Yuanjue Sun

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.

Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND The use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence and risk of GI perforation associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has not been well described. We conduct a systematic review and meta-analysis of published trials to evaluate the overall incidence and risk of GI perforation associated with VEGFR-TKIs. METHODS Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS A total of 5352 patients with a variety of solid tumors from 20 clinical trials were included in our analysis. The incidence of GI perforation was 1.3% (95%CI: 0.8-2.0%) among patients receiving VEGFR-TKIs, with a mortality of 28.6% (15.0-47.6%). Patients treated with VEGFR-TKIs did not significantly increase the risk of GI perforation compared with patients treated with control medication, with an OR of 2.99 (95%CI: 0.85-10.53, p=0.089). Sub-group analysis showed that the incidence of GI perforation did not significantly vary with tumor types, VEGFR-TKIs and treatments regimens. No evidence of publication bias was observed. CONCLUSIONS The use of VEGFR-TKIs dose not significantly increase the risk of GI perforation in comparison with the controls. Further studies are recommended to investigate this association and the risk differences among different tumor types, VEGFR-TKIs or treatment regimens.

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.

Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24 phase III clinical trials

Abstract Purpose: To assess the risk of interstitial lung disease (ILD) with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib, erlotinib, and afatinib. Method: PubMed databases were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR), and 95% confidence intervals (CIs) by using either random-effects or fixed-effect models. Results: The incidence of all-grade and high-grade (≧grade 3) ILD associated with EGFR-TKIs was 1·6% (95% CI, 1·0–2·4%) and 0·9% (95% CI, 0·6%–1·4%), with a mortality of 13·0% (95% CI, 7·6–21·6%). Patients treated with EGFR-TKIs had a significantly increased risk of developing all-grade (OR, 1·74; 95% CI, 1·25–2·43; P = 0·001) and high-grade (OR, 4·38; 95% CI, 2·18–8·79; P<0·001) ILD. No significant difference in the risk of ILD was found in sub-group analysis according to EGFR-TKIs, percentage of EGFR mutation, study location, EGFR-TKIs-based regimens, and controlled therapy. Conclusions: Treatment with EGFR-TKIs is associated with a significantly increased risk of developing ILD.

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.

Incidence and risk of hemorrhagic events with vascular endothelial growth factor receptor tyrosine-kinase inhibitors: an up-to-date meta-analysis of 27 randomized controlled trials

BACKGROUND We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine-kinase inhibitors (VEGFR-TKIs). METHODS We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies. RESULTS The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8-12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19-2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86-1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all-grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high-grade hemorrhagic events. CONCLUSIONS While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events.

CD133 expression predicts lung metastasis and poor prognosis in osteosarcoma patients: A clinical and experimental study

Identifying prognostic factors for osteosarcoma (OS) aids in the selection of patients who require more aggressive management. CD133 has been found to be a prognostic factor of certain tumor types. However, the association between CD133 expression and the prognosis of OS remains unknown. In this study, we analyzed the association of CD133 expression in OS with clinical factors and overall survival, and further investigated its potential role in metastasis in vitro. We found CD133 expression in 65.7% (46/70) of OS samples using immunohistochemistry, and it was positively correlated with lung metastasis analyzed by Chi-square test (P=0.002) and shorter overall survival time using the Kaplan-Meier method compared by log-rank test (P=0.000). Multivariate analysis showed that CD133 expression was an independent prognostic factor of patients with OS. To test for direct participation of CD133, we separated CD133+ and CD133− cells in the MG63 cell line using magnetic-activated cell sorting and found that CD133+ cells were more active in migration by scratch wound-healing assay and invasion by Matrigel invasion assay compared with CD133− cells. Elevated mRNA expression of the stemness gene octamer-binding transcription factor 4 (Oct-4) and NANOG, and the metastasis-related receptor C-X-C chemokine receptor type 4 (CXCR4) were also found in CD133+ cells by reverse transcription-polymerase chain reaction. Thus, expression of CD133 was correlated with lung metastasis and poor prognosis in OS patients. CD133+ cells may be a type of cancer stem cell with high expression of self-renewal capacity and metastasis-related genes.

Clinical analysis of Chinese limb osteosarcoma patients treated by two combinations of methotrexate, cisplatin, doxorubicin and ifosfamide.

Aims:  The objective of this study was to investigate the efficacy and toxic side effects of two combinations of methotrexate, cisplatin, doxorubicin and ifosfamide on treating Chinese osteosarcoma patients.

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.