Li-Na Tang

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.

Congestive heart failure risk in cancer patients treated with vascular endothelial growth factor tyrosine kinase inhibitors: a systematic review and meta-analysis of 36 clinical trials

Congestive heart failure (CHF) associated with vascular endothelial growth factor tyrosine‐kinase inhibitors (VEGFR‐TKIs) has emerged as a relevant problem in clinical and scientific communities. We performed an up‐to‐date, comprehensive meta‐analysis to determine the overall incidence and risk of CHF in cancer patients receiving VEGFR‐TKIs.

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 arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: An up-to-date meta-analysis

PURPOSE Arterial thromboembolic events (ATEs) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have emerged as a serious concern, we perform a meta-analysis of randomized controlled trials (RCTs) to determine the incidence and risk of ATEs in cancer patients treated with these agents. METHODS The databases of PubMed and Web of Science 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 according to the heterogeneity of included studies. RESULTS A total of 9711 patients from 19 RCTs were included. The overall incidence of ATEs was 1.5% (95%CI: 1.0-2.3%). The use of VEGFR-TKIs significantly increased the risk of developing ATEs when compared with controls (OR 2.26, 95%CI: 1.38-3.68, p=0.001). Sensitivity analysis indicated that the significance estimate of pooled ORs was not significantly influenced by omitting any single study. In subgroup analyses, the odds ratio of ATEs did not significantly vary with tumor types (p=0.70), VEGFR-TKIs (p=0.32), treatment regimens (p=0.76), phase of trials (p=0.37) and sample size (p=0.89). Additionally, the most common events for ATEs were cardiac ischemia/infarction (67.4%), CNS ischemia (7.9%) and cerebrovascular accident (6.7%). CONCLUSION In this largest meta-analysis to date, we find that treatment with VEGFR-TKIs significantly increase the risk of developing ATEs. Further studies are still needed to investigate this association. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

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.

Incidence and risk of denosumab-related hypocalcemia in cancer patients: a systematic review and pooled analysis of randomized controlled studies

Abstract Purpose: The aim of this study is to evaluate the frequency and relative risk of hypocalcemia in cancer patients receiving denosumab. Methods: We searched the PubMed (data from 1966 to October 2012), Embase (data from 1980 to October 2012) and Cochrane Library (up to October 2012) electronic databases for relevant randomized controlled trials (RCTs). Abstracts presented at conferences were also searched. Phase II and III trials of denosumab in patients with any type of cancer that reported occurrence of hypocalcemia were eligible. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity among included trials. Results: A total of 8990 patients with a variety of solid tumors from seven RCTs were included for the meta-analysis. The overall incidences of all-grade and high-grade hypocalcemia in cancer patients were 5.2% (95% confidence interval [CI]: 2.8–9.3%) and 2.0% (95% CI: 0.7–5.5%), respectively. The use of denosumab was associated with significantly increased risk of developing all-grade (RR 1.932, 95% CI: 1.590–2.347, p < 0.001) and high-grade hypocalcemia (RR 4.027, 95% CI: 2.346–6.912, p < 0.001) in comparison with controls. Conclusions: The use of denosumab is associated with a significantly increased risk of developing hypocalcemia (p < 0.001). Physicians should be aware of this adverse effect and should monitor cancer patients receiving denosumab.

Efficacy and Safety of Gemcitabine-Docetaxel Combination Therapy for Recurrent or Refractory High-grade Osteosarcoma in China: A Retrospective Study of 18 Patients

OBJECTIVE In this study, we describe experiences with gemcitabine-docetaxel combination therapy as salvage treatment for Chinese patients with recurrent or refractory high-grade osteosarcoma. METHODS We retrospectively reviewed the medical records of 18 patients with recurrent or refractory high-grade osteosarcoma who had undergone gemcitabine-docetaxel combination treatment as salvage chemotherapy. Gemcitabine at 675 mg/m(2) was administered on Days 1 and 8, and docetaxel at 75-100 mg/m(2) was administered on Day 8. The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. RESULTS The patients (ages 12-57 years) received a total of 44 cycles of chemotherapy (median: 2 courses; range: 2-6 courses). The overall response rate was 5.6% and the disease control rate was 22.3%, with one partial response and three patients with stable disease. The median time to progression and overall survival time were 2 months (range: 2-6 months) and 8 months (range: 3-21 months), respectively. Major severe toxicities were hematologic toxicities, including Grade 3 or 4 anemia (9.1%), leucopenia (29.5%) and thrombocytopenia (18.1%) in total cycles; mild toxicities included Grade 1 or 2 nausea and vomiting (31.8%), fatigue (38.6%) and alopecia (20.5%). There were no treatment-related deaths. CONCLUSIONS In the current study, gemcitabine-docetaxel combination therapy at this dosage and schedule was found to be well tolerated and marginally effective, which could be considered as salvage therapy for patients with recurrent or refractory high-grade osteosarcoma.