Xinji Zhang

Maintenance Therapy With Continuous or Switch Strategy in Advanced Non-small Cell Lung Cancer: A Systematic Review and Meta-analysis

BACKGROUND Maintenance therapy for patients with non-small cell lung cancer (NSCLC) has gained extensive interest. Varying results for this treatment underpin the need for a synthesis of evidence. METHODS Trials investigating maintenance therapy with either a continuous or a switch strategy for patients with nonprogressing NSCLC compared with placebo or observation were identified. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS) and toxicity. RESULTS Eight trials of 3,736 patients were included in the analysis. Switch maintenance therapy substantially improved OS compared with placebo or observation (hazard ratio [HR], 0.85; 95% CI, 0.79-0.92; P < .001). A similar trend of improved OS was found in continuous maintenance therapy, despite lacking statistical significance (HR, 0.88; 95% CI, 0.74-1.04; P = .124). The interaction test suggested that the difference in OS between the two maintenance strategies was not statistically significant (P = .777). Clinically substantial and statistically significant improvement in PFS was found with both maintenance strategies (switch maintenance therapy HR, 0.67; 95% CI, 0.57-0.78; continuous maintenance therapy HR, 0.53; 95% CI, 0.43-0.65; interaction P = .128). Subgroup analyses revealed no statistically significant differences in OS or PFS between switch maintenance therapy with cytotoxic agents and that with tyrosine kinase inhibitor agents. Toxicity was greater in maintenance therapy. CONCLUSIONS Maintenance therapy with either a continuous or a switch strategy significantly increases OS and PFS compared with placebo or observation. However, the benefits must be balanced against toxicity.

Adjuvant Chemotherapy, with or without Taxanes, in Early or Operable Breast Cancer: A Meta-Analysis of 19 Randomized Trials with 30698 Patients

Background Taxanes have been extensively used as adjuvant chemotherapy for the treatment of early or operable breast cancer, particularly in high risk, node-negative breast cancer. Previous studies, however, have reported inconsistent findings regarding their clinical efficacy and safety. We investigated disease-free survival (DFS), overall survival (OS), and drug-related toxicities of taxanes by a systematic review and meta-analysis. Methodology and Principal Findings We systematically searched PubMed, EMBASE, the Cochrane Center Register of Controlled Trials, proceedings of major meetings, and reference lists of articles for studies conducted between January 1980 and April 2011. Randomized controlled trials (RCTs) comparing chemotherapy with and without taxanes in the treatment of patients with early-stage or operable breast cancer were eligible for inclusion in our analysis. The primary endpoint was DFS. Nineteen RCTs including 30698 patients were identified, including 8426 recurrence events and 3803 deaths. Taxanes administration yielded a 17% reduction of hazard ratio (HR) for DFS (HR = 0.83, 95% CI 0.79–0.88, p<0.001) and a 17% reduction of HR for OS (HR = 0.83, 95% CI 0.77–0.90, p<0.001). For high risk, node-negative breast cancer, the pooled HR also favoured the taxane-based treatment arm over the taxane-free treatment arm (HR = 0.82, 95% CI 0.77–0.87, p = 0.022). A significantly increased rate of neutropenia, febrile neutropenia, fatigue, diarrhea, stomatitis, and oedema was observed in the taxane-based treatment arm. Conclusions/Significance Adjuvant chemotherapy with taxanes could reduce the risk of cancer recurrence and death in patients with early or operable breast cancer, although the drug-related toxicities should be balanced. Furthermore, we also demonstrated that patients with high risk, node-negative breast cancer also benefited from taxanes therapy, a result that was not observed in previous studies.

Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis

Background and aims Previous studies have reported inconsistent findings that proton pump inhibitors (PPIs) therapy might increase the risk of hip fracture. We investigated the association between PPIs therapy and hip fracture by a systematic review and meta-analysis. Methods We systematically searched PubMed, EMBASE, and the Cochrane Library. We included studies assessing the effects of PPIs on hip fracture. Data from the studies about odds ratio and 95% confidence interval were gathered and summarized. Results Seven studies met the inclusion criteria. PPIs therapy was associated with a statistically significant increase of hip fracture risk (pooled odds ratio=1.24; 95% confidence interval: 1.15–1.34; P<0.00001) under a random model. Meanwhile, we found that the effect of PPIs on hip fracture differs in different duration groups. Conclusion These results indicate that PPIs therapy might have the potential risk of hip fracture. Different effects on hip fracture in the subgroup analysis do not support a causal relationship between PPIs and hip fracture. Whether the risk exists warrants further investigation.

Adoptive Immunotherapy in Postoperative Hepatocellular Carcinoma: A Systemic Review

Purpose The effectiveness of immunotherapy for postoperative hepatocellular carcinoma patients is still controversial. To address this issue, we did a systemic review of the literatures and analyzed the data with emphasis on the recurrence and survival. Methods We searched six randomized controlled trials that included adoptive immunotherapy in the postoperative management of hepatocellular carcinoma and compared with non-immunotherapy postoperation. A meta-analysis was carried out to examine one- and 3-year recurrence and survival. Results The overall analysis revealed significantly reduced risk of 1-year recurrence in patients receiving adoptive immunotherapy (OR = 0.35; 95% CI, 0.17 to 0.71; p = 0.003), in that the risk of 3-year recurrence with a pooled OR estimated at 0.31 (95% CI 0.16 to 0.61; p = 0.001). However, no statistically significant difference was observed for 3-year survival between groups with adoptive immunotherapy and without adjuvant treatment (OR = 0.91; 95% CI, 0.45 to 1.84; P = 0.792). Conclusions Adjuvant immunotherapy with cytokine induced killer cells or lymphokine activated killer cells may reduce recurrence in postoperative hepatocellular carcinoma patients, but may not improve survival.

Adverse Drug Reactions of Spontaneous Reports in Shanghai Pediatric Population

Background Knowledge of drug safety in the pediatric population of China is limited. This study was designed to evaluate ADRs in children reported to the spontaneous reporting system (SRS) of Shanghai in 2009. Methodology and Principal Findings Crude ADR reports submitted to Shanghai SRS in 2009 for individuals aged from birth to 17 years (including 17 years) were included. Data were analyzed with respect to age, gender, category of ADR (System Organ Class [SOC]), the severity of reports and type of reporter. Results A male overrepresentation was observed regarding the total number of reports. The most frequently reported group of drugs were vaccines (42.15%). Skin rash and fever were the commonest symptoms reported in the total pediatric dataset. The proportion of children that suffered from a serious ADR was 2.16% and that for drug related deaths was 0.34%. And we found that the multiple drug exposure experienced a high proportion of serious ADRs compared with the single drug use (χ2 = 15.99, P<0.0001). Sixty-five percent of ADRs were for children less than 6 years of age. And more than half of reports were from doctors. Conclusions In our study, consumers were more likely to report new ADRs though they appear to contribute a relatively small percentage of total reports. We propose that patients would take an active role in reporting ADRs. More researches are needed in order to achieve better understanding the characteristics of ADRs in pediatric population of China.

Effects of three injectable antidiabetic agents on glycaemic control, weight change and drop-out in type 2 diabetes suboptimally controlled with metformin and/or a sulfonylurea: A network meta-analysis

AIMS The objective of this review was to assess glucagon-like peptide-1 receptor agonists (GLP-1 RAs), basal insulin, and premixed insulin among participants with type 2 diabetes inadequately controlled with metformin and/or a sulfonylurea. METHODS We searched PubMed, EmBase, and the Cochrane Library to identify eligible randomized controlled trials (RCTs) for a network meta-analysis. RESULTS A total of 17 RCTs involving 5874 adult individuals were included. Compared with placebo, all three therapies showed a significant effect on achieving target glycated hemoglobin (HbA1c) (GLP-1 RAs: 31.7%, 95% CI, 24.7-38.6%; premixed insulin: 31.1%, 95% CI, 20.4-41.8%; basal insulin: 26.0%, 95% CI, 16.4-35.7%). However, there was no significant difference between the three therapies. A similar result was found in HbA1c reduction. The use of GLP-1 RAs resulted in significant body weight loss (-3.73 kg, 95% CI, -4.52 to -2.95 kg vs. basal insulin and -5.27 kg, 95% CI, -6.17 to -4.36 kg vs. premixed insulin) but there was a higher drop-out rate of participants. Premixed insulin seemed associated with more severe hypoglycemic episodes. CONCLUSIONS The three injectables had similar impact on glycemic control but other differentiating features relevant to the management of type 2 diabetes with GLP-1 RAs having the most favorable profile.

Pemetrexed plus platinum or gemcitabine plus platinum for advanced non-small cell lung cancer: final survival analysis from a multicentre randomized phase II trial in the East Asia region and a meta-analysis

Background and Objective:  Pemetrexed plus platinum has shown efficacy as a first‐line treatment for advanced non–small cell lung cancer (NSCLC), but little is known about its efficacy and safety in East Asian patients. We report the final analysis of overall survival (OS) from a multicentre, randomized, phase II trial in chemotherapy‐naive Chinese patients with advanced NSCLC. An additional meta‐analysis was performed to systematically evaluate pemetrexed/platinum as first‐line treatment for advanced NSCLC.

Combined EGFR and VEGFR versus Single EGFR Signaling Pathways Inhibition Therapy for NSCLC: A Systematic Review and Meta-Analysis

Background Lung cancer is a heterogeneous disease with multiple signaling pathways influencing tumor cell survival and proliferation, and it is likely that blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Whether combined inhibition therapy has greater anti-tumor activity than single inhibition therapy is a matter of debate. Hence, a meta-analysis comparing therapy inhibiting both VEGFR and EGFR signaling pathways with that inhibiting EGFR signaling pathway alone was performed. Methodology and Principal Findings We searched PubMed, EMBASE database and the proceedings of major conferences for relevant clinical trials. Outcomes analyzed were objective tumor response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Besides, subgroup analyses were performed to investigate whether the combined inhibition therapy is best performed using combination of selective agents or a single agent with multiple targets. Six trials recruiting 3,302 patients were included in the analysis. Combined inhibition therapy was associated with a 3% improvement in OS as compared with single-targeted therapy, but this difference was not statistically significant (HR, 0.97; 95% CI, 0.89–1.05; P = 0.472). Patients receiving combined inhibition therapy had significant longer PFS than the group with single-targeted therapy (HR, 0.80; 95% CI, 0.67–0.95; P = 0.011). There was no difference in the ORR between the groups (OR, 1.44; 95% CI, 0.95–2.18; P = 0.085). Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS. Toxicity was greater in combined inhibition therapy. Conclusions There is no evidence to support the use of combined inhibition therapy in unselected patients with advanced NSCLC. However, given the significant advantage in ORR and PFS, combined inhibition therapy using combination regimens may be considered for further evaluation in subsets of patients who may benefit from this treatment.

Risk of treatment-related mortality with sorafenib in patients with cancer.

BACKGROUND Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. METHODS Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. RESULTS 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). CONCLUSIONS It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry

Objective Phase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data. Methods A data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation. Results A total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment <300 with 96.5% <3000. Among these trials, 8.2% were terminated or withdrawn. Factors associated with the use of blinding and randomisation included the intervention model, clinical specialty and lead sponsor. Conclusions Phase IV trials evaluating drug safety in the ClinicalTrials.gov registry were dominated by small trials that might not have sufficient power to detect less common adverse events. An adequate sample size should be emphasised for phase IV trials with safety surveillance as main task.