Amygdalar Activity Measured Using FDG-PET/CT at Head and Neck Cancer Staging Independently Predicts Survival and Cardiovascular Outcomes: A Retrospective Cohort Study

Abstract

Background Chronic stress associates with higher mortality among individuals with cancer; however, the mechanisms underlying this association remain incompletely understood. Quantification of amygdalar metabolic activity (AmygA) using 18F-fluorodexoyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) provides a measure of stress-related neurobiological activity, that associates with increased systemic inflammation and a higher risk of cardiovascular disease events. Accordingly, we sought to test the hypotheses, in individuals with active cancer, that higher AmygA at cancer staging associates with:1) increased inflammation, and 2) higher mortality. Methods We studied 240 patients with head and neck cancer (HNCA) at a single academic center who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. AmygA and metabolic activity of the bone marrow (a measure of leukopoiesis) were measured using validated methods. Image analysis, clinical data assessments and adjudication were performed by mutually blinded, independent teams. The primary outcome of interest, the association between AmygA and mortality, was determined using Cox proportional hazard models. The secondary outcome of interest was a composite of the mortality plus cancer progression. Findings Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1·7-5·1). AmygA associated with heightened bone marrow activity, leukocytosis, CRP (P<0·05 each) and cancer progression. In adjusted analyses, AmygA associated with subsequent mortality (1·28, [1·01-1·61], P=0·039) and the association between AmygA and cancer mortality persisted when analyses were restricted to patients with advanced cancer stage (P<0·001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P=0·01). Interpretation AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality via a mechanism which may, in part, be mediated through increased leukopoietic activity and inflammation and cancer progression. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.