Influence and Mechanism of Lung Cavitation Development on Antiangiogenic Therapy

Man Jiang; Chuantao Zhang; Dong Liu; Yongjie Wang; Hongmei Wang; Tianjun Li; Helei Hou; Na Zhou; Jingjuan Zhu; Hongying Lv; Chuanyu Zhang; Bingliang Fang; Xiaochun Zhang


Transl Lung Cancer Res. 2019;8(4):500-512. 

In This Article

Abstract and Introduction


Background: Antiangiogenic agent-treated patients usually develop cavitation in their lung lesions. The clinical significance of lung cavitation development during antiangiogenic therapy has not been determined yet. Herein, we evaluated the clinical outcomes of patients who developed tumor cavitation following apatinib treatment and explored the mechanisms.

Methods: In this study (Clinical Trial No. NCT03629691), 187 patients (77 lung cancer and 110 gastric adenocarcinoma patients) who had progressed or relapsed after undergoing at least two lines of systemic therapy in accordance with the NCCN guidelines for primary or metastatic lung tumors were treated with apatinib at a dosage of 250 mg per day between February 1, 2015 and May 19, 2017. The effect of lung cavitation development on locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) was analyzed with Kaplan-Meier estimates and compared with the log-rank test. Zebrafish experiments were used to study the anticancer mechanism of apatinib in different tumors. Western-blotting was used to analyze the expression of Cyclin D1, p53, HIF-α, and VEGFR before and after apatinib treatment in both normoxia and hypoxia.

Results: Cavitation development was beneficial in patients receiving apatinib therapy regardless of whether they had primary or metastatic lung cancer. Zebrafish experiments showed that apatinib inhibited tumor growth by both suppressing vascular growth and inhibiting cell proliferation. Vascular proliferation induced by the H1299 cell lines showed higher sensitivity to apatinib than that induced by the SCG-7901 cell line. However, apatinib showed weak tumor type selectivity on cell proliferation inhibition in vivo. Under hypoxic conditions, apatinib could not inhibit the protein expression of VEGFR and HIF-α in both cell lines; however, apatinib decreased the expression of cyclin D1 and P53 significantly.

Conclusions: Lung cavitation development is common with apatinib therapy and is a potential prognostic marker. Apatinib inhibits tumor growth by both vessel growth inhibition and proliferation inhibition.


Lung cavitation often occurs in lung cancer patients who have failed multiple lines of chemotherapy and have been treated with antiangiogenic agents.[1,2] It is often considered a risk factor for the deterioration of a patient's survival status.[3] However, results may vary depending on the drug used. In a previous phase II trial, which included 67 non-small cell lung cancer (NSCLC) patients treated with bevacizumab, lung cavitation was associated with patient death.[3] In another study of cediranib, Crabb et al. reported no clear link between clinical response and tumor cavitation in NSCLC patients.[4] It is essential to study the relationship between lung cavitation development and antiangiogenic therapy to avoid serious adverse events and guide clinical treatments. Apatinib, a novel small-molecule vascular endothelial growth factor receptor (VEGFR) inhibitor, has been approved to treat advanced or metastatic chemorefractory gastric cancer in China.[5,6] Recently, apatinib has been shown to have positive effects on multiple tumors, including lung cancer.[6,7] According to our observations, apatinib-treated patients with lung lesions usually develop lung cavitation although the clinical significance of this finding has not been studied yet. Herein, we retrospectively reviewed apatinib-treated patients to evaluate the clinical significance of lung cavitation development during apatinib therapy (Clinical Trial Register No. NCT03629691). This is the first study concerning lung lesions of both primary and metastatic lung cancer. The study design was accepted as a poster at the 18th World Conference on Lung Cancer (WCLC, October 15–18, 2017, Yokohama, Japan P3.03–014).