Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.

Patients with advanced gastric cancer (AGC) can be treated with multiple lines of chemotherapy. Although several randomized trials have demonstrated the benefit of second-line chemotherapy compared with best supportive care, there is no evidence that further lines of chemotherapy will result in substantial prolongation of survival. Despite this, the practice of offering chemotherapy beyond second-line agents to AGC patients is not uncommon if their performance status is well-preserved and they are willing to receive subsequent active treatments. The choice of chemotherapeutic agents depends on the patient's prior regimens. However, there are important controversial issues in the salvage setting of AGC, including a subset of patients who may benefit from chemotherapy, that still remain unanswered. This report reviews the available evidence regarding the impact of third- and subsequent lines of chemotherapy on survival and quality of life in patients with AGC.