The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: a meta-analysis and systemic review

Osteosarcoma is a primary malignancy of bone. Although new therapies continue to emerge, osteosarcoma-related morbidity and mortality remain high. Various studies have evaluated the prognostic value of VEGF levels in osteosarcoma patients, but they have yielded conflicting results. The 5-year survival of each study was aggregated following a methodological assessment, and a systematic review of eligible studies with meta-analysis and univariate analysis was performed to quantitatively review the correlation of VEGF overexpression with 5-year survival in patients with osteosarcoma. A total of 387 patients in eleven papers were finally considered to be eligible for inclusion in our analysis. Aggregation of the 6 positive results in Kaplan-Meier curve showed a risk ratio of 2.84 (95% CI: 1.39-5.83, P = 0.004) associated with VEGF-positive conditions in comparison with VEGF-negative conditions, suggesting that there was significant association between VEGF positive and the 5-year mortality. But univariate analysis of eleven studies showed that there was a small inverse but not significant relationship between VEGF expression level and the 5-year survival of osteosarcoma patients, but stage III, neo-chemotherapy, the primary tumor location, osteoblastic histological subtype and the source of patients showed a significant impact on the 5-year survival of patients. The prognostic significance of VEGF expression in all its isoforms is still unknown based on the limited data available, but we find VEGF165 may play an important role. Future studies should examine the relationship between VEGF isoform expression and patients' survival and the relationship between VEGF isoform expression and EMMPRIN expression, which could be helpful for predicting the prognosis of patients with osteosarcoma. Once the conclusion of whether the VEGF and its isoforms playing a role in osteosarcoma were reached, it would help guide clinical decision-making regarding therapy and outcomes. In addition, we recommend a > 25% positive staining of the cells as a VEGF-positive cut-off value in immunohistochemistry, since we find a relatively strict detecting method is likely to yield significant result in the 5-year survival of patients.