The prognostic value of hypoxia-inducible factor-1α in advanced cancer survivors: a meta-analysis with trial sequential analysis.

Background: Expression of hypoxia-inducible factors (HIFs) has been observed, but their prognostic role in advanced cancers remains uncertain. We conducted a meta-analysis to establish the prognostic effect of HIFs and to better guide treatment planning for advanced cancers. Methods: Pooled hazard ratios (HRs) and 95% confidence intervals (Cis) were calculated. Trial sequential analysis (TSA) was also performed. The clinical outcomes included overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) in patients with advanced tumors according to multivariate analysis. Results: A total of 31 studies including 3453 cases who received chemotherapy, radiotherapy, or chemoradiotherapy were identified. Pooled analyses revealed that HIF-1 alpha expression was correlated with worse OS (HR=1.61, p<0.001), DFS (HR=1.61, p<0.001), PFS (HR=1.49, p=0.01), CSS (HR=1.65, p=0.056), RFS (HR=2.10, p=0.015), or MFS (HR=2.36, p=0.002) in advanced cancers. HIF-la expression was linked to shorter OS in the digestive tract, epithelial ovarian, breast, non-small cell lung, and clear cell renal cell carcinomas. Subgroup analysis by study region showed that HIF-1 alpha expression was correlated with poor OS in Europeans and Asians, while an analysis by histologic subtypes found that HIF-1 alpha expression was not associated with OS in squamous cell carcinoma. No relationship was found between HIF-2 alpha expression and OS, DFS, PFS, or CSS. Conclusions: Targeting HIF-1 alpha may be a useful therapeutic approach to improve survival for advanced cancer patients. Based on TSA, more randomized controlled trials are strongly suggested.