Supplementary Material for: Lifestyle factors and development and natural course of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): a review of the literature

Introduction: The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation, complicate the identification of risk factors for their development and natural course. Several tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aims to identify studies on smoking, alcohol use, physical activity, diet body mass index (BMI) and diabetes and their association with the development and course of GEP-NETs. Methods: The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle -Ottawa scale. Results: A total of 22 eligible studies out of 2915 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but little studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, whilst a protective effect was observed with metformin use. Conclusion: Different tissues, i.e., pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NET with a protective role in disease progression, while BMI is not unequivocally associated with development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.