Purpose: We aimed at assessing the overall efficacy of angiogenesis inhibitor (AI)-containing regimens in the treatment of advanced non-small-cell lung cancer (NSCLC) according to histological types.
Methods: Studies from PubMed and Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to October 31, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating AIs in advanced NSCLC with survival data according to patients’ histologies. The endpoints were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies.
Results: A total of 10,035 patients with advanced NSCLC from 13 RCTs were identified for analysis. The pooled results demonstrated that AI-containing regimens significantly improved the PFS (HR, 0.84, 95% confidence interval (CI): 0.78–0.91, P<0.001) and OS (HR, 0.92, 95% CI: 0.85–0.99,P=0.017) in lung adenocarcinoma when compared to non-AI-containing regimens. Additionally, there was a significantly improved PFS (HR, 0.87, 95% CI: 0.77–0.98, P=0.027) for AI-containing regimens in squamous cell lung carcinoma, but it did not translated into OS benefit (HR, 1.02, 95% CI: 0.92–1.15, P=0.68). For NSCLC patients with other histological types, the use of AIs did not significantly improve PFS (HR, 0.90, 95% CI: 0.75–1.09, P=0.27) and OS (HR, 0.90, 95% CI: 0.76–1.08,P=0.19).
Conclusion: The findings of this study suggest that the addition of AIs to the treatment therapies for patients with lung adenocarcinoma offers improved survival benefits. Prospective clinical trials investigating the role of AIs in this setting are recommended.
Keywords: non-small-cell lung cancer, histological types, randomized controlled trials, angiogenesis inhibitors, meta-analysis


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Lung cancer is the leading cause of cancer-related mortality, with an estimated 1.4 million deaths each year.1 Non-small-cell lung cancer (NSCLC) accounts for 85% of the cases. Most of the NSCLC patients have advanced disease at diagnosis. For these patients, platinum-based doublet therapy is the standard of care.2 Regardless of the emergence of new cytotoxic agents, chemotherapy provides only marginal benefit in overall survival (OS). Clearly, novel therapeutic approaches to improve outcomes for patients with NSCLC are urgently needed.3

Angiogenesis, the process of new blood vessel formation, is critical for tumor progression, invasion, and metastasis in solid tumors.4–6 The vascular endothelial growth factor (VEGF) pathway has been the most well studied.7 Currently, bevacizumab is the only approved antiangiogenic agent for NSCLC patients when added to first-line carboplatin/paclitaxel chemotherapy.8–10 More recently, many new antiangiogenic agents targeting platelet-derived growth factor (PDGF) and fibroblast growth factor pathways are under clinical evaluation in NSCLC.11–17 In fact, a recent meta-analysis has demonstrated that the use of angiogenesis inhibitors (AIs) significantly improved OS and progression-free survival (PFS) in comparison with non-AI-containing therapies.18 However, NSCLC contains several different histological subtypes, and the biological behavior of each cell type appears to be different, which might affect the efficacy of AIs in different histological types. As a result, we performed this meta-analysis based on histologies to identify patients who will most likely benefit from AI-combining therapies.


Selection of studies

We searched PubMed (data from January 2000 to October 2014), Embase (data from January 2000 to October 2014), and the Cochrane Library electronic databases. The search criteria included only randomized controlled trials (RCTs) published in the English language, and the keywords “bevacizumab”, “avastin”, “aflibercept”, “VEGFR-TKIs”, “sorafenib”, “nexavar”, “sunitinib”, “sutent”, “SU1248”, “vandetanib”, “caprelsa”, “ZD6474”, “axitinib”, “pazopanib”, “votrient”, “GW786034”, “regorafenib”, “apatinib”, “ramucirumab”, “nintedanib”, “BIBF1120”, “thalidomide”, “lenalidomide”, “motesanib”, “angiogenesis inhibitors”, “randomized”, and “non-small-cell lung cancer”. We also searched abstracts and virtual meeting presentations from the American Society of Clinical Oncology (http://www.asco.org/ASCO) conferences that took place between January 2004 and June 2014. Each publication was reviewed and in case of duplicate publication only the most complete, recent, and updated report of the clinical trial was included in the meta-analysis.

Data extraction and clinical end point

Data extraction was conducted independently by two investigators according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (see checklist Table S1)19 and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: first author’s name, year of publication, trial phase, number of enrolled patients, treatment arms, age, primary end points, and median follow-up. Phase I trials and single-group Phase II trials were omitted from analysis because of lack of controls. Trials that met the following criteria were included in our analysis: 1) prospective RCTs comparing AI-containing regimen to AI-free regimens as any line treatments in advanced NSCLC; 2) trials involving patients who were pathologically confirmed to have NSCLC; and 3) trials having sufficient survival data according to histological types for extraction. If multiple publications of the same trial were retrieved or if there was a case mix between publications, only the most recent publication (and the most informative) was included. The quality of reports of clinical trials was assessed and calculated using the 5-item Jadad scale including randomization, double-blinding, and withdrawals as described previously.20