Background: For advanced upper gastrointestinal (GI) cancers, patient-reported symptoms are driven by both disease and treatment toxicities. This real-world longitudinal study was designed to evaluate patient-reported outcomes (PROs) of symptom burden and functioning among patients (pts) treated with anti-cancer therapy. Methods: Adult pts with advanced esophageal, gastroesophageal junction (GEJ), or gastric cancer were invited to participate in a prospective, longitudinal study. PRO assessment included pre-treatment and weekly completion of the M.D. Anderson Symptom Inventory GI module (MDASI-GI) as pts initiated a new line of therapy. Clinical and disease characteristics and treatment details were obtained from electronic health records. Up to 12 weeks longitudinal PRO data were analyzed using mixed-effect modeling with random intercept. Pts were classified into high or low symptom groups by group-based trajectory modeling. Time to deterioration in functioning (defined as a ≥2-point increase from baseline on 0-10 scale) was examined with Kaplan-Meier method. Results: At the interim analysis, 76 pts had enrolled: 33 (43%) were chemotherapy naïve for advanced disease, 18 (24%) had received 1 line of therapy, 14 (18%) had received > 1 line of therapy, and 11 (14%) were excluded from this analysis due to study discontinuation without follow-up assessment. Among the 65 eligible pts in this analysis, 46 (70.8%) were male, most were white (n = 56, 86.2%), and 44 (67.7%) had an ECOG performance status score of 0-1. Pain, fatigue, disturbed sleep, lack of appetite and inability to eat were the most common severe symptoms reported prior to and during therapy. Pts who had received one line of therapy reported worsening symptoms of pain, fatigue, lack of appetite, difficulty swallowing, and reduced general activity, work, and enjoyment of life over time (group and time interaction P<.05). Pts with > 1 line of prior therapy had increased neuropathy symptoms (numbness/tingling) than those who were treatment-naïve (P= 0.022). The median time to functioning deterioration of ≥2 points from baseline on the MDASI-“General activity” was 7 weeks. Up to 57% of pts were classified into high symptom trajectory group of pain, fatigue, disturbed sleep, and drowsiness with moderate to severe symptoms (≥4 points out of possible 10) over time; group membership was related to moderate to severe symptoms at baseline, after adjusting for age, sex, ECOG performance status, cancer site and prior therapies. Conclusions: This real-world observational study suggests that pts with advanced stage upper GI cancer undergoing standard therapy report high symptom burden. These preliminary findings support the use of a targeted symptom monitoring using well-defined PROs during active therapy, thereby adding the knowledge obtained from PROs to improve routine patient care.