Background: Providing accurate symptom profiles is essential to facilitate integration of patient-reported outcome measures (PROs) into routine oncologic care. This study described the symptom trajectories and functioning status in patients with advanced esophageal, gastroesophageal junction (GEJ), or gastric cancers. Methods: The study included adult patients with advanced upper gastrointestinal (UGI) cancers who were initiating a new line of therapy at time of enrollment. Multiple symptoms were assessed weekly for 12 weeks, then every two weeks until Week 36 using the electronically administered M.D. Anderson Symptom Inventory GI module (MDASI-GI). Patients also completed the EORTC QLQ-C30 every six weeks. Longitudinal PRO data were analyzed using mixed-effect models. Time to deterioration was estimated using Kaplan-Meier method. Multivariable regression models evaluated the association of PROs with tumor response. Patients were classified in a high symptom burden group if their MDASI-GI symptoms were scored > 4 (scale of 0-10) for trajectory analysis. Results: Of the 111 enrolled patients, primary tumor site was available for 108 patients: esophageal (33%), GEJ (26%), gastric (41%). The mean age was 60.2 years; 70% were male. Nineteen patients who dropped within one week after baseline reported more severe vomiting and inability to eat than those who provided more post-baseline data (n=92). For the 92 patients, the top 6 most severe items at baseline were fatigue, lack of appetite, disturbed sleep, pain, drowsiness, and inability to eat. At baseline, patients who were treatment-naïve (n=43) reported more severe symptom burden and financial difficulty than patients who had received prior therapy (n=49). Those who were treatment-naïve reported faster general activity deterioration during the first 12 weeks than those who had received prior treatment (hazard ratio=2.183, 95% CI: 1.018, 4.673). More severe shortness of breath at baseline was significantly associated with better tumor response by Week 12 (odds ratio=1.35, 95% CI: 1.05, 1.74) for all patients with tumor response data. Trajectory analysis showed high symptom burden for pain (35% of patients), fatigue (60%), disturbed sleep (32%), lack of appetite (60%), drowsiness (54%), difficulty swallowing (37%), and inability to eat (50%) during the initial 12 weeks. High symptom burden continued for pain (41% of patients), fatigue (55%), lack of appetite (59%), drowsiness (48%), and numbness (29%) for Weeks 12-36. Conclusions: This longitudinal study documented high prevalence of disease- and treatment-related symptom burden and functioning deterioration among patients with advanced UGI cancers. These data support the implementation of PRO assessment in the routine patient care of this cohort of patients with significant physical and psychosocial challenges.