Efficacy and safety of angiogenesis inhibitors in advanced gastric cancer: a systematic review and meta-analysis

Abstract

Monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) directed against the vascular endothelial growth factor (VEGF) or its receptors have been investigated in several studies for the treatment of advanced gastric cancer (GC). In the present study, we aimed to evaluate the efficacy and safety of angiogenesis inhibitors in advanced GC. We searched published randomized controlled trials (RCTs) comparing angiogenesis inhibitors with non-angiogenesis inhibitors for the treatment of GC. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched. The extracted data on progression-free survival (PFS) and overall survival (OS) were measured in terms of hazard ratios (HR) and corresponding 95 % confidence intervals (CIs). In addition, risk ratios (RR) and corresponding 95 % CIs were pooled for objective response rate (ORR), disease control rate (DCR), and risk of adverse events (AEs). Ten RCTs involving 2786 patients were included. Compared with non-angiogenesis inhibitor-containing regimens, angiogenesis inhibitor-containing regimens resulted in a significant improvement in OS (HR 0.80, 95 % CI 0.69-0.93, P = 0.004), prolonged PFS (HR 0.66, 95 % CI 0.51-0.86, P = 0.002), and superior ORR (RR 1.34, 95 % CI 1.09-1.65, P = 0.005) and DCR (RR 1.37, 95 % CI 1.17-1.61, P = 0.0001). Angiogenesis inhibitors were associated with a greater number of AEs, but most of these were predictable and manageable. However, hand-foot syndrome, diarrhea, and gastrointestinal (GI) perforation were significantly increased in patients treated with angiogenesis inhibitors. In summary, angiogenesis inhibitor-containing regimens were superior to non-angiogenesis inhibitor-containing regimens in terms of OS, PFS, RR, and DCR in patients with advanced GC.

Keywords: Angiogenesis; Gastric cancer; Monoclonal antibodies; Tyrosine kinase inhibitors.

Fig. 1

Flow chart of search process

Fig. 2

Assessment of risk of bias. a Risk of bias summary. b Risk of bias graph

Fig. 3

Forest plot and pooled HR and 95 % CI for OS (a) and PFS (b): anti-angiogenesis therapy versus non-anti-angiogenesis therapy. The pooled HR for OS and PFS showed that the patients receiving anti-angiogenesis therapy possessed a significant improvement in OS and PFS. HR hazard ratios, OS overall survival, PFS progression-free survival, CI confidence intervals

Fig. 4

Forest plot and pooled HR and 95% CI for subgroup OS: anti-angiogenesis therapy versus non-anti-angiogenesis therapy. HR hazard ratios, CI confidence intervals, OS overall survival. (a: OS of subgroups of angiogenesis inhibitors alone threapy; b: OS of subgroups of angiogenesis inhibitors combined with chemotherapy threapy; c: OS of subgroups of the first line threapy; d: OS of subgroups of the second line threapy; e: OS of subgroups of anti-VEGF threapy; f: OS of subgroups of anti-VEGFR and multiple receptor inhibitors threapy)

Fig. 5

Forest plot and pooled HR and 95 % CI for subgroup PFS: anti-angiogenesis therapy versus non-anti-angiogenesis therapy. HR hazard ratios, CI confidence intervals, PFS progression-free survival. (a: PFS of subgroups of angiogenesis inhibitors alone threapy; b: PFS of subgroups of angiogenesis inhibitors combined with chemotherapy threapy; c: PFS of subgroups of the first line threapy; d: PFS of subgroups of the second line threapy; e: PFS of subgroups of anti-VEGF threapy; f: PFS of subgroups of anti-VEGFR and multiple receptor inhibitors threapy)

Fig. 6

Forest plot and pooled RR and 95 % CI for DCR (a) and ORR (b): anti-angiogenesis therapy versus non-anti-angiogenesis therapy. The pooled RR for DCR and ORR showed that the patients receiving anti-angiogenesis therapy had superior DCR and ORR. RR risk ratios, CI confidence intervals, ORR overall response rate, DCR disease control rate

Fig. 7

Forest plot and pooled RR and 95 % CI for subgroup DCR: anti-angiogenesis therapy versus non-anti-angiogenesis therapy. RR risk ratios, CI confidence intervals, DCR disease control rate. (a: DCR of subgroups of angiogenesis inhibitors alone threapy; b: DCR of subgroups of angiogenesis inhibitors combined with chemotherapy threapy; c: DCR of subgroups of the first line threapy; d: DCR of subgroups of the second line threapy; e: DCR of subgroups of anti-VEGF threapy; f: DCR of subgroups of anti-VEGFR and multiple receptor inhibitors threapy)

Fig. 8

Forest plot and pooled RR and 95 % CI for subgroup ORR: anti-angiogenesis therapy versus non-anti-angiogenesis therapy. RR risk ratios, CI confidence intervals, ORR overall response rate. (a: ORR of subgroups of angiogenesis inhibitors alone threapy; b: ORR of subgroups of angiogenesis inhibitors combined with chemotherapy threapy; c: ORR of subgroups of the first line threapy; d: ORR of subgroups of the second line threapy; e: ORR of subgroups of anti-VEGF threapy; f: ORR of subgroups of anti-VEGFR and multiple receptor inhibitors threapy)