Retrospective Study of Apatinib Combined with Whole-Brain Radiotherapy and Simultaneous Integrated Boost for Multiple Brain Metastases from Non-Small Cell Lung Cancer

Abstract

Brain metastases (BMs) develop in 22-54% of non-small cell lung cancer (NSCLC) patients during the disease course, and are associated with a poor prognosis. As neo-angiogenesis is crucial to BM growth, the combination of angiogenesis inhibitors and brain radiotherapy (RT) is an active focus of research. Apatinib, a tyrosine kinase inhibitor that highly selectively inhibits the vascular endothelial growth factor receptor 2 (VEGFR-2), is safe and significantly prolongs survival in chemotherapy-refractory gastric cancer. It may also inhibit the growth of many other solid tumors including NSCLC. This retrospective study evaluated the safety and efficacy of concurrent brain RT with apatinib in NSCLC patients with multiple BMs. Apatinib (500mg/day) was administered orally for one week before brain RT, and continued in the same manner concurrently with RT (49.5-52.5Gy/15 fractions intralesional boost with whole brain radiotherapy [WBRT] to 37.5Gy/15 fractions). The same dosage of apatinib was given for another one week after brain RT completion, and 250-500mg/day thereafter until progression of the disease or unacceptable toxicity (or economic reasons). The intracranial overall response rate (IORR), intracranial disease control rate (IDCR), brain edema index (EI), intracranial progression-free survival (IPFS), and overall survival (OS) after BM were analyzed. From July 2016 to October 2018, seven (6 males and 1 female) patients were treated with this paradigm. The median follow-up time was 29 months (4-31 months), by which time five of seven patients had died. At three months after brain RT, IORR was 85.7% (6/7, 2 with complete response), IDCR was 100%, and EI was significantly reduced, compared to before WBRT (3.86 VS. 1.89, P=0.018). Median IPFS was 16.9 months (95% confidence interval [CI], 9.5-24.3 months), and the 1-year and 2-year IPFS rates were 71.4% and 28.6%, respectively. The median OS after BM was 20.1 months (95% CI, 12.7-21.5 months); the 1- and 2-year rates were 85.7% and 28.6%, respectively. All but one patients experienced adverse events, most commonly grade 1 or 2; most common were hypertension (42.9%, 3/7), oral mucositis (28.6%, 2/7), hearing loss (28.6%, 2/7), and proteinuria (14.3%, 1/7). Only two patients experienced grade 3 adverse events (oral mucositis and proteinuria); no grade 4 or 5 toxicities were observed. Apatinib combined with simultaneous integrated boosted WBRT may be a safe and effective therapeutic method to treat metastatic NSCLC with multiple BMs. Prospective study is recommended.