Real-World Survival and Toxicity Outcomes of Fluorouracil With vs. Without Leucovorin in Metastatic Colorectal Cancer

Fluorouracil (5-FU) remains a cornerstone of systemic therapy for metastatic colorectal cancer (mCRC). Leucovorin enhances fluorouracil cytotoxicity through thymidylate synthase modulation. Although randomized trials established the benefit of leucovorin modulation, real-world survival and toxicity outcomes remain incompletely characterized.

We conducted a retrospective cohort study using the TriNetX US Collaborative Network, which includes electronic health record data from 67 healthcare organizations. Adult patients with mCRC receiving intravenous fluorouracil between January 2000 and January 2026 were included. Patients were stratified by leucovorin exposure. Propensity score matching (1:1 nearest neighbor) balanced demographics, comorbidities, treatment exposures, surgical history, and genomic alterations. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization, granulocyte colony-stimulating factor use, blood transfusion, sepsis, thrombocytopenia, and gastrointestinal toxicity. Kaplan-Meier and Cox proportional hazards analyses were performed.

After propensity score matching, 2,403 patients were included in each cohort. Survival analysis included 2,385 patients in the leucovorin cohort and 2,391 patients in the fluorouracil-alone cohort after exclusions. Mortality occurred in 38.8% of patients receiving fluorouracil with leucovorin compared with 47.1% receiving fluorouracil alone (hazard ratio 0.752, 95% CI 0.690-0.821). Median survival was longer in the leucovorin cohort (964 vs. 718 days). Leucovorin use was associated with increased hospitalization (HR 1.222), granulocyte colony-stimulating factor use (HR 1.360), blood transfusion (HR 1.593), and gastrointestinal toxicity.

In this large real-world cohort, leucovorin significantly improved survival in patients with metastatic colorectal cancer receiving fluorouracil but was associated with increased treatment-related toxicity. These findings support the continued use of leucovorin as a key component of fluorouracil-based chemotherapy regimens.