Research progress of vascular endothelial growth factor in esophageal cancer_West China Medical Journal

Authors：

YANG Lulu , KANG Xiaohong ,  MIAO Zhanhui

Department of Oncology, the First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P. R. China;

Corresponding author：

MIAO Zhanhui, Email: miaozhanhui@sina.com

Keywords：

Esophageal cancer; Vascular endothelial growth factor; Vascular endothelial growth factor inhibitors; Research progress

DOI：

10.7507/1002-0179.202011038

Video：

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Esophageal cancer is one of the common malignant tumors with high incidence and poor prognosis. Angiogenesis-related pathways play an important role in the occurrence and development of esophageal cancer. Vascular endothelial growth factor (VEGF) is the main mediator of angiogenesis. In addition to promoting angiogenesis and maintaining the survival of neovascularization, VEGF can also directly act on esophageal cancer cells and promote the occurrence and development of tumors. This article reviews the biology of VEGF and its effect on blood vessels, the expression of VEGF in esophageal cancer cells and its influencing factors, the role of VEGF in esophageal cancer cells, the immunomodulatory activity of VEGF and the clinical study of VEGF inhibitors. The purpose of this study is to provide a basis for more rational use of VEGF inhibitors in the treatment of esophageal cancer.

Citation： YANG Lulu, KANG Xiaohong, MIAO Zhanhui. Research progress of vascular endothelial growth factor in esophageal cancer. West China Medical Journal, 2021, 36(10): 1434-1438. doi: 10.7507/1002-0179.202011038 Copy

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2.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3.	Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6): 1248-1264.
4.	Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci, 2020, 77(9): 1745-1770.
5.	Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin^®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev, 2020, 86: 102017.
6.	Hou X, Wei JC, Fu JH, et al. Vascular endothelial growth factor is a useful predictor of postoperative distant metastasis and survival prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol, 2015, 22(11): 3666-3673.
7.	Kashyap MK, Abdel-Rahman O. Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma. Mol Cancer, 2018, 17(1): 54.
8.	Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer, 2013, 13(12): 871-882.
9.	Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018, 59(2): 455-467.
10.	Sikarwar B, Singh VV, Sharma PK, et al. DNA-probe-target interaction based detection of Brucella melitensis by using surface plasmon resonance. Biosens Bioelectron, 2017, 87: 964-969.
11.	Shimizu A, Zankov DP, Kurokawa-Seo M, et al. Vascular endothelial growth factor-A exerts diverse cellular effects via small g proteins, rho and rap. Int J Mol Sci, 2018, 19(4): 1203.
12.	Frezzetti D, Gallo M, Maiello MR, et al. VEGF as a potential target in lung cancer. Expert Opin Ther Targets, 2017, 21(10): 959-966.
13.	Peng K, Bai Y, Zhu Q, et al. Targeting VEGF-neuropilin interactions: a promising antitumor strategy. Drug Discov Today, 2019, 24(2): 656-664.
14.	Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res, 2006, 12(17): 5018-5022.
15.	El Baba N, Farran M, Khalil EA, et al. The role of Rho GTPases in VEGF signaling in cancer cells. Anal Cell Pathol (Amst), 2020, 2020: 2097214.
16.	Siveen KS, Prabhu K, Krishnankutty R, et al. Vascular endothelial growth factor (VEGF) signaling in tumour vascularization: potential and challenges. Curr Vasc Pharmacol, 2017, 15(4): 339-351.
17.	Zhang L, Wang Y, Bai G, et al. The relationship between the expression of VEGF, EGFR, and HER-2 mRNA in esophageal squamous cell carcinoma (ESCC) and clinicopathological features of different ethnic groups in Xinjiang. Tumour Biol, 2015, 36(12): 9277-9283.
18.	Couvelard A, Paraf F, Gratio V, et al. Angiogenesis in the neoplastic sequence of Barrett’s oesophagus. Correlation with VEGF expression. J Pathol, 2000, 192(1): 14-18.
19.	di Somma M, Vliora M, Grillo E, et al. Role of VEGFs in metabolic disorders. Angiogenesis, 2020, 23(2): 119-130.
20.	Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab, 2018, 27(2): 281-298.
21.	Saman H, Raza SS, Uddin S, et al. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel), 2020, 12(5): 1172.
22.	Hong G, Kuek V, Shi J, et al. EGFL7: master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis. J Cell Physiol, 2018, 233(11): 8526-8537.
23.	Kong R, Ma Y, Feng J, et al. The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A. Cell Mol Biol Lett, 2016, 21: 3.
24.	Gao P, Wang D, Liu M, et al. DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways. PLoS Genet, 2020, 16(4): e1008592.
25.	Li B, Xu WW, Han L, et al. MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF. Oncogene, 2017, 36(28): 3986-4000.
26.	Shinkaruk S, Bayle M, Laïn G, et al. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anticancer Agents, 2003, 3(2): 95-117.
27.	Eng L, Azad AK, Qiu X, et al. Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome. Carcinogenesis, 2015, 36(9): 956-962.
28.	Ladeira K, Macedo F, Longatto-Filho A, et al. Angiogenic factors: role in esophageal cancer, a brief review. Esophagus, 2018, 15(2): 53-58.
29.	Alattar M, Omo A, Elsharawy M, et al. Neuropilin-1 expression in squamous cell carcinoma of the oesophagus. Eur J Cardiothorac Surg, 2014, 45(3): 514-520.
30.	Tian S, Quan H, Xie C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci, 2011, 102(7): 1374-1380.
31.	Xu WW, Li B, Lam AK, et al. Targeting VEGFR1- and VEGFR2-expressing non-tumor cells is essential for esophageal cancer therapy. Oncotarget, 2015, 6(3): 1790-1805.
32.	Jiang YY, Shang L, Shi ZZ, et al. Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma. Oncogene, 2016, 35(37): 4846-4856.
33.	Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
34.	Li J, Xie Y, Wang X, et al. Overexpression of VEGF-C and MMP-9 predicts poor prognosis in Kazakh patients with esophageal squamous cell carcinoma. PeerJ, 2019, 7: e8182.
35.	Bouzin C, Brouet A, De Vriese J, et al. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J Immunol, 2007, 178(3): 1505-1511.
36.	Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol, 2018, 52(Pt 2): 117-124.
37.	Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J Exp Med, 2015, 212(2): 139-148.
38.	Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res, 2019, 25(18): 5449-5457.
39.	Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol, 2016, 37(7): 462-476.
40.	Hoff S, S Grünewald, Rse L, et al. Immunomodulation by regorafenib alone and in combination with anti PD1 antibody on murine models of colorectal cancer. Ann Oncol, 2017, 28(suppl 5): 423.
41.	Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med, 2017, 9(385): eaak9679.
42.	Zhang B, Qi L, Wang X, et al. Phase 2 study of camre-lizumab(anti-PD-1 antibody) combined with apatinib and chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma. J Clin Oncol, 2019, 37(Suppl 15): 4033.
43.	Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol, 2020, 38(11): 1154-1163.
44.	Falcon BL, Chintharlapalli S, Uhlik MT, et al. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacol Ther, 2016, 164: 204-225.
45.	Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 2004, 350(23): 2335-2342.
46.	Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol, 2011, 29(30): 3968-3976.
47.	Shen L, Li J, Xu J, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer, 2015, 18(1): 168-176.
48.	Cunningham D, Stenning SP, Smyth EC, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol, 2017, 18(3): 357-370.
49.	Aprile G, Ongaro E, Del Re M, et al. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: a critical insight. Crit Rev Oncol Hematol, 2015, 95(2): 165-178.
50.	Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet, 2014, 383(9911): 31-39.
51.	Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol, 2014, 15(11): 1224-1235.
52.	Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol, 2016, 34(13): 1448-1454.
53.	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)食管癌诊疗指南2020. 北京: 人民卫生出版社, 2020.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6): 1248-1264.
4. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci, 2020, 77(9): 1745-1770.
5. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin^®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev, 2020, 86: 102017.
6. Hou X, Wei JC, Fu JH, et al. Vascular endothelial growth factor is a useful predictor of postoperative distant metastasis and survival prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol, 2015, 22(11): 3666-3673.
7. Kashyap MK, Abdel-Rahman O. Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma. Mol Cancer, 2018, 17(1): 54.
8. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer, 2013, 13(12): 871-882.
9. Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018, 59(2): 455-467.
10. Sikarwar B, Singh VV, Sharma PK, et al. DNA-probe-target interaction based detection of Brucella melitensis by using surface plasmon resonance. Biosens Bioelectron, 2017, 87: 964-969.
11. Shimizu A, Zankov DP, Kurokawa-Seo M, et al. Vascular endothelial growth factor-A exerts diverse cellular effects via small g proteins, rho and rap. Int J Mol Sci, 2018, 19(4): 1203.
12. Frezzetti D, Gallo M, Maiello MR, et al. VEGF as a potential target in lung cancer. Expert Opin Ther Targets, 2017, 21(10): 959-966.
13. Peng K, Bai Y, Zhu Q, et al. Targeting VEGF-neuropilin interactions: a promising antitumor strategy. Drug Discov Today, 2019, 24(2): 656-664.
14. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res, 2006, 12(17): 5018-5022.
15. El Baba N, Farran M, Khalil EA, et al. The role of Rho GTPases in VEGF signaling in cancer cells. Anal Cell Pathol (Amst), 2020, 2020: 2097214.
16. Siveen KS, Prabhu K, Krishnankutty R, et al. Vascular endothelial growth factor (VEGF) signaling in tumour vascularization: potential and challenges. Curr Vasc Pharmacol, 2017, 15(4): 339-351.
17. Zhang L, Wang Y, Bai G, et al. The relationship between the expression of VEGF, EGFR, and HER-2 mRNA in esophageal squamous cell carcinoma (ESCC) and clinicopathological features of different ethnic groups in Xinjiang. Tumour Biol, 2015, 36(12): 9277-9283.
18. Couvelard A, Paraf F, Gratio V, et al. Angiogenesis in the neoplastic sequence of Barrett’s oesophagus. Correlation with VEGF expression. J Pathol, 2000, 192(1): 14-18.
19. di Somma M, Vliora M, Grillo E, et al. Role of VEGFs in metabolic disorders. Angiogenesis, 2020, 23(2): 119-130.
20. Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab, 2018, 27(2): 281-298.
21. Saman H, Raza SS, Uddin S, et al. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel), 2020, 12(5): 1172.
22. Hong G, Kuek V, Shi J, et al. EGFL7: master regulator of cancer pathogenesis, angiogenesis and an emerging mediator of bone homeostasis. J Cell Physiol, 2018, 233(11): 8526-8537.
23. Kong R, Ma Y, Feng J, et al. The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A. Cell Mol Biol Lett, 2016, 21: 3.
24. Gao P, Wang D, Liu M, et al. DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways. PLoS Genet, 2020, 16(4): e1008592.
25. Li B, Xu WW, Han L, et al. MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF. Oncogene, 2017, 36(28): 3986-4000.
26. Shinkaruk S, Bayle M, Laïn G, et al. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anticancer Agents, 2003, 3(2): 95-117.
27. Eng L, Azad AK, Qiu X, et al. Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome. Carcinogenesis, 2015, 36(9): 956-962.
28. Ladeira K, Macedo F, Longatto-Filho A, et al. Angiogenic factors: role in esophageal cancer, a brief review. Esophagus, 2018, 15(2): 53-58.
29. Alattar M, Omo A, Elsharawy M, et al. Neuropilin-1 expression in squamous cell carcinoma of the oesophagus. Eur J Cardiothorac Surg, 2014, 45(3): 514-520.
30. Tian S, Quan H, Xie C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci, 2011, 102(7): 1374-1380.
31. Xu WW, Li B, Lam AK, et al. Targeting VEGFR1- and VEGFR2-expressing non-tumor cells is essential for esophageal cancer therapy. Oncotarget, 2015, 6(3): 1790-1805.
32. Jiang YY, Shang L, Shi ZZ, et al. Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma. Oncogene, 2016, 35(37): 4846-4856.
33. Shih CH, Ozawa S, Ando N, et al. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2000, 6(3): 1161-1168.
34. Li J, Xie Y, Wang X, et al. Overexpression of VEGF-C and MMP-9 predicts poor prognosis in Kazakh patients with esophageal squamous cell carcinoma. PeerJ, 2019, 7: e8182.
35. Bouzin C, Brouet A, De Vriese J, et al. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J Immunol, 2007, 178(3): 1505-1511.
36. Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol, 2018, 52(Pt 2): 117-124.
37. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J Exp Med, 2015, 212(2): 139-148.
38. Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res, 2019, 25(18): 5449-5457.
39. Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol, 2016, 37(7): 462-476.
40. Hoff S, S Grünewald, Rse L, et al. Immunomodulation by regorafenib alone and in combination with anti PD1 antibody on murine models of colorectal cancer. Ann Oncol, 2017, 28(suppl 5): 423.
41. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med, 2017, 9(385): eaak9679.
42. Zhang B, Qi L, Wang X, et al. Phase 2 study of camre-lizumab(anti-PD-1 antibody) combined with apatinib and chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma. J Clin Oncol, 2019, 37(Suppl 15): 4033.
43. Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol, 2020, 38(11): 1154-1163.
44. Falcon BL, Chintharlapalli S, Uhlik MT, et al. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacol Ther, 2016, 164: 204-225.
45. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 2004, 350(23): 2335-2342.
46. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol, 2011, 29(30): 3968-3976.
47. Shen L, Li J, Xu J, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer, 2015, 18(1): 168-176.
48. Cunningham D, Stenning SP, Smyth EC, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol, 2017, 18(3): 357-370.
49. Aprile G, Ongaro E, Del Re M, et al. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: a critical insight. Crit Rev Oncol Hematol, 2015, 95(2): 165-178.
50. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet, 2014, 383(9911): 31-39.
51. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol, 2014, 15(11): 1224-1235.
52. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol, 2016, 34(13): 1448-1454.
53. 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)食管癌诊疗指南2020. 北京: 人民卫生出版社, 2020.

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