Background: Cancer is the second leading cause of death worldwide next to cardiovascular diseases. Despite the advancement in screening, early diagnosis, and development in treatment technology in last several decades, cancer incidence overall, particularly that of gastrointestinal (GI) cancers, is far from being controlled, and is expected to increase worldwide. Summary: Although numerous preclinical and population-based clinical studies have already made important progress in restraining the overall cancer incidence and mortality, the full potential of preventive strategy is still far from being realized, and remains at an early stage. There are several major challenges regarding this issue, and one of the crucial challenges is to maintain the balance between risks and benefits. As a result of past investments, primary prevention nowadays include the integration of various activities such as lifestyle changes to reduce risk, screening to detect early lesions, vaccines and preventive therapies aimed to actively interrupt the carcinogenic pathway. Long-term aspirin use seems to have the largest potential effect on the general population on cancer incidence and mortality overall, especially GI cancers. Helicobacter pylori eradication reduces the risk for gastric cancer and is advocated regardless of the symptoms and stage of disease. Metformin and statins are promising in cancer prevention in patients with type 2 diabetes. Vitamin D supplementation is promising in the prevention of colorectal adenoma recurrence. Key Message: However, additional studies are warranted to establish the potential of various agents and to identify more specific and highly targeted new agents for chemoprevention in digestive oncology.

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