Clinical burden and downstream consequences of severe fluoropyrimidine-associated toxicity in a single-center study.

e24176 Background: Fluoropyrimidines are widely used in the treatment of gastrointestinal and other solid tumors but are associated with potentially life-threatening toxicities. While fluoropyrimidine-associated toxicity has been well described in European cohorts, real-world data on severe toxicity and downstream clinical consequences in U.S. practice remain limited. Methods: We conducted a retrospective observational study of adult patients treated with systemic fluoropyrimidine-based chemotherapy within a single health system serving a predominantly rural population in Southwest Virginia. Between 2015 and 2025, 299 patients received systemic fluoropyrimidine therapy, of whom 21 met inclusion criteria for grade ≥3 chemotherapy-induced toxicity (7%). Toxicities were graded according to CTCAE v6. Toxicities and downstream acute care utilization events were included if they occurred within 90 days of treatment initiation. Time to toxicity was defined as days from treatment initiation to the first documented event. Descriptive statistics were used. Results: Of patients with severe fluoropyrimidine-associated toxicity, median age was 64 years, and 52.4% of patients were female. Most patients had an ECOG performance status 0–1. Colorectal cancer was the most common malignancy. Regimens included FOLFOX (42.9%), single-agent oral fluoropyrimidine therapy (38.1%), FOLFIRINOX (14.3%), and XELOX (4.8%); treatment intent was palliative in 66.7% and curative or adjuvant in 33.3%. Maximum toxicity grade was 3 in 66.7% and 4 in 33.3% of patients. Median time to toxicity was 22 days (IQR, 15–30), with 85.7% developing grade ≥3 toxicity within 30 days and 23.8% within 14 days. Common grade ≥3 toxicities included neutropenia (42.9%), thrombocytopenia (33.3%), hand-foot syndrome (28.6%), diarrhea (23.8%), and mucositis (14.3%). Within 90 days, 52.4% required emergency care, 61.9% were hospitalized, and 23.8% required ICU admission; overall, 66.7% experienced a high-acuity clinical event. Permanent fluoropyrimidine discontinuation occurred in 57.1% of patients. Compared with patients with grade 3 toxicity, those with grade 4 toxicity experienced higher rates of hospitalization (85.7% vs 50.0%), ICU admission (42.9% vs 7.1%), and treatment discontinuation (85.7% vs 42.9%). Grade ≥3 hand-foot syndrome was more common with oral capecitabine, whereas hematologic toxicities were more frequent with IV 5-FU–based regimens. Conclusions: Severe fluoropyrimidine-associated toxicity occurred early and was associated with substantial acute care utilization and frequent treatment discontinuation in this U.S. population, highlighting the need for improved upfront risk stratification strategies.