Iron in the biology and treatment of gastrointestinal cancer

Abstract

Background Iron is intimately related to the biology and pathology of gastrointestinal cancer with both iron excess and iron deficiency influencing disease. This thesis examines the biological and clinical effects of iron replacement in gastrointestinal cancer. Methods This thesis reports the effects of iron replacement in colorectal cancers at a biological level using immunohistochemistry, real time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) during clinical treatment for iron deficiency anaemia prior to surgery. Systematic review of the literature also investigates the clinical evidence for such an approach to pre-operative anaemia. The thesis then examines the natural history and impact of anaemia in oesophagogastric cancer before reporting a pilot randomised control study using intravenous iron to treat anaemia in this setting. Results Examining iron administration in colorectal cancer demonstrated that colorectal adenocarcinomas reprogram their iron metabolism to increase the potential labile iron pool. These changes appear to be decoupled from the normal intracellular iron sensing mechanisms. Route of administration of iron to patients did not alter tumour growth or effect iron transport mechanisms. Differential compartmentalisation of iron was noted however. Clinical anaemia in oesophagogastric cancer becomes more severe with time and treatment and was associated with poorer survival outcomes. Furthermore, higher initial haemoglobin, rather than just the absence of anaemia, was associated with better survival outcomes. In a randomised control pilot study for intravenous iron use compared to standard care for anaemia in oesophagogastric cancer, intravenous iron effectively replenished iron stores measured using ferritin and transferrin saturations. Despite chemotherapy and the tumour in situ the intravenous iron group saw an increase in haemoglobin. This was despite a significantly lower starting haemoglobin in the intravenous iron group. Quality of life was also significantly improved in the intravenous iron group. Conclusion This thesis supports the continued clinical use of intravenous iron for anaemia in gastrointestinal cancer, showing no deleterious effects at a biological level despite replenishment of iron stores and increases in haemoglobin at a clinical level. More research is required to investigate compartmentalisation of iron and conclude clinical efficacy in larger adequately powered studies