Bufalin suppresses the migration and invasion of prostate cancer cells through HOTAIR, the sponge of miR-520b.

Bufalin, the major active component of the traditional Chinese medicine ChanSu obtained from the skin and parotid venom glands of toads, has long been known as an anticancer agent. Recent studies show that microRNAs (miRs) are involved in the anticancer activities of bufalin, while long non-coding RNAs (lncRNAs) are known to interact with miRNAs to regulate various biological functions. In this paper, we investigated the possible network related to the antimetastatic effect of bufalin in prostate cancer (PCa) cells. We demonstrated that bufalin (0.05-10 µM) dose-dependently suppressed the proliferation of prostate cancer DU145 and PC3 cells with IC50 values of 0.89 and 1.28 µM, respectively. Furthermore, bufalin treatment significantly suppressed the cell migration and invasion. To explore the role of lncRNAs in the antimetastatic activity of bufalin, we used an lncRNA microarray and found that HOX transcript antisense RNA (HOTAIR) was the most markedly downregulated lncRNA in bufalin-treated PCa cells. Overexpression of HOTAIR counteracted the suppressing effects of bufalin on DU145 and PC3 cells. We then predicted and verified that HOTAIR upregulated FGFR1 expression by sponging miR-520b in PCa cells. In 40 patients with PCa bone metastasis, we used in situ hybridization or immunohistochemical assay to assess the HOTAIR and FGFR1 expression, which revealed that both HOTAIR and FGFR1 expression were significantly higher in bone metastasis tissues than in the primary PCa tissues. In addition, the level of serum HOTAIR was positively associated with the levels of serum bone metabolic markers (CTx, OST, B-ALP and PINP) and may serve as a reasonable biomarker for PCa bone metastasis. Taken together, this is the first study revealing that HOTAIR promotes PCa bone metastasis, and bufalin may be a promising candidate for the treatment of this disease.

Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1.

Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/ß-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/ß-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. KEY MESSAGES: CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/ß-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.

Dihydromethysticin kavalactone induces apoptosis in osteosarcoma cells through modulation of PI3K/Akt pathway, disruption of mitochondrial membrane potential and inducing cell cycle arrest.

The objective of the present study was to evaluate the tumor and apoptotic effects of dihydromethysticin kavalactone against human osteosarcoma (MG-63) cells. Antiproliferative activity was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induction by dihydromethysticin was demonstrated by fluorescence microscopy, quantitative videomicroscopy and Annexin V-FITC apoptosis detection kit. Mitochondrial membrane potential disruption was demonstrated by rhodamine-123 dye using flow cytometry. We also evaluated the effect of dihydromethysticin on PI3K/Akt pathway with an immunoblotting analysis. The results showed that the compound induced dose-dependent as well as time-dependent antiproliferative effects against MG-63 cell growth. Cell death and apoptotic body formation was noticed followed dihydromethysticin treatment at various doses. The percentage of apoptotic cells (early apoptosis+late apoptosis) increased from 6.63% in untreated control to 23.92%, 23.81% and 93.9% in 25 µM, 75 µM and 100 µ Mdihydromethysticin-treated cells respectively. Flow cytometric analysis showed dihydromethysticin induced an increase in G0/G1 cells (apoptotic cells). Furthermore, we observed mitochondrial transmembrane depolarization along with decreased phosphorylation levels for PI3K, AKT (Ser 473), AKT (Thr 308), GSK-3ß, and BAD. These reductions were associated with down regulation of AKT and upregulation of both GSK-3ß and BAD.

Continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for recurrent or refractory osteosarcoma patients in China: a retrospective study.

OBJECTIVE: The aim of this retrospective study was to evaluate the feasibility and efficacy of response to continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for patients with recurrent or refractory osteosarcoma. MATERIALS AND METHODS: Eighteen recurrent or refractory osteosarcoma patients who were treated with continuous-infusion ifosfamide and doxorubicin combination between May 1999 and April 2011 were included in the analysis. Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days, and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1. The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. RESULTS: The patients (ages 7-53 years) received a total of 42 cycles of chemotherapy (median: 2 courses; range: 2-5 courses). The overall response rate was 0% and the disease control rate was 22.3%, with four patients having stable disease. The median time to progression and overall survival time were 2 months (range: 2-5 months) and 9 months (range: 3-29 months), respectively. Major severe toxicities were leucopenia 7 (38.9%), nausea and vomiting 3 (16.7%) and alopecia 9 (50%). There were no treatment-related deaths. CONCLUSIONS: In our experience, continuous-infusion ifosfamide and doxorubicin combination therapy at this dosage and schedule was found to be well tolerated and moderate effective, which could be considered as salvage therapy for patients with recurrent or refractory osteosarcoma. Further assessment is necessary to confirm the safety and efficacy of this treatment.

Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials.

AIMS: The aim of this study is to gain a better understanding of the overall incidence and risk of osteonecrosis of the jaw (ONJ) in cancer patients receiving denosumab. METHODS: We performed a meta-analysis of relevant randomized controlled trials identified in Pubmed, Embase, and Cochrane databases. Abstracts presented at the conferences were also searched. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: A total of 8963 patients with a variety of solid tumors from 7 randomized controlled trials (RCTs) were included for the meta-analysis. The overall incidence of ONJ in cancer patients receiving denosumab was 1.7 % [95 % CI: 0.9-3.1 %]. Also, the use of denosumab was associated with significantly increased risk of ONJ in comparison with bisphosphonates (BPs)/placebo treatment (RR 1.61, 95 % CI: 1.05-2.48, P = 0.029). Subgroup analysis based on controlled therapies demonstrated an increased risk of ONJ in denosumab therapy, when compared with BPs (RR 1.48, 95 % CI: 0.96-2.29, P = 0.078) or placebo (RR 16.28, 95 % CI: 1.68-158.05, P = 0.017). Similar results were observed in prostate cancer (RR 3.358, 95 % CI: 1.573-7.166, P = 0.002) while there was a non-significantly increased risk of denosumab-related osteonecrosis of the jaw (DONJ) in non-prostate cancers (RR 1.142, 95 % CI: 0.678-1.921, P = 0.618). CONCLUSIONS: The use of denosumab is associated with an increased risk of developing ONJ when compared with BP treatment or placebo, although the increased risk was not statistically significant between denosumab and BP treatment. Further studies are still needed to establish guidelines for the prevention and effective treatment of ONJ.

Incidence and risk of treatment-related mortality in cancer patients treated with EGFR-TKIs: a meta-analysis of 22 phase III randomized controlled trials.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the cornerstone in the treatment of lung cancers that harbor EGFR mutations, but also play an important role in the treatment of other lung cancers and have been investigated among various types of solid tumors. However, these drugs have been associated with an increase in the risk of potentially life-threatening adverse event, such as arterial and venous thrombotic events. We performed a meta-analysis to determine the incidence and risk of fatal adverse events (FAEs) in cancer patients treated with EGFR-TKIs. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 13,825 patients from 22 trials were included. Among patients treated with EGFR-TKIs, the overall incidence of FAEs was 1.9% (95%CI: 1.2-2.9%), and the risk of FAEs was 0.99 (95%CI: 0.70-1.41, p = 0.97). No increase in FAEs was detected in any prespecified subgroup. Additionally, using EGFR-TKIs as salvage treatment significantly reduced the risk of FAEs when compared to the controls (RR 0.51, 95%CI: 0.29-0.87, p = 0.013). In conclusion, this analysis suggests that the use of EGFR-TKIs does not increase the risk of FAEs in patients with advanced solid tumors, and EGFR-TKIs are safety and tolerable for cancer patients, especially for those previously treated patients.

The prognostic value of survivin expression in patients with colorectal carcinoma: a meta-analysis.

OBJECTIVE: The prognostic role of survivin in colorectal carcinoma remains controversial. This meta-analysis aimed to explore the association between survivin expression and survival outcomes in patients with colorectal carcinoma. METHODS: A comprehensive literature search for relevant studies published up to April 2013 was performed using PubMed, MEDLINE and ISI Web of Science. Only articles in which survivin was detected by immunohistochemical staining were included. This meta-analysis was done using STATA and Review Manager. RESULTS: A total of 1784 patients from 14 studies were included in the analysis. Our results showed that survivin overexpression in patients with colorectal carcinoma was significantly associated with poor overall survival (hazard ratio, 1.505; 95% confidence interval, 1.197-1.893; P = 0.000) and disease-free survival (hazard ratio, 2.323; 95% confidence interval, 1.687-3.199; P = 0.000). The results indicated that a significant relationship between survivin expression and overall survival was also exhibited in studies with an Asian country (hazard ratio, 1.684; 95% confidence interval, 1.477-1.921), patient number >100 (hazard ratio, 1.604; 95% confidence interval, 1.371-1.877), the cut-off level <50% (hazard ratio, 1.449; 95% confidence interval, 1.045-2.010), the percentage of survivin overexpression >50% (hazard ratio, 1.528; 95% confidence interval, 1.056-2.211) and the hazard ratio estimated (hazard ratio, 1.643; 95% confidence interval, 1.262-2.139). Moreover, upregulation of survivin was associated with stages (III/IV vs. I/II: odds ratio, 1.08; 95% confidence interval, 0.80-1.46), the depth of invasion (T3/T4 vs. T1/T2: odds ratio, 1.79; 95% confidence interval 0.67-4.74), lymph node metastasis (positive vs. negative: odds ratio, 1.49; 95% confidence interval, 0.99-2.26), distant metastasis (positive vs. negative: odds ratio, 2.37; 95% confidence interval, 0.99-5.72) and grade of differentiation (well/moderate vs. poor: odds ratio, 1.02; 95% confidence interval, 0.43-2.41), but without significance. CONCLUSION: The present meta-analysis indicated that upregulation of survivin was associated with poor prognosis in patients with colorectal carcinoma.

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

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.

Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis.

AIMS: To investigate the overall incidence and risk of hypertension in cancer patients who receive axitinib and compare the differences in incidences between axitinib and the other four approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). METHODS: Several databases were searched, including Pubmed, Embase and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned axitinib at a starting dose of 5 mg orally twice daily with data on hypertension available. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. RESULTS: A total of 1908 patients from 10 clinical trials were included. The overall incidences of all grade and high grade hypertension in cancer patients were 40.1% (95% CI 30.9, 50.2%) and 13.1% (95% CI 6.7, 24%). The use of axitinib was associated with significantly increased risk of all grade (RR 3.00, 95% CI 1.29, 6.97, P = 0.011) and high grade hypertension (RR 1.71, 95% CI 1.21, 2.43, P = 0.003). The risk of axitinib associated all grade and high grade hypertension in renal cell carcinoma (RCC) was significantly higher than that in non-RCC. Additionally, the risk of hypertension with axitinib was substantially higher than other approved VEGFR-TKIs, while the risk of all grade hypertension with axitinib was similar to pazopanib (RR 1.05; 95% CI 0.95-, 1.17, P = 0.34). CONCLUSIONS: While sharing a similar spectrum of target receptors with other VEGFR-TKIs, axitinib is associated with an unexpectedly high risk of developing hypertension. Close monitoring and appropriate management for hypertension are recommended during the treatment.

Prognostic value of tissue vascular endothelial growth factor expression in bladder cancer: a meta-analysis.

OBJECTIVE: The prognostic role of vascular endothelial growth factor (VEGF) in bladder cancer remains controversial. This meta-analysis aimed to explore any association between overexpression and survival outcomes. METHODS: We systematically searched for studies investigating the relationships between VEGF expression and outcome of bladder cancer patients. Study quality was assessed using the Newcastle-Ottawa Scale. After careful review, survival data were extracted from eligible studies. A meta-analysis was performed to generate combined hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: A total of 1,285 patients from 11 studies were included in the analysis. Our results showed that tissue VEGF overexpression in patients with bladder cancer was associated with poor prognosis in terms of OS (HR, 1.843; 95% CI, 1.231-2.759; P = 0.003), DFS (HR, 1.498; 95% CI, 1.255-1.787; P = 0.000) and DSS (HR, 1.562; 95% CI, 0.996-1.00; P = 0.052), though the difference for DSS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg's and Egger's tests except for DFS (Begg's test, P = 0.221; Egger's test, P = 0.018). CONCLUSION: The present meta-analysis indicated elevated VEGF expression to be associated with a poor prognosis in patients with bladder cancer.

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.

Comparison between doublet agents versus single agent in metastatic breast cancer patients previously treated with an anthracycline and a taxane: a meta-analysis of four phase III trials.

AIM: To compare doublet agents with single agent as salvage treatment in metastatic breast cancer (MBC) patients pre-treated with an anthracycline and a taxane. METHODS: We systematically searched for randomised clinical trials that compared doublet agents with single agent in MBC patients pre-treated with an anthracycline and a taxane. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate and grade 3 or 4 toxicity. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, TX, USA). RESULTS: Four trials comprising 2373 patients were eligible for inclusion. Meta-analysis showed that there was significant improvement in progression-free survival (PFS) (hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.72-0.86, P = 0.000) and overall response rate (risk ratio (RR) 1.47, 95%CI 1.13-1.91; p = 0.004) in doublet agents group, though the pooled HR for OS (HR 0.96, 95%CI 0.87-1.05; p = 0.356) showed no significant difference. Subgroup analysis also favoured capecitabine-based doublet agents therapy in terms of PFS (HR 0.77, 95%CI 0.70-0.86; p = 0.000) and overall response rate (ORR) (RR 1.65, 95%CI 1.06-2.56; p = 0.026), but gemcitabine-based doublet agents therapy gained no clinical benefits. There were more incidences of grade 3 or 4 anaemia (RR 1.610, 1.212-2.314, p = 0.01), neutropenia (RR 2.239, 1.231-4.071, p = 0.008), thrombocytopaenia (RR 2.401, 1.595-3.615, p = 0.000), fatigue (RR 2.333, 1.338-4.006, p = 0.000) and nausea and vomiting (RR 2.233, 1.558-3.199, p = 0.000) in the combination group. With regard to the risk of grade 3 or 4 stomatitis (RR 1.666, 0.818-3.392, p = 0.160), diarrhoea (RR 0.739, 0.542-1.008, p = 0.056) and hand-foot syndrome (RR 1.002, 0.835-1.203, p = 0.983), equivalent frequencies were found between the two groups. CONCLUSION: Combination chemotherapy offered a significant improvement in PFS and ORR in patients with MBC pre-treated with an anthracycline and a taxane but did not benefit OS. With present available data from randomised clinical trials, we were still unable to clearly set the role of combination therapy in the treatment of MBC in this setting.

Overall survival benefits for irinotecan-containing regimens as first-line treatment for advanced gastric cancer: an updated meta-analysis of ten randomized controlled trials.

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan-containing regimen as first-line treatment for those patients are controversial. We performed a systematic review and meta-analysis of randomized controlled trials to determine the survival benefits of irinotecan-containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan-containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78-0.94, p = 0.002] and progression-free survival [HR = 0.82, 95% CI = 0.69-0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77-1.04, p = 0.15), 1-year survival rate [1-year SR: relative risk (RR) 1.10, 95% CI = 0.97-1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91-1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan-containing regimens. This updated meta-analysis provided strong evidence for a survival benefit of irinotecan-containing regimen as first-line treatment for AGC. A clear advantage of irinotecan-containing over nonirinotecan-containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.

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

AIM: 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. METHODS: A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1-30.2%] and 6.4% (95% CI, 3.3-9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15-30.5%] and 7.6% (95% CI, 2.8-18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3-37.3%) and 8.8% (5.9%-12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2-33.7%) and 3.4% (95% CI: 1%-11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76-6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41-19.04, P = 0.000) in comparison with controls. CONCLUSIONS: There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

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.

Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis.

PURPOSES: To gain a better understanding of the overall incidence and risk of hypertension in cancer patients who receive pazopanib and to compare the differences in incidence among sorafenib, sunitinib, and pazopanib. METHODS: Several databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned single drug pazopanib 800 mg/day with data on hypertension available. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. RESULTS: A total of 1,651 patients with a variety of solid tumors from 13 clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hypertension in cancer patients were 35.9 % (95 % CI 31.5-40.6 %) and 6.5 % (95 % CI 5.2-8.0 %), respectively. The use of pazopanib was associated with an increased risk of developing all-grade (RR 4.97, 95 % CI 3.38-7.30, p < 0.001) and high-grade hypertension (RR 2.87, 95 % CI 1.16-7.12, p = 0.023). Additionally, there was no significant difference in the incidence of all-grade (RR 1.21, 95 % CI 0.96-1.53, p = 0.11) and high-grade hypertension (RR 1.29, 95 % CI 0.80-2.07, p = 0.30) between RCC and non-RCC patients. Interestingly, the risk of all-grade hypertension with pazopanib was substantially higher than sorafenib (RR 1.99; 95 % CI 1.73-2.29, p = 0.00) and sunitinib (RR 2.20; 95 % CI 1.92-2.52, p = 0.00), while the risk of pazopanib-induced high-grade hypertension was similar to sorafenib (RR 0.98; 95 % CI 0.75-1.30, p = 0.90) and sunitinib (RR 0.81; 95 % CI 0.62-1.06, p = 0.12). CONCLUSIONS: The use of pazopanib is associated with a significantly increased risk of developing hypertension. Close monitoring and appropriate managements are recommended during the therapy. Future studies are still needed to investigate the risk reduction and possible use of pazopanib in selected patients.

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

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.

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.

Doublet versus single cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to perform a systematic review and meta-analysis of all randomized controlled trials that compared the efficacy of doublet versus single third-generation cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Several databases including PubMed, Embase, and Cochrane databases were searched. The endpoints were overall survival (OS), time to progression (TTP), 1-year survival rate (1-year SR), overall response rate (ORR), and grade 3 or 4 adverse event (AE). We performed a meta-analysis of the randomized controlled trials using a fixed-effects model and an additional random-effects model when applicable. The results of the meta-analysis were expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95 % confidence intervals (95 % CI). A subgroup meta-analysis was performed based on chemotherapy regimens. RESULTS: Ten eligible trials involving 2,510 patients were identified. The intention-to-treatment (ITT) analysis demonstrated that doublet therapy was superior to single agent in terms of OS (HR = 0.84, 95 % CI = 0.71-1.00, p = 0.053), TTP (HR = 0.76, 95 % CI = 0.60-0.96, p = 0.022), 1-year SR (RR = 1.17, 95 % CI = 1.02-1.35, p = 0.03), and ORR (RR = 1.54, 95 % CI = 1.36-1.73, p = 0.000). Subgroup analysis also favored platinum-based doublet therapy in terms of 1-year SR (RR = 1.40, 95 % CI = 1.09-1.81, p = 0.009) and ORR (RR = 1.64, 95 % CI = 1.38-1.96, p = 0.000). Though gemcitabine-based doublet significantly increased ORR compared with single agent (RR = 1.45, 95 % CI = 1.23-1.71, p = 0.000), it did not translate into an increase in survival benefits. In addition, more incidences of grade 3 or 4 anemia, thrombocytopenia, and neurotoxicity were observed in the doublet combination group. With respect to grade 3 or 4 neutropenia and nonhematologic toxicities such as diarrhea, fatigue, nausea, and vomiting, equivalent frequencies were found between the two groups. CONCLUSIONS: Our results indicated that doublet therapy was superior to a single third-generation cytotoxic agent for elderly patients with advanced NSCLC. The optimal dosage and schedule of platinum-based doublet should be investigated in future prospective clinical trials. Gemcitabine-based doublet could be considered for elderly patients who were not suitable for platinum-based chemotherapy.

Erlotinib and pemetrexed as maintenance therapy for advanced non-small-cell lung cancer: a systematic review and indirect comparison.

BACKGROUND: Two new agents have recently been licensed as maintenance therapy for advanced non-small-cell lung cancer (NSCLC) by the US Food and Drug Administration. This paper aims to systematically review the evidence from all available clinical trials of erlotinib and pemetrexed as maintenance therapy for advanced NSCLC. METHODS: Systematic literature searches were performed in PUBMED, EMBASE and Cochrane databases. Abstracts presented at two conferences were also researched. The effects of erlotinib and pemetrexed on overall survival and progression-free survival were compared using an indirect treatment comparison method with placebo or observation as a common comparator. RESULTS: Five randomized controlled studies were included. Both interventions offered significant advantages for overall survival (OS) and progression-free survival (PFS) compared with placebo or observation. Using indirect comparison meta-analysis, the relative hazards ratio of pemetrexed compared with erlotinib for PFS was 0.71 (95% CI 0.60-0.85; p = 0.0001), suggested that pemetrexed was superior to erlotinib in terms of progression-free survival. Although relative hazards ratio for OS showed no significant difference between the two agents (HR 0.88; 95% CI 0.71-1.08, p = 0.22). CONCLUSIONS: There is evidence to suggest that maintenance treatment with erlotinib or pemetrexed has clinically relevant and statistically significant advantages over treatment with placebo or observation in patients with advanced NSCLC.