| Objective: Lung cancer is the leading cause of cancer-related mortality worldwidely, and there is an upward trend in the mortality. Approximately 85% of patients with lung cancer have non-small-cell lung cancer. Platinum-based doublet is the backbone of the first-line treatment for advanced NSCLC but it is circumscribed in therapeutic effect. Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs) are another first-line treatment of advanced NSCLC, however, benefit of EGFR-TKIs are limited to patients with EGFR activating mutation. So the antiangiogenic agents are more and more be taken seriously. The effect of antiangiogenic agents combine with chemotherapy treatment of advanced NSCLC was approved and abundant of clinical researchs were carryed out. But if antiangiogenic agents combine with chemotherapy first-line or second-line treatment of advanced NSCLC is better than chemotherapy is not clear answer. This study investigated the overall and histology subtype specific result of antiangiogenic agents combine with chemotherapy versus chemotherapy for the first and second line treatment of advanced non small cell lung cancer. Our results could be used as basis to guide clinical therapy.Mothods: Randomized controlled trials(RCT) evaluating the efficacy of antiangiogenic agents combine with chemotherapy versus chemotherapy for the first and second line treatment of advanced non small cell lung cancer were obtained from electronic databases, namely, Pubmed, Embase, Cochrane Library, American Society of Clinical Oncology(ASCO), European Society for Medical Oncology(ESCO). We used the bias risk assessment standards of Cochrane Reviewer Handbook 5.2.0 to evaluate the quality of included studies. Basic information, interventions, the object of study, research methods and outcome indications such as effection, progression-free survival, overall survival and 3 or 4 degrees of adverse reaction was collected. Statistical analysis was performed and the forest plots were generated using Review Manager. Risk ratios(RR) and their 95% confidence intervals(CIs) were calculated for tumor response and side effect endpoints as dichotomous outcomes. Hazard ratios(HR) were summarized and their corresponding standard errors were computed to analyze the time-to-event data as generic inverse variance outcomes. Statistical heterogeneity between studies was assessed by the means of the Cochrane’s Chi2 statistic, and the extent of inconsistency with I2 statistic. When we perform statistical analysis and forest plot, to antiangiogenic agents first-line treatment NSCLC, we part separately monoclonal anti-angiogenesis drugs group with multiple targers tyrosine kinase inhibitors group, non-squamous cancer group with squamous cancer group to analysis. Because there is only one research about monoclonal antiangiogenesis second-line treatment NSCLC, so in second-line treatment we did not part separately monoclonal anti-angiogenesis drugs group with multiple targers tyrosine kinase inhibitors group, and we only analysis the total curative effect and curative effect non squamous carcinoma group and squamous carcinoma group.Results: In accordance with the retrieval strategy, there were 270 articals were retrievaled, by reading the title, abstract and full text, 19 randomized controlled clinical studies were collected. After evaluating quality of researches, in 19 studies, there are 4 studies are “A” levels, 12 studies are “B” levels, 3 studies are “C” levels. By using the fixed or random effects modle for efficient, OS, PFS and adverse reaction of meta-analysis, the results are as follows:(1) The meta-analysis results of antiangiogenic agents combine with chemotherapy first-line treatment of advanced NSCLC: Meta-analysis showed higher response rate in antiangiogenic agents combine with chemotherapy versus chemotherapy at monoclonal antibody group, multi-targets tyrosine kinase inhibitor group and nonsquamous non small cell lung cancer group(RR=1.81; 95%CI: 1.51-2.18),(RR=1.37; 95%CI: 1.13-1.67),(RR=1.60; 95%CI: 1.35-1.89). The two treatments were not significant difference in squamous non small cell lung cancer group(RR=0.71; 95%CI: 0.47-1.07).Similaly, antiangiogenic agents combine with chemotherapy versus chemotherapy at monoclonal antibody group, multi-targets tyrosine kinase inhibitor group and nonsquamous non small cell lung cancer group improvement in progression-free survival(HR=1.67; 95%CI: 0.61-0.73),(HR=0.85; 95%CI: 0.78-0.92),(HR=0.77; 95%CI: 0.72-0.82). The two treatments were not significant difference in squamous non small cell lung cancer group(HR=1.22; 95%CI: 0.90-1.67). Compared antiangiogenic agents combine with chemotherapy with the chemotherapy seem improvement in overall survival in monoclonal antibody group and nonsquamous non small cell lung cancer group(HR=0.88; 95%CI: 0.79-0.98),(HR=0.92; 95%CI: 0.86-0.99), but sensitivity analysis showed this results were not reliable. No significant difference was observed in multi-targets tyrosine kinase inhibitor group and squamous non small cell lung cancer group(HR=0.96; 95%CI: 0.88-1.05),(HR=1.77; 95%CI: 1.21-2.59).(2) The meta-analysis results of antiangiogenic agents combine with chemotherapy second-line treatment of advanced NSCLC: compared with the chemotherapy, antiangiogenic agents combine with chemotherapy showed a higher response rate(RR=1.90; 95%CI: 1.63-2.21). Antiangiogenic agents combine with chemotherapy groups versus chemotherapy at all patients group and nonsquamous non small cell lung cancer group improvement in progression-free survival(HR=0.79; 95%CI: 0.74-0.85),(HR=0.79; 95%CI: 0.69-0.91), but no significant difference was observed in squamous non small lung cancer group(HR=0.82; 95%CI: 0.66-1.03). Antiangiogenic agents combine with chemotherapy versus chemotherapy at nonsquamous non small cell lung cancer group improvement in overall survival(HR=0.84; 95%CI: 0.75-0.95), there were no significant difference in overall survival at squamous non small cell lung cancer group(HR=0.93; 95%CI: 0.78-1.12).(3) There were more adverse drug reactions such as neutropenia, thrombocytopenia, febrile neutropenia, hypertension, proteinuria, rash, fatigue, diarrhea, bleeding, hyponatremia, headach in antiangiogenic agents combine with chemotherapy than chemotherapy, but these adverse drug reactions did not affect survival time of patients.Conclusion: In patients with advanced NSCLC for first-line or second-line therapy, the antiangiogenesis drugs(monoclonal antiangiogenesis drugs and multi-targets tyrosine kinase inhibitor) combination chemotherapy is to improve the patient’s efficient and PFS. But antiangiogenesis drugs combination chemotherapy first-line or second-line treatment NSCLC seems no advantagement compared with chemotherapy. The survival benefit is more significant to patients with nonsquamous cell tumors. There were more adverse drug reactions in antiangiogenic agents combine with chemotherapy than chemotherapy, but these adverse drug reactions did not affect survival time of patients. |
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