Discussion
GC is one of the most common malignant tumors of the digestive tract worldwide. With the development of therapeutic strategies, the survival time of GC patients has significantly increased over the past 20 years. However, the prospects for the treatment of GC are not optimistic. Chemotherapy is currently the main treatment for advanced GC; however, there is no standard first-line chemotherapy regimen for advanced GC. Moreover, traditional chemotherapy has reached an efficacy plateau. Therefore, it is necessary to identify a more effective treatment for advanced GC.
In the last 10 years, the rapid development of molecular biology has provided new directions for the treatment of GC. Many studies on immunotherapy and anti-angiogenic therapy are underway [
28]. For example, the results of KEYNOTE-012 and KEYNOTE-028 indicated that pembrolizumab, a type of anti-PD-1 antibody, may be a promising agent in pretreated and PD-L1-positive advanced GC. However, there is still a long way to go before patients can benefit from this treatment. Among the novel target treatment strategies, the most widely studied, the most extensive, and the most in-depth is the study of angiogenesis. The angiogenic pathway modulated by the VEGF family has been extensively studied in many tumors [
29]. Angiogenesis contributes to the progression, invasion, and metastasis of malignancy and the importance of anti-angiogenesis therapy in inhibiting malignant tumor growth has been confirmed. Targeting the VEGF pathway in GC started to receive more attention when the results from phase III trials confirmed its efficacy in inducing superior survival outcome beyond standard therapy [
9,
10,
13]. Ramucirumab, a monoclonal antibody, can selectively bind to VEGFR-2 and block the downstream effects of the VEGF pathway in angiogenesis. The REGARD [
9] and RAINBOW [
10] studies reported that advanced GC patients may benefit from treatment with ramucirumab (HR
OS 0.776, 95 % CI 0.603–0.998,
P = 0.047, HR
OS 0.807, 95 % CI 0.678–0.962,
P < 0.0001, respectively, and HR
PFS 0.483, 95 % CI 0.376–0.620,
P < 0.0001, HR
PFS 0.635, 95 % CI 0.536–0.752,
P < 0.0001, respectively). The survival benefits in the REGARD and RAINBOW studies led to the approval of ramucirumab by the FDA for the treatment of advanced GC. Apatinib, a small molecule oral TKI, can inhibit the intracellular function of VEGFR by blocking the receptors of tyrosine kinases expressed by endothelial cells. A phase II [
11] and phase III [
13] trial explored the effects of apatinib in patients with advanced GC and the results showed that the patients benefited from apatinib treatment. Bevacizumab, a monoclonal antibody, can bind VEGF-A ligand, thus inhibiting VEGF-mediated angiogenesis. The results of the AVAGAST [
25] study showed that bevacizumab can improve ORR (HR 8.61, 95 % CI 0.6–16.6,
P = 0.0315) and prolong PFS (HR, 0.80; 95 % CI 0.68–0.93,
P = 0.0037), but there was no significant difference in OS (HR 0.87, 95 % CI 0.73–1.03,
P = 0.1002) when compared with the placebo. In addition, the outcomes of the AVATAR [
26] study were similar to those of the AVAGAST study.
Fontana et al. [
30] summarized the clinical efficacy of bevacizumab and ramucirumab in advanced GC and discussed the results of clinical trials but paid little attention on other angiogenic inhibitors, such as apatinib and sunitinib. Aprile et al. [
31] mainly focused on the current status of novel angiogenesis inhibitors in advanced GC, the underlying biology, their mechanism of action, and recent clinical trial results. They suggested that VEGFR-2 plays a key role in GC, and VEGFR-2 blockade may be associated with improved outcomes. Future efforts in translational research should aim to clarify which patients may benefit from the anti-angiogenic therapy. The aforementioned reviews extensively describe the major clinical results of the angiogenic inhibitors, their efficiency and disadvantages in advanced GC. However, they are all narrative reviews and may lead to a number of methodological flaws without a clear and objective methods section. Furthermore, there is still controversy regarding the effects of angiogenesis inhibitors on advanced GC. Hence, we performed this updated meta-analysis to provide valuable clues for the clinical application of angiogenesis inhibitors.
According to the current results, regimens containing angiogenesis inhibitors showed substantial improvements in OS (HR 0.80, 95 % CI 0.69–0.93,
P = 0.004, Fig.
3a), PFS (HR 0.66, 95 % CI 0.51–0.86,
P = 0.002, Fig.
3b), ORR (HR 1.34, 95 % CI 1.09–1.65,
P = 0.005, Fig.
6b), and DCR (HR 1.37, 95 % CI 1.17–1.11,
P = 0.0001, Fig.
6a) compared with regimens without angiogenesis inhibitors. Subgroup analyses showed that OS was significantly improved following treatment with angiogenesis inhibitor monotherapy (HR 0.61, 95 % CI 0.42–0.89,
P = 0.01, Fig.
4a) or combined with chemotherapy (HR 0.88, 95 % CI 0.79–0.97,
P = 0.01, Fig.
4b) when compared with placebo and chemotherapy alone. However, angiogenesis inhibitor monotherapy was unable to prolong PFS (HR 0.86, 95 % CI 0.71–1.03,
P = 0.1, Fig.
5a) in patients with advanced GC. The reason may be the anti-VEGF-based drugs combined with chemotherapy can prolong PFS (HR 0.82, 95 % CI 0.71–0.93,
P = 0.003), while anti-VEGFR-2 and multiple tyrosine kinase receptor inhibitors combined with chemotherapy failed to improve PFS (HR 0.92, 95 % CI 0.65–1.03,
P = 0.63). With regard to the line of treatment, the efficacy of angiogenesis inhibitor therapy may be different in the first-line and ≥ the second-line setting. Significant PFS (HR 0.50, 95 % CI 0.34–0.73,
P = 0.0004, Fig.
5d), OS (HR 0.71, 95 % CI 0.58–0.88,
P = 0.002, Fig.
4d), ORR (RR 1.75, 95 % CI 1.36–2.25,
P < 0.0001, Fig.
8d), and DCR (RR 1.81, 95 % CI 1.27–2.58,
P = 0.001, Fig.
7d) benefits were observed in ≥ the second-line setting. However, there were ORR (RR 1.16, 95 % CI 1.00–1.33,
P = 0.04, Fig.
8c) and DCR (RR 1.13, 95 % CI 1.02–1.26,
P = 0.02, Fig.
7c) gains, but no OS (HR 0.92, 95 % CI 0.80–1.06,
P = 0.23, Fig.
4c) and PFS (HR 0.87, 95 % CI 0.75–1.01,
P = 0.08, Fig.
5c) benefits in the first-line setting. This may be due to the results of the most RCTs showed no significant survival benefits regarding OS and PFS, which included in this meta-analysis. With respect to the anti-angiogenic drug class, subgroup analysis showed that anti-VEGFR-2 and multiple tyrosine kinase receptor inhibitor treatment was more efficacious than anti-VEGF treatment in terms of OS, PFS, ORR, and DCR. One possible explanation is the differences in the targets of the angiogenesis inhibitors. Anti-VEGFR-2 and multiple tyrosine kinase receptor inhibitor drugs selectively bind to VEGFR-2, which plays a key role in the VEGF/VEGFR pathway. Anti-VEGF drugs only bind to VEGF-A and thus cannot block other members of the VEGF family binding to VEGFR-2. Another possible reason is related to the two clinical trials included in the anti-VEGF subgroup, which included patients treated with bevacizumab who had negative survival outcomes. Ramucirumab and apatinib were included in the VEGFR-2 and multiple tyrosine kinase receptor inhibitor group. The mechanistic advantage of ramucirumab, which binds to VEGFR-2 and has a long half-life, may be better than bevacizumab. In addition, the recent phase III study of apatinib [
13], an oral small molecule VEGFR-2 TKI, in Chinese patients with advanced GC, demonstrated prolonged median OS in the apatinib arm of 195 versus 140 days in the placebo arm (HR 0.71, 95 % CI 0.54–0.94,
P < 0.0001). The reason for these differences is a current challenge, and further studies may elucidate the pharmacological differences and possibly improve clinical outcome.
As the incidence of GC is region-specific, and treatment approaches are different between eastern and western countries, we divided the patients into two subgroups: the Asian group and the non-Asian group. The results show that angiogenesis inhibitors increased PFS in both Asian patients (HR 0.62, 95 % CI 0.42–0.93,
P = 0.02, Additional file
2: Figure S1C) and non- Asian patients (HR 0.61, 95 % CI 0.53–0.69,
P < 0.00001, Additional file
2: Figure S1D) but only improved OS in non-Asian patients (HR 0.82, 95 % CI 0.70–0.95,
P < 0.007, Additional file
2: Figure S1B). Given that angiogenesis is a host mechanism, the observed differences between Asian patients and non-Asian patients may be attributed to the inherent differences in these ethnic populations. This should be confirmed in future clinical trials by focusing on the influence of racial/ethnic factors.
Another focus in the treatment of GC patients is safety and tolerability. Angiogenesis inhibitors have more adverse reactions, such as hemorrhage, hypertension, and proteinuria, and most are predictable and manageable [
12]. However, hand-foot syndrome (RR 2.83, 95 % CI 1.57–5.11,
P = 0.0005), diarrhea (RR 1.66, 95 % CI 1.11–2.50,
P = 0.01), and GI perforation (RR 4.10, 95 % CI 1.14–15.05,
P = 0.03) were significantly increased in patients treated with angiogenesis inhibitors. VEGF is also a vital factor in angiogenesis in normal tissues. Consequently, anti-angiogenic agents can destroy the network of capillaries in healthy tissues, and this is the major reason underlying the adverse reactions of these drugs. In this meta-analysis, the safety of angiogenesis inhibitors was similar to previous results for non-small cell lung carcinoma. Gastrointestinal perforation and diarrhea are due to damage to the blood flow in normal tissues by angiogenesis inhibitors and lead to intestinal ischemia and necrosis, resulting in GI perforation and diarrhea. Hand-foot syndrome, a type of skin toxicity, is a known adverse reaction of angiogenesis inhibitors, although the mechanism of this reaction is unknown, it may be associated with the effects of angiogenesis inhibitors on endothelial cells, resulting in vascular bed degradation. The hands and feet are rich in capillaries and capillary degradation is likely to lead to abnormal sensation and changes in the skin.
Although the toxicity profiles of biologics (bevacizumab, ramucirumab) and small molecule TKIs (afatinib, sunitinib, and TSU-68) overlap but are not the same, we conducted a subgroup analysis. This analysis showed that the biologics are more likely to lead to hypertension (RR 5.87, 95 % CI 3.34–10.34,
P < 0.0001, Additional file
3: Table S4), neutropenia (RR 1.56, 95 % CI 1.27–1.93,
P < 0.0001, Additional file
3: Table S4), diarrhea (RR 1.83, 95 % CI 1.14–2.94,
P = 0.01, Additional file
3: Table S4), and gastrointestinal perforation (RR 4.14, 95 % CI 1.14–10.09,
P = 0.03, Additional file
3: Table S4), while small molecule TKIs are more likely to lead to hand-foot syndrome (RR 7.70, 95 % CI 1.83–32.39,
P = 0.005, Additional file
4: Table S3) and thrombocytopenia (RR 0.68, 95 % CI 0.46–1.00,
P = 0.04, Additional file
4: Table S3).
Although angiogenesis inhibitors can improve OS and PFS and achieve a better response rate in advanced GC, the clinical effect is quite different in individuals due to heterogeneity of the tumor. It is unclear which patients benefit most from angiogenesis inhibitors. In an effort to limit the toxicity and cost of therapy, a large number of basic and clinical studies need to be conducted, in order to identify biomarkers which can be used to predict efficacy and choose the most suitable patients to reduce the blindness of clinical medication.
There are many limitations in this meta-analysis. Firstly, a small number of trials were included, and there were no subgroups related to tumor pathological staging or pathological types. Moreover, the subgroup analysis included in the literature was limited to one type of angiogenesis inhibitor, and the conclusions were limited. Secondly, the differences between statistical quality, follow-up period, courses, and race in patients receiving angiogenesis inhibitors resulted in heterogeneity. Thirdly, the angiogenesis inhibitors included mainly targeted VEGF and its receptor family, thus the conclusions do not cover all types of angiogenesis inhibitors. Finally, this is a trial-level meta-analysis based on studies and not on individual patient data. Confounding variables such as patient co-morbidities, extent of disease, and differences in other possible prognostic factors could not be incorporated into this analysis. Therefore, future research should focus on high-quality studies and clinical features in patients with comprehensive evaluation, thus resulting in more standardized research and more accurate conclusions.