Daliu Min

Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta‐analysis of clinical trials

To perform a systematic review and meta‐analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients.

Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR‐TKIs to venous thromboembolism is still unknown. We performed a meta‐analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR‐TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed‐ or random‐effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta‐analysis. The incidence of VTEs related to VEGFR‐TKIs was 3% (95%CI: 1.7–5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR‐TKIs versus controls in overall population (RR0.912, 95%CI: 0.617–1.348, p = 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR‐TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFR‐TKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR‐TKIs to treat patients with solid cancer.

Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis.

PURPOSE To compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitor monotherapy (EFGR-TKIs: gefitinib or erlotinib) with standard second-line chemotherapy (single agent docetaxel or pemetrexed) in previously treated advanced non-small-cell lung cancer (NSCLC). METHODS We systematically searched for randomized clinical trials that compared EGFR-TKI monotherapy with standard second-line chemotherapy in previously treated advanced NSCLC. The end points were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), 1-year survival rate (1-year SR) and grade 3 or 4 toxicities. The pooled hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS Eight randomized controlled trials (totally 3218 patients) were eligible. Our meta-analysis results showed that EGFR-TKIs were comparable to standard second-line chemotherapy for advanced NSCLC in terms of overall survival (HR 1.00, 95%CI 0.92-1.10; p=0.943), progression-free survival (HR 0.90, 95%CI 0.75-1.08, P=0.258) and 1-year-survival rate (RR 0.97, 95%CI 0.87-1.08, P=0.619), and the overall response rate was higher in patients who receiving EGFR-TKIs(RR 1.50, 95%CI 1.22-1.83, P=0.000). Sub-group analysis demonstrated that EGFR-TKI monotherapy significantly improved PFS (HR 0.73, 95%CI: 0.55-0.97, p=0.03) and ORR (RR 1.96, 95%CI: 1.46-2.63, p=0.000) in East Asian patients, but it did not translate into increase in OS and 1-year SR. Furthermore, there were fewer incidences of grade 3 or 4 neutropenia, febrile neutropenia and neurotoxicity in EGFR-TKI monotherapy group, excluding grade 3 or 4 rash. CONCLUSION Both interventions had comparable efficacy as second-line treatments for patients with advanced NSCLC, and EGFR-TKI monotherapy was associated with less toxicity and better tolerability. Moreover, our data also demonstrated that EGFR- TKI monotherapy tended to be more effective in East Asian patients in terms of PFS and ORR compared with standard second-line chemotherapy. These results should help inform decisions about patient management and design of future trials.

Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data.

Background Combining targeted therapy has been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but it is still unclear whether combining targeted therapy might offer any benefits against standard monotherapy with erlotinib. We thus performed a meta-analysis of randomized controlled trials to compare the efficacy and safety of combining targeted therapy versus erlotinib alone as second-line treatment for advanced NSCLC. Methods Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Results Eight eligible trials involved 2417 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that combining targeted therapy significantly improved OS (HR 0.90, 95%CI: 0.82–0.99, p = 0.024), PFS (HR 0.83, 95%CI: 0.72–0.97, p = 0.018), and ORR (OR 1.35, 95%CI 1.01–1.80, P = 0.04). Sub-group analysis based on phases of trials, EGFR-status and KRAS status also showed that there was a tendency to improve PFS and OS in combining targeted therapy, except that PFS for patients with EGFR-mutation or wild type KRAS favored erlotinib monotherapy. Additionally, more incidence of grade 3 or 4 rash, fatigue and hypertension were observed in combining targeted therapy. Conclusions With the available evidence, combining targeted therapy seems superior over erlotinib monotherapy as second-line treatment for advanced NSCLC. More studies are still needed to identify patients who will most likely benefit from the appropriate combining targeted therapy.

Analysis of prognostic factors in 333 Chinese patients with high-grade osteosarcoma treated by multidisciplinary combined therapy

To investigate prognostic factors for long‐term outcomes in Chinese patients with high‐grade osteosarcoma of the extremities or trunk treated by multidisciplinary combined therapy.

Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials

Abstract Objectives: Docetaxel and paclitaxel show significant clinical activity in metastatic breast cancer (MBC) and have been approved for MBC by the U.S. Food and Drug Administration, but it is still unclear whether a paclitaxel-based regimen improves outcomes over a docetaxel-based regimen in patients with MBC. We therefore performed a meta-analysis of randomized controlled trials to compare the safety and efficacy of these two regimens in MBC. Methods: We systematically searched for randomized controlled trials that comparing paclitaxel-based with docetaxel-based regimens in patients with MBC in PubMed (up to January 2012), Embase (1980 to January 2012), and the Cochrane databases (up to January 2012). Abstracts presented at conferences (up to January 2011) were also searched. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 12.0 software (Stata Corporation, College Station, TX, USA). Results: Seven eligible trials involving 1694 patients with MBC were selected. Our results showed that a paclitaxel-based regimen was comparable to a docetaxel-based regimen for MBC patients in terms of OS (HR: 0.87, 95% CI: 0.60–1.27, p = 0.48), PFS (HR: 0.76, 95% CI: 0.58–1.00, p = 0.052), TTP (HR: 1.13, 95% CI: 0.81–1.58, p = 0.46), and ORR (RR: 1.01, 95% CI: 0.88–1.15, p = 0.92), but fewer grade 3 or 4 adverse events including anemia (RR: 0.64, 95% CI: 0.44–0.94, p = 0.023), neutropenia (RR: 0.74, 95% CI: 0.58–0.93, p = 0.011), febrile neutropenia (RR: 0.38, 95% CI: 0.15–0.96, p = 0.041), thrombopenia (RR: 0.62, 95% CI: 0.41–0.96, p = 0.033), mucositis (RR: 0.082, 95% CI: 0.025–0.27, p < 0.001), diarrhea (RR: 0.19, 95% CI: 0.081–0.47, p < 0.001) and fatigue (RR: 0.43, 95% CI: 0.20–0.96, p = 0.039) were observed in the paclitaxel-based regimen. However, limitations of our study needed to be considered when interpreting these results: our study was a meta-analysis of published data, and there was significant heterogeneity among included trials. Potential publication bias might also exist. Conclusion: The present systematic review and meta-analysis demonstrates that both taxane-based regimens have comparable efficacy for patients with MBC, and the paclitaxel-based regimen is associated with less toxicity and better tolerability, especially in older patients and when used in weekly regimens.

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression.

Aim:Multi-drug resistance poses a critical bottleneck in chemotherapy. Given the up-regulation of mTOR pathway in many chemoresistant cancers, we examined whether sirolimus (rapamycin), a first generation mTOR inhibitor, might induce human osteosarcoma (OS) cell apoptosis and increase the sensitivity of OS cells to anticancer drugs in vitro.Methods:Human OS cell line MG63/ADM was treated with sirolimus alone or in combination with doxorubicin (ADM), gemcitabine (GEM) or methotrexate (MTX). Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. MiRNAs in the cells were analyzed with miRNA microarray. The targets of miR-34b were determined based on TargetScan analysis and luciferase reporter assays. The expression of relevant mRNA and proteins was measured using qRT-PCR and Western blotting. MiR-34, PAK1 and ABCB1 levels in 40 tissue samples of OS patients were analyzed using qRT-PCR and in situ hybridization assays.Results:Sirolimus (1–100 nmol/L) dose-dependently suppressed the cell proliferation (IC50=23.97 nmol/L) and induced apoptosis. Sirolimus (10 nmol/L) significantly sensitized the cells to anticancer drugs, leading to decreased IC50 values of ADM, GEM and MTX (from 25.48, 621.41 and 21.72 μmol/L to 4.93, 73.92 and 6.77 μmol/L, respectively). Treatment of with sirolimus increased miR-34b levels by a factor of 7.5 in the cells. Upregulation of miR-34b also induced apoptosis and increased the sensitivity of the cells to the anticancer drugs, whereas transfection with miR-34b-AMO, an inhibitor of miR-34b, reversed the anti-proliferation effect of sirolimus. Two key regulators of cell cycle, apoptosis and multiple drug resistance, PAK1 and ABCB1, were demonstrated to be the direct targets of miR-34b. In 40 tissue samples of OS patients, significantly higher miR-34 ISH score and lower PAK5 and ABCB1 scores were detected in the chemo-sensitive group.Conclusion:Sirolimus increases the sensitivity of human OS cells to anticancer drugs in vitro by up-regulating miR-34b interacting with PAK1 and ABCB1. A low miR-34 level is an indicator of poor prognosis in OS patients.

Interleukin-6 as a Prognostic Marker for Breast Cancer: A Meta-analysis:

Aims and background Interleukin-6 (IL-6) has been shown to promote tumor survival, metastasis, and angiogenesis, in addition to possessing antitumor activities. In light of the conflicting data, we sought to determine whether IL-6 could be used as a prognostic factor for patients with breast cancer. Methods Eligible studies describing the use of IL-6 as a prognostic factor for breast cancer were identified. Data describing overall survival (OS), disease-free survival (DFS), and clinicopathologic features were collected and analyzed. Results Thirteen articles containing 3,224 breast cancer patients were identified. The results showed that IL-6 expression was not associated with lymph node metastasis, tumor size, or histologic grade. Moreover, there was no correlation between IL-6 expression and DFS. However, the combined hazard ratio (95% confidence interval) for OS was 2.15 (1.46, 3.17). Sensitivity analysis further demonstrated that, for OS, the results of this meta-analysis were stable. A subgroup analysis showed that the source used to detect IL-6 levels may have altered the pooled results for OS. Conclusions Taken together, these results indicate that IL-6 expression is associated with poor prognosis for breast cancer and the prognostic role is affected by the source used to detect IL-6 levels.

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis

Background Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined. Methods We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies. Results A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3–2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21–8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed. Conclusion With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

p21-activated kinase 7 is an oncogene in human osteosarcoma

p21‐activated kinase 7 (PAK7), also named as PAK5, is a member of Rac/Cdc42‐associated Ser/Thr protein kinases. It is overexpressed in some types of cancer such as colorectal and pancreatic cancers. However, the expression status and biological function of PAK7 in osteosarcoma are still ambiguous. To evaluate the expression levels of PAK7 in osteosarcoma tissues and cell lines, immunohistochemistry was used. To investigate the role of PAK7 in cell proliferation, apoptosis and tumorigenicity in vitro and vivo, a recombinant lentivirus expressing PAK7 short hairpin RNA (Lv‐shPAK7) was developed and transfected into Saos‐2 cells. The silencing effect of PAK7 was confirmed by quantitative real‐time PCR (qRT‐PCR) and Western blot technique. PAK7 was overexpressed in osteosarcoma tissue and cell line. By knocking‐down of PAK7, the proliferation and colony formation of Saos‐2 cells were inhibited and apoptosis enhanced significantly. The in vivo tumorigenic ability in xenograft model of Saos‐2 cells was also notably inhibited when PAK7 was knocked down. Our results imply that PAK7 promotes cell proliferation and tumorigenesis and may be an attractive candidate for the therapeutic target of osteosarcoma.