Safety and efficacy of the FOLFOX regimen in patients with metastatic gastrointestinal cancers and severe hyperbilirubinemia: A real‑world experience

Patients with gastrointestinal (GI) malignancies and hyperbilirubinemia secondary to liver metastases are routinely excluded from clinical trials, leaving their management without evidence-based guidance.Oxaliplatin, cleared through non-enzymatic biotransformation and renal excretion, is a rational candidate in this setting.The present study examined the feasibility, safety and outcomes of folinic acid, fluorouracil and oxaliplatin (FOLFOX)-based chemotherapy in this population.The present retrospective, single-center analysis included 27 patients with histologically confirmed metastatic GI cancers (gastric, biliary tract, pancreatic and colorectal) with serum total bilirubin of ≥4.5 mg/dl at treatment initiation who received individualized FOLFOX-based chemotherapy at Etlik City Hospital (Ankara, Türkiye) between July 2023 and March 2025.Bilirubin response was defined as a ≥50% reduction within 4-8 weeks or normalization to ≤1.2 mg/dl within 12 weeks.Survival was estimated by Kaplan-Meier analysis; Cox regression identified predictors of progression-free survival (PFS) and overall survival (OS).Median baseline bilirubin was 6.9 mg/dl.Bilirubin declined significantly at weeks 4, 8 and 12 (medians 3.0, 2.5 and 0.8 mg/dl; P<0.001, P= 0.009 and P= 0.001 vs. baseline).Among Response Evaluation Criteria in Solid Tumors-evaluable patients (11/27), the objective response rate was 72.7% and disease control rate 81.8%.Median PFS was 2.56 months [95% confidence interval (CI) 1.81-3.65]and median OS 3.65 months (95% CI 2.56-5.72).A ≥50% bilirubin reduction at week 4 was associated with longer PFS [univariable hazard ratio (HR) 0.37; 95% CI 0.14-0.93;log-rank P= 0.028] and longer OS (univariable HR 0.37; 95% CI 0.14-0.94;log-rank P= 0.030) in a week 4 landmark analysis performed to address immortal time bias.In the present cohort of patients with Eastern Cooperative Oncology Group Performance Status 0-1 and severe hyperbilirubinemia due to liver metastases, FOLFOX achieved rapid bilirubin reductions without grade ≥3 hepatotoxicity.Early bilirubin response was associated with longer survival in the present small, exploratory analysis; these hypothesis-generating findings warrant prospective validation.