Disentangling the obesity paradox in upper gastrointestinal cancers: Weight loss matters more than body mass index.

Abstract Objectives The obesity paradox, whereby obesity appears to confer protection against cancer-related mortality, remains controversial. This has not yet been evaluated in upper gastrointestinal cancers. Designs We identified esophageal, cardia, and non-cardia gastric adenocarcinomas in the Veterans Health Administration between 2006–2016. Multivariable Cox proportional hazard models evaluate the impact of BMI at- and prior to- cancer diagnosis on mortality, adjusting for demographics, clinical characteristics, weight loss, and clinical stage (early: T1B/2N0; locally advanced: ≥T2N+). Results We identify 1308 patients: 99 % male, median 66 years. In early disease, relative to BMI 30, BMI 18 and 20 at diagnosis had increased risk of death (HR 1.83, 95 %CI: 1.38–2.44 and HR 1.50, 95 %CI: 1.20–1.87, respectively, p 30 did not. In locally advanced disease, at diagnosis BMI 18 (HR 1.58, 95 %CI: 1.0001–1.48, p = 0.05), BMI 20 (HR 1.46, 95 %CI: 1.01–2.09, p = 0.04), and BMI 25 (HR 1.20, 95 %CI: 1.04–1.38, p = 0.01) had increased risk of death, but BMI > 30 did not. In models assessing premorbid BMI and weight loss, increasing amounts of weight loss were associated with mortality independent of BMI in early cancers. For locally advanced cancers, without weight loss, there was no association with death, regardless of BMI. Conclusion The predominant driver of mortality across clinical stages is weight loss. The obesity paradox appears to exist in early stage disease only. Future studies should investigate mechanisms for the obesity paradox, accompanying physiologic changes with weight loss preceding diagnosis, and if patients with low BMI and weight loss benefit from early nutritional support.