Hypoxia and hypoxia response-associated molecular markers in esophageal cancer: A systematic review

摘要

Highlights ? HIF-1α and CAIX are molecular markers able to estimate hypoxia response in EC. ? Population and histological differences affect esophageal hypoxia assessment. ? For personalized treatment, tumor microenvironment, stage and histology need to be considered. ? Standardization of measuring techniques is crucial for guiding hypoxia research and clinical application in EC. ? Hypoxia imaging techniques have the potential to provide individualized information to guide treatment of EC. Abstract Purpose In this systematic review, the existing evidence of available hypoxia-associated molecular response biomarkers in esophageal cancer (EC) patients is summarized and set into the context of the role of hypoxia in the prediction of esophageal cancer, treatment response and treatment outcome. Methods A systematic literature search was performed in Web of Science, MEDLINE, and PubMed databases using the keywords: hypoxia, esophagus, cancer, treatment outcome and treatment response. Eligible publications were independently evaluated by two reviewers. In total, 22 out of 419 records were included for systematic review. The described search strategy was applied weekly, with the last update being performed on April 3rd, 2017. Results In esophageal cancer, several (non-)invasive biomarkers for hypoxia could be identified. Independent prognostic factors for treatment response include HIF-1α, CA IX, GLUT-1 overexpression and elevated uptake of the PET-tracer 18 F-fluoroerythronitroimidazole ( 18 F-FETNIM). Hypoxia-associated molecular responses represents a clinically relevant phenomenon in esophageal cancer and detection of elevated levels of hypoxia-associated biomarkers and tends to be associated with poor treatment outcome (i.e., overall survival, disease-free survival, complete response and local control). Conclusion Evaluation of tumor micro-environmental conditions, such as intratumoral hypoxia, is important to predict treatment outcome and efficacy. Promising non-invasive imaging-techniques have been suggested to assess tumor hypoxia and hypoxia-associated molecular responses. However, extensive validation in EC is lacking. Hypoxia-associated markers that are independent prognostic factors could potentially provide targets for novel treatment strategies to improve treatment outcome. For personalized hypoxia-guided treatment, safe and reliable makers for tumor hypoxia are needed to select suitable patients.