treated and 68 % of placebo-treated patients, respectively. Grade 3–5 AEs of special interest with bevacizumab occurred in 8 % of bevacizumab-treated patients and 15 % of placebo-treated patients, mainly grade 3–5 hemorrhage (bevacizumab 4 %, placebo 12 %).Conclusions: Addition of bevacizumab to capecitabine–cisplatin in Chinese patients with advanced gastric cancer did not improve outcomes in AVATAR. There was no difference in OS between the two arms and PFS was similar in both arms. Safety findings were as previously experienced with bevacizumab, including AVAGAST; no new safety signals were reported. © 2014, The Author(s).
Kong X.,PLA Fourth Military Medical University |
Liu Y.,PLA Fourth Military Medical University |
Ye R.,Nanjing University |
Zhu B.,PLA Fourth Military Medical University |
And 7 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2013
Background: The fate and differentiation of mesenchymal stem cells (MSCs) depend on various microenvironmental cues. In chronic inflammatory bone disease, bone regeneration is inhibited. The present study therefore sought to identify the underlying molecule mechanisms. Methods We isolated periodontal ligament stem cells (PDLSCs), a new population of MSCs, from the periodontal ligament tissues of periodontitis patients and healthy controls (p-PDLSCs and h-PDLSCs). The secretion of inflammatory cytokines, like TNF-α, IL-1β, IL-6 and IL-8, after LPS stimulation was measured by ELISA. The expressions of p-GSK3β and GSK3β in two types of PDLSCs were detected by Western blot. TOPFlash was used to assay the Tcf/Lef transcriptional activity. Knockdown of GSK3β by siRNA and over-expression of GSK3β by adenoviruses were performed to confirm the role of GSK3β in the impaired osteogenic differentiation of PDLSCs under inflammatory microenvironment. Results We demonstrated that p-PDLSCs displayed impaired osteogenic capacity than h-PDLSCs. Upon inflammatory stimulation, monocytes, but not PDLSCs, released inflammatory cytokines among which TNF-α directly act on PDLSCs and suppressed their osteogenic differentiation. TNF-α induced the phosphorylation of GSK3β, the deactivated form of GSK3β, which increased nuclear β-catenin and Lef-1 accumulation, and eventually reduced the Runx2-associated osteogenesis in PDLSCs. Over-expression of GSK3β rescued osteogenesis in TNF-α-stimulated PDLSCs, whereas inactivation of GSK3β was sufficient to liberate the β-catenin/Lef-1/Runx2 pathway. Conclusion GSK3β plays an obligatory role in the TNF-α-mediated inhibition of osteogenesis in MSCs. General significance The strategy to target GSK3β may provide a potential approach to bone regeneration in inflammatory microenvironments. © 2013 Published by Elsevier B.V.
Cheng A.-L.,National Taiwan University Hospital |
Guan Z.,Sun Yat Sen University |
Chen Z.,Anhui Medical University |
Tsao C.-J.,Chi Mei Medical Center |
And 12 more authors.
European Journal of Cancer | Year: 2012
Background: The phase III Sorafenib Asia-Pacific (AP) trial - conducted in China, Taiwan and South Korea - confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. Methods: In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400 mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1-2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety. Findings: Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32-0.87 and 0.31-0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups. Interpretation: The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status. © 2012 Elsevier Ltd. All rights reserved.
Herbst R.S.,University of Houston |
Sun Y.,Cancer Hospital |
Eberhardt W.E.E.,University of Duisburg - Essen |
Germonpre P.,University of Antwerp |
And 14 more authors.
The Lancet Oncology | Year: 2010
Background: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods: Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m2 intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. Findings: 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0·79, 97·58% CI 0·70-0·90; p<0·0001); median PFS was 4·0 months in the vandetanib group versus 3·2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0·79, 0·62-1·00, p=0·024); median PFS was 4·6 months in the vandetanib group versus 4·2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). Interpretation: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. Funding: AstraZeneca. © 2010 Elsevier Ltd.