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Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 727-729

Angiogenesis and apatinib: Can be used for the patients with non-gastic cancer?

Department of Oncology, Shandong Provincial Hospital, Affiliated to Shandong University, Ji'nan, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Xin Ye
Department of Oncology, Shandong Provincial Hospital, Affiliated to Shandong University, Ji'nan 250014
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_222_18

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How to cite this article:
Ni Y, Ye X. Angiogenesis and apatinib: Can be used for the patients with non-gastic cancer?. J Can Res Ther 2018;14:727-9

How to cite this URL:
Ni Y, Ye X. Angiogenesis and apatinib: Can be used for the patients with non-gastic cancer?. J Can Res Ther [serial online] 2018 [cited 2020 May 25];14:727-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/727/235081

Angiogenesis contributes mainly to malignant tumor growth and metastasis. Since the 1970s, antiangiogenic treatment has been investigated and widely accepted as an effective anticancer strategy for multiple types of malignancies.[1],[2] Most of these therapies target vascular epidermal growth factor receptor (VEGFR) or its ligand VEGF. Of which, VEGFR-2 is identified as the predominant receptor involved in solid tumors angiogenesis.

Apatinib is one of the latest orally small-molecule tyrosine kinase inhibitors (TKI) which highly selectively binds to and strongly inhibits VEGFR-2), resulting in a decrease in VEGF-mediated endothelial cell migration, proliferation, and tumor microvascular density. Due to its encouraging results obtained in the preclinical and clinical settings,[3],[4] apatinib was approved and launched in People's Republic of China in 2014 as a subsequent-line treatment for patients with advanced gastric cancer. Furthermore, it is also being undergoing Phase II/III clinical trials in many other cancer types, such as breast cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), and colorectal cancer. Here, we summarized clinical data of apatinib for patients with non-gastric cancer.

 > Apatinib for Breast Cancer Top

Metastatic triple-negative breast cancer is particularly challenging because tumors lack recognized therapeutic targets. A two-part phase II trial by Hu et al. evaluated apatinib as a subsequent-line therapy in patients with metastatic triple-negative breast cancer (NCT01176669). In that study, overall response rate and clinical benefit rate were 10.7% and 25%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.3 (95% confidence interval (CI), 1.7–5.0) and 10.6 (95% CI, 5.6–15.7) months, respectively.[5] Grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%), and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand-foot syndrome, proteinuria, hypertension, and increased ALT. In another multicenter, open-label, single arm phase II study (NCT01653561), Hu et al. evaluated the clinical efficacy of apatinib in patients with nontriple-negative breast cancer, pretreated with anthracycline, taxanes, and capecitabine, and who failed in the metastatic setting at least one and at most four prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. A total of 38 patients were enrolled in the study and received apatinib for a median of four cycles (500 mg daily on days 1 through 28 of each 4 week cycle). Median PFS of all patients was 4.0 (95% CI, 2.8–5.2) while median OS was 10.3 (95% CI, 9.1–11.6) months. As the secondary endpoints, objective response rate (ORR) and disease control rate (DCR) reached up to 16.7% and 66.7%.[6] In a recent study, the efficacy and safety of apatinib was evaluated in metastatic breast cancer under nonclinical trial setting. The median PFS, OS, and TTF were 4.90 (95% CI, 3.44–6.36), 10.3 (unable to calculate 95% CI), and 3.93 (95% CI, 1.96–5.90) months, respectively. Interesting, previous treatment of bevacizumab did not affect the efficacy of apatinib.[7]

 > Apatinib for NSCLN Top

NSCLC remains as the most common and fatal cancer worldwide. Monoclonal antibodies against VEGF and VEGFR such as bevacizumab and ramucirumab have been recommended in the treatment of advanced NSCLC. The possible benefits of apatinib for the treatment of NSCLC were also investigated in multiple studies.[8] The preliminary results of phase II clinical trial in advanced non-squamous NSCLC had been released in ASCO Annual Meeting. The ORR and DCR were 12.2% and 68.9%, respectively, and the median PFS was 4.7 months.[9] Xu et al. retrospectively reviewed clinical data of 25 patients who received apatinib as second/third-line or beyond treatment. The median PFS was 5.17 (95% CI, 0.76–9.57) months while the ORR and DCR were 8% and 68%, respectively. It is noteworthy that a DCR of 57.1% in the seven patients with brain metastases was reported, which suggests the promising efficacy of apatinib for metastatic lesions of the central nervous system.[10] In addition, apatinib in combination with EGFR-TKIs was reported to be efficacious in treating patients with advanced NSCLC after TKIs treatment failure.[11] Apatinib was also recommended as a third- or further-line therapy in advanced NSCLC patients with EGFR wildtype.[12]

 > Apatinib for Hepatocellular Carcinoma Top

Hepatocellular carcinoma (HCC) is one of the five most common cancers worldwide, and over half of the patients with HCC are found in China.[13] Apatinib was investigated in a prospective observational study for the treatment of patients with intermediate/advanced hepatocellular carcinoma. The median time to tumor progression was 4.8 months (95% CI, 3.75–5.86 months). Furthermore, 6 and 12 months OS rates were 73.8% and 55.4%, respectively.[14] In a retrospective study, apatinib was administered at 500 mg/day or 250 mg/day continuously for the treatment of advanced HCC. The median TTP of treated patients was 10.4 months (95% CI, 3.4–17.5).[15] Moreover, transcatheter arterial chemoembolization (TACE) combined with apatinib showed a relatively good efficacy compared with TACE alone. In a recently published study, Lu et al. reported that the combination therapy group had a better ORR and PFS than TACE alone group.[16] Another study conducted by Liu et al. also suggested that apatinib combined with TACE therapy was safe and might improve overall and progression-free survival in patients with hepatocellular carcinoma with portal venous tumor thrombus.[17]

 > Apatinib for Other Cancers Top

The efficacy and safety of apatinib in advanced sarcomas was also reviewed in some single-center retrospective studies. In a recently published retrospective analysis for 16 patients with stage IV sarcomas who failed in prior chemotherapy, apatinib was given 500 mg/daily and 4 weeks as a cycle. The median PFS was 8.84 months while the ORR and DCR was 20% and 80%, respectively.[18] In addition, the safety and efficacy of apatinib in prostate cancer, malignant glioma was also reported.[19],[20]

 > Conclusion Top

Apatinib, as a novel orally bioavailable small molecule TKI of VEGFR-2, has shown improved outcomes in variety types of nongastric cancers. However, the limitation is that most studies are single-center retrospective studies with relatively small sample sizes, and they are mainly performed in patients from China. Thus, it is of great importance to verify effectiveness and safety of apatinib by more international multi-center, prospective, randomized, control, phase II clinical trials. Moreover, the multiple therapeutics strategies of apatinib combined with other therapies, such as chemotherapy, radiotherapy and thermal ablation, should be considered in the future clinical trials. With favorable toxicity and ongoing trials into multiple cancer types, apatinib offers a promise in improved outcomes for patients with non-gastric cancer.

 > References Top

Tian RH, Wu X, Liu X, Yang JW, Ji HL, Yan YJ, et al. The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials. J Cancer Res Ther 2016;12:571-5.  Back to cited text no. 1
Jiang L, Sun JH, Quan LN, Tian YY, Jia CM, Liu ZQ, et al. Abnormal vascular endothelial growth factor protein expression may be correlated with poor prognosis in diffuse large B-cell lymphoma: A meta-analysis. J Cancer Res Ther 2016;12:605-11.  Back to cited text no. 2
Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: Results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 2013;31:3219-25.  Back to cited text no. 3
Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, 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;34:1448-54.  Back to cited text no. 4
Hu X, Zhang J, Xu B, Jiang Z, Ragaz J, Tong Z, et al. Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer. Int J Cancer 2014;135:1961-9.  Back to cited text no. 5
Hu X, Cao J, Hu W, Wu C, Pan Y, Cai L, et al. Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer. BMC Cancer 2014;14:820.  Back to cited text no. 6
Lin Y, Wu Z, Zhang J, Hu X, Wang Z, Wang B, et al. Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment. Tumour Biol 2017;39:1010428317711033.  Back to cited text no. 7
Yang C, Feng W, Wu D. Apatinib for advanced non small cell lung cancer: A retrospective case series analysis. J Cancer Res Ther 2018;14:159-62.  Back to cited text no. 8
Zhang L, Shi M, Huang C, Liu X, Xiong JP, Chen G, et al. A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens. J Clin Oncol 2012;30 15 Suppl.  Back to cited text no. 9
Xu J, Liu X, Yang S, Zhang X, Shi Y. Clinical response to apatinib monotherapy in advanced non-small cell lung cancer. Asia Pac J Clin Oncol 2017; (Suppl 1).  Back to cited text no. 10
Xu J, Liu X, Yang S, Zhang X, Shi Y. Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: A retrospective study. Onco Targets Ther 2017;10:4989-95.  Back to cited text no. 11
Fang S, Zhang M, Wei G, Lu KH. Apatinib as a third-or further-line treatment in patients with advanced NSCLC harboring wild-type EGFR. Oncotarget 2018;9:7175-81.  Back to cited text no. 12
Qiu WQ, Shi JF, Guo LW, Mao AY, Huang HY, Hu GY, et al. Medical expenditure for liver cancer in urban China: A 10-year multicenter retrospective survey (2002-2011). J Cancer Res Ther 2018;14:163-70.  Back to cited text no. 13
Yu WC, Zhang KZ, Chen SG, Liu WF. Efficacy and safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma: A prospective observation study. Medicine (Baltimore) 2018;97:e9704.  Back to cited text no. 14
Kong Y, Sun L, Hou Z, Zhang Y, Chen P, Cui Y, et al. Apatinib is effective for treatment of advanced hepatocellular carcinoma. Oncotarget 2017;8:105596-605.  Back to cited text no. 15
Lu W, Jin XL, Yang C, Du P, Jiang FQ, Ma JP, et al. Comparison of efficacy between TACE combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma: A single-center randomized controlled trial. Cancer Biol Ther 2017;18:433-8.  Back to cited text no. 16
Liu C, Xing W, Si T, Yu H, Guo Z. Efficacy and safety of apatinib combined with transarterial chemoembolization for hepatocellular carcinoma with portal venous tumor thrombus: A retrospective study. Oncotarget 2017;8:100734-45.  Back to cited text no. 17
Li F, Liao Z, Zhao J, Zhao G, Li X, Du X, et al. Efficacy and safety of apatinib in stage IV sarcomas: Experience of a major sarcoma center in China. Oncotarget 2017;8:64471-80.  Back to cited text no. 18
Wang L, Liang L, Yang T, Qiao Y, Xia Y, Liu L, et al. Apilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical trial/experimental study. Medicine (Baltimore) 2017;96:e9053.  Back to cited text no. 19
Zhao F, Tian W, Zeng M, Xia J, Hu H, Hao X, et al. Apatinib alone or combined with radiotherapy in metastatic prostate cancer: Results from a pilot, multicenter study. Oncotarget 2017;8:110774-84.  Back to cited text no. 20


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