Tumor growth depends on the formation of neovascularization, which has been recognized by cancer biology.Glioma is highly vascular and rich in vascular endothelial growth factor(VEGF) that promotes angiogenesis.The angiogenesis mechanism of glioma may be as follow: tumor growth leads to hypoxia of tumor cells, which causes upregulation of related cytokines, including VEGF, vascular endothelial growth factor receptor (VEGFR), matrix metalloproteinases (MMPs) and hypoxia inducible factor (HIF), etc.These cytokines act on not only vascular endothelial cells but also extracellular matrix to accelerate neovascularization.In consequence, scholars have made a great deal of attempts in the anti-angiogenic treatment of malignant gliomas, and some studies have shown that bevacizumab(BEV) has certain effectiveness in the treatment of malignant gliomas.Therefore, BEV, as a humanized monoclonal antibody against VEGF, was approved for the treatment of recurrent GBM by the FDA on May 9, 2009. In 2014, Olivier L. Chinot et alreported a phase III clinical study. The results showed that compared with the radiotherapy-temozolomide plus placebo group, the PFS of the radiotherapy-temozolomide plus BEV group was longer (10.6 months vs. 6.2 months; 95% CI 0.55 to 0.74; P < 0.001). There was no significant difference in OS between the two groups (95% CI 0.76 to 1.02; P = 0.10). However, the occurrence of adverse events of BEV was higher than that of placebo. On the side, the expensive price also limits its clinical use to some extent.
Apatinib is a new type of small molecule anti-angiogenesis inhibitor that can highly selectively compete with the adenosine triphosphate (ATP) binding site of intracellular VEGFR-2 to inhibit the activation of VEGFR-2, thereby blocking downstream signal transduction to control tumor growth.It has been indicated that apatinib can directly promote the apoptosis of tumor cells by inhibiting the PI3K / Akt signaling pathway, up-regulating the expression of Bax and caspase-9 and down-regulating the expression of bcl-2.In addition, apatinib can reverse tumor multidrug resistance by inhibiting the function of various ATP-binding cassette transporter(ABC). This may suggest that the combination of apatinib and traditional chemotherapy drugs can achieve effective results and resist the emergence of multidrug resistance.Some studies have shown that apatinib can not only inhibit the proliferation and colony formation of glioma cells and the invasion of glioma cells by inducing apoptosis, but also promote the TMZ-mediated proliferation inhibition of glioma cells and improve the TMZ-mediated invasion inhibition of glioma cells, thus enhancing the role of TMZ in glioma cells.
Based on the anti-tumor activity of apatinib and the synergistic anti-tumor effect with TMZ in glioma cells, the following studies were carried out.Wang Yong et alreported a phase II clinical study of apatinib combined with dose-dense TMZ for recurrent glioblastoma.In this clinical study, the objective response rate (ORR) and disease control rate (DCR) were 45% (9 / 20) and 90% (18/20), mPFS was 6 months and mOS was 9 months. Another pilot clinical trial study of apatinib combined with irinotecan in the treatment of recurrent high-grade glioma and some other case reports also indicated that apatinib has a certain effect in recurrent glioma. It has also been reported that the combination of apatinib and TMZ in the treatment of brainstem glioma has achieved more than 8 months of PFS.
With the concept in mind,we designed such a scheme which combined apatinib with TMZ in concurrent chemoradiotherapy for malignant glioma to carry out exploratory research.
The results showed that compared with the control group, the treatment of malignant glioma in the apatinib group prolonged the PFS by 2.3 months (p > 0.05). Although the difference was not statistically significant, the results also showed that the apatinib group significantly improved the cerebral edema of the patients.
Most malignant glioma patients have obvious PTBE, which can cause or aggravate neurological dysfunction and intracranial hypertension,seriously affecting the patients' quality of life and improving the patients' mortality and disability rate.The increase of blood-brain barrier permeability is a key factor in the development of PTBE, and radiotherapy can also damage the vascular endothelium, destroy the blood-brain barrier and aggravate edema.Therefore, for postoperative adjuvant chemoradiotherapy of glioma patients, anti-edema treatment is particularly important.BEV has a certain anti-edema effect, but it also has a large side effect in clinical application.The more common serious side effects are as follows: gastrointestinal perforation; bleeding; arterial thromboembolism, high blood pressure and proteinuria.
The VEGF/VEGFR pathway is closely related to the development of PTBE, among which VEGFR2 mainly plays a role in monitoring the function of vascular endothelium.Compared with other TKI, apatinib shows a strong inhibitory effect on VEGFR2, effectively blocking VEGF / VEGFR2 signal transduction, then reducing vascular permeability and PTBE. Our results are also in accordance with that.