Esophageal cancer is a more common malignant tumor in the world. Radical resection is feasible for patients with early esophageal cancer. Because the early symptoms are not typical, most patients only come to hospital when they have symptoms. Therefor, fewer patients are diagnosed at the early stageand and feasible surgery patients are less, only about 20%. For patients with esophageal cancer who can not be surgically resected, multidisciplinary comprehensive treatment should be adopted, in which the 5-year survival rate<10% for radiotherapy and 6.4% for chemotherapy-based systemic therapy.The 5-year survival rate of esophageal cancer is low, only 10% -25%.
The majority of patients with esophageal squamous cell carcinoma in China are moderately sensitive to chemotherapy. First-line chemotherapy regimen for esophageal cancer is mainly based on platinum or fluorouracil combination, and its effective rate can reach 40%-60%. After the failure of first-line chemotherapy, in the choice of second-line chemotherapy regimen,you can choose a single drug, such as yew drugs and irinotecan; dual-drug combinations can also be selected, such as docetaxel combined with platinum,docetaxel combined with fluorouracil, irinotecan combined with fluorouracil; or a three-drug combination regimen. However, these drugs have limited benefit in the treatment of late esophageal cancer after failure of first-line chemotherapy.
Molecular targeted therapy has the advantages of strong specificity and small side effects, and has become an effective method for the treatment of advanced esophageal cancer. The molecular basis of targeted therapy for advanced esophageal cancer mainly includes Epidermal Growth Factor Receptor(EGFR), Human Epidermalgrowth Factor Receptor-2(HER-2) and VEGF. Vascular endothelial growth factor and their receptors(VEGF/VEGFRs) are important cytokines in tumor angiogenesis, which can promote the proliferation of blood vessels as well as lymphatic endothelial cells to form new vessels and then promote the growth and metastasis of tumor cells. VEGF is a signal peptide structural glycoprotein that exerts biological effects by binding the KDR/FLt domain on VEGFR outside the membrane of endothelial cells and constitutes the tumor angiogenesis pathway, forming a series of signal transduction mechanisms, inducing the formation of blood vessels and lymphatic vessels, and promoting tumor growth. VEGF are expressed in most solid human tumors, mainly located in the cytoplasm and cell membrane of tumor cells, and are more concentrated in the marginal region of the tumor than in the central region . VEGFR1 mainly regulates the migration of monocytes and macrophages; VEGFR2 plays an important role in the occurrence and generation of blood vessels; VEGFR3 is mainly related to the formation of lymphatic vessels; VEGF expresses its activity by binding to VEGFR-2. Studies have shown that the overexpression rate of VEGF in esophageal squamous cell carcinoma was 24% -74%.
VEGFR-2 is mainly expressed in endothelial cells, and its expression is closely related to angiogenesis and cell mitosis. VEGFR-2 overexpression can not only promote angiogenesis ,but also promote cell mitosis. Therefore, VEGFR-2 expression plays a crucial role in neovascularization of tumors. When VEGF specifically binds to VEGFR-2, the VEGFR-2 is activated, which in turn occurs a series of signal transduction responses that promotes tumor cell growth,proliferation and migration. Apatinib is a novel oral small molecule antiangiogenic preparation that can highly selectively bind and inhibit vascular endothelial cell growth factor receptor-2. Apatinib can compete with VEGF to combine with VEGFR-2. The combination of apatinib and VEGFR-2 reduces and inhibits the combination of VEGF and VEGFR-2, thereby inhibits the autophosphorylation of VEGFR-2 and the growth of tumor cells and neovascularization .
NF-kB, as a multidirectional functional transcription factor, often exists as a heterodimer in many cells in the body and plays an important role in many diseases. Recently, it has been found that NF-KB is highly expressed in a variety of tumors and can induce-regulation of some anti-apoptotic genes and inhibit apoptosis. Paeeez confirmed that the existence of activated NF-KB pathways in esophageal squamous cell carcinoma cell lines, and activated NF-KB plays an important role in the survival and proliferation of esophageal squamous cell carcinoma cells. The results of this study showed that NF-KB was closely related to lymph node metastasis in esophageal cancer (P<0.05). Moreover, the MVD of the NF-KB positive group was significantly higher than that of the negative group, but there was no statistically significant difference in intratumoral MLVD between the two groups, indicating that NF-KB is involved in the development of esophageal cancer development and plays an important role in promoting angiogenesis and lymph node metastasis, may induce the production of tumor vessels and promote tumor metastasis by regulating VEGF and IL-8 expression related to angiogenesis. Immunohistochemistry and immunoblotting methods found that chromosome region maintenance 1(CRMl) is highly expressed in esophageal squamous cell carcinoma. CRMl gene silencing can cause apoptosis of squamous cell carcinoma.NF-KB is affected by CRMl genes during the development, invasion and metastasis of esophageal squamous cell carcinoma. The results of our experiment showed that the positive effective rate of NF-KB esophageal cancer was significantly higher than that of negative expression, suggesting that NF-KB could be a potential molecular target for the evaluation of the efficacy of apatinib targeted therapy.Existing studies have suggested that some drugs can exert effects by interfering with NF-KB,inhibit the development of malignant tumors and can be used in the treatment of esophageal cancer. Studies have found that for patients with advanced gastric cancer and adenocarcinoma of the esophagogastric junction with higher VEGFR-2 positive expression, oral apatinib can significantly prolong PFS and OS in patients. The results of this study found that VEGFR-2 positive expression in esophageal cancer benefited significantly, and the expression rate of VEGFR-2 in esophageal cancer with lymph node metastasis was significantly higher than that in patients without lymph node metastasis. The MVD of VEGFR-2 positive group was also significantly higher than that of negative group.However,in esophageal cancer VEGFR-2 positive and negative expression tissues,there was no significant difference in the MLVD count of the tumor center region, indicating that VEGFR-2 may promote lymph node metastasis by inducing lymphatic formation in the peripheral region rather than in the central region, and the specific mechanism needs to be further studied.
The main adverse reactions of apatinib in the treatment of malignant tumors include hypertension, proteinuria, hand and foot skin reaction and so on. The results of our study showed that the main adverse reactions were hypertension(60.87%); hand and foot syndrome(34.77%); proteinuria (36.96%). The degree of adverse reactions was mainly grade 1-2, and all patients could tolerate. Because the adverse reactions of apatinib drugs were dose-restrictive, all were relieved after active symptomatic treatment, and there did not appear serious adverse event.In the phase II/III clinical study of apatinib, it was found that the incidence of hypertension was 36.32%, the incidence of proteinuria was 44.36%, and the incidence of hand and foot skin reaction was 27.35%. Most patients have mild to moderate blood pressure elevation, which can be better controlled after taking antihypertensive drugs. Some patients with proteinuria usually present around 3 weeks after taking apatinib and are reversible, and usually does not require special treatment. The occurrence of hand and foot skin reaction is generally occur 2-3 weeks after taking apatinib,and symptomatic supportive treatment is available.
To date, apatinib has been studied in phase I/II/III trials and has shown positive results in a variety of tumors, such as gastric cancer, breast cancer, lung cancer, and esophageal cancer. Phase II clinical studies of these tumors suggest that apatinib can significantly prolong PFS in patients, and patients' ORR and DCR also increase to varying degrees[23-24], suggest that the application of apatinib in patients with multiple advanced malignancies who failed after standard regimen treatment can still achieve better results[25-26]. In 2017, a study reported the efficacy of apatinib in advanced esophageal squamous cell carcinoma. Among the 62 patients given 500mg/days, 15 patients had PR and 31 patients achieved SD, the disease control rate was 74.2%. The median of PFS and OS was 3.8 and 7.0 months,respectively. Compared with second-line chemotherapy,apatinib is more effective in advanced esophageal squamous cell carcinoma. The results of a phase II study at the 14th esophageal cancer conference showed that patients with metastatic esophageal squamous cell carcinoma after failure of first-line or multi-line chemotherapy, the objective remission rate and disease control rate after apatinib were 12% and 60%, respectively. The progression-free survival period and the overall survival period reached 3.2 and 5.3 months, respectively, consistent with the results of many previous studies. Another study showed that apatinib was safe and feasible for advanced esophageal squamous cell carcinoma with better survival benefit and lighter toxic response than traditional second-line chemotherapy, and was considered to be suitable for second-line or subsequent treatment of esophageal squamous cell carcinoma. In this experiment, the patient's partial response rate was 26.09%, the disease control rate was 67.39%, the median progression-free survival was 3.7 months and the median overall survival was 7.2 months. Univariate and multivariate analysis showed that the prognosis of patients was related to the degree of adverse reactions and ECOG scores after taking apatinib, and the results were consistent with other research reports,suggesting that apatinib is important for the maintenance treatment of advanced esophageal squamous cell carcinoma after radiotherapy and chemotherapy.