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To examine the prevalence, severity, and co-occurrence of SPPADE symptoms as well as their association with cancer type and patient characteristics. The SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy /fatigue) are prevalent, co-occurring, and undertreated in oncology and other clinical populations. Baseline SPPADE symptom data were analyzed from the E2C2 study, a stepped wedge pragmatic, population-level, cluster randomized clinical trial designed to evaluate a guideline-informed symptom management model targeting the six SPPADE symptoms. Symptom prevalence and severity were measured with a 0–10 numeric rating (NRS) scale for each of the six symptoms. Prevalence of severe (NRS ≥ 7) and potential clinically relevant (NRS ≥ 5) symptoms as well as co-occurrence of clinical symptoms were determined. Distribution-based methods were used to estimate the minimally important difference (MID). Associations of cancer type and patient characteristics with a SPPADE composite score were analyzed. A total of 31,886 patients were assessed for SPPADE symptoms prior to, during, or soon after an outpatient medical oncology encounter. The proportion of patients with a potential clinically relevant symptom ranged from 17.5% for depression to 33.4% for fatigue. Co-occurrence of symptoms was high, with the proportion of patients with three or more additional clinically relevant symptoms ranging from 45.2% for fatigue to 68.6% for depression. The summed SPPADE composite score demonstrated good internal reliability (Cronbach's alpha of 0.86), with preliminary MID estimates of 4.1–4.3. Symptom burden differed across several types of cancer but was generally similar across most sociodemographic characteristics. The high prevalence and co-occurrence of SPPADE symptoms in patients with all types of cancer warrants clinical approaches that optimize detection and management. [ABSTRACT FROM AUTHOR]