Publication bias

Begg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures. Begg’s funnel plots did not reveal any evidence of obvious asymmetry for PFS (adenocarcinoma:P=0.46, SCC: P=0.13, and other histologies: P=0.80, respectively) and OS (adenocarcinoma:P=0.76, SCC: P=0.12, and other histologies: P=0.06). Then, Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not suggest any evidence of publication bias for PFS (adenocarcinoma: P=0.27, SCC: P=0.13, and other histologies: P=0.56, respectively) and OS (adenocarcinoma: P=0.94 and SCC: P=0.33 respectively), but not for OS in patients with other histologies (P=0.02). The difference in the results obtained from the two methods might be due to a greater statistical power of the regression methods.35

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NSCLC includes various histological types; SCC and adenocarcinoma are the most common. There are several differences in the clinical behavior of the histological types. Adenocarcinoma has a relatively higher possibility of developing distant metastases without local progression in NSCLC patients treated with definitive radiotherapy. A Japanese randomized Phase III trial of adjuvant chemotherapy with uracil-tegafur for completely resected pathological stage I NSCLC showed a survival benefit for patients with adenocarcinoma; however, there was no benefit for patients with SCC.36,37 Similarly, a Phase III trial in regionally advanced, unresectable NSCLC to test whether chemotherapy followed by radiotherapy resulted in survival superior to either hyperfractionated radiotherapy alone or standard radiotherapy alone revealed a survival benefit in patients with nonsquamous cell carcinoma, whereas no benefit was recognized in those with SCC. These data suggest that the histological subtype is a very important factor to establish the treatment strategy for NSCLC. We thus performed this meta-analysis according to histologies identify patients who will most likely benefit from AI-combining therapies.

To the best of our knowledge, this study is the first meta-analysis with a focus on investigating the impact of histological types on the efficacy of AIs in advanced NSCLC. This study includes 13 RCTs incorporating 10,035 patients. The pooled results confirm that AI-containing regimens significantly improve PFS and OS in patients with lung adenocarcinoma compared to non-AI-containing regimens. For patients with squamous cell lung carcinoma, the use of AIs significantly improves PFS, but not OS. Additionally, there is a tendency to improve OS and PFS in patients with other histologies receiving AI-containing regimens. Therefore, the current findings suggest that, in patients with lung adenocarcinoma, AI-containing regimens could be a preferable treatment option over standard chemotherapy alone, although this recommendation cannot be conclusive because the overall comparisons are not based on randomization. Furthermore, the efficacy of AIs in patients with other histological types still needs to be assessed due to limited patients included in this study.

Our analysis has some obvious limitations. First, all included studies are conducted at major academic institutions among patients with adequate major organ function; thus, the results may not entirely apply to the general patient population in the community or patients with organ dysfunction. Second, we included patients receiving different antiangiogenesis agents for analysis. While each of these molecules inhibits angiogenesis, these drugs have different potencies, and have inhibitory properties against a range of nonoverlapping targeted receptors. Given the limited sample size of patients treated with any single AI, we decide to include patients treated with all of these drugs in this class with adequate data on survival of patients with NSCLC according to histologies, which would increase the clinical heterogeneity among included trials. Third, the toxicity profile is another important factor for choosing treatment options. However, it is not possible to perform an analysis to deal with such a concern because reports of adverse events from each subgroup are not available. Finally, in the meta-analysis of published studies, publication bias is important because trials with positive results are more likely to be published and trials with null results tend not to be published. Our research detects no publication bias for OS, but not for PFS.