Abstract / Summary
Background: Gemcitabine-based chemotherapy is first-line for advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), but toxicity patterns are poorly defined at high altitude (>2,000 m). Clinical observations of heightened treatment toxicity at our high-altitude institution (Xining, ~2,261 m) prompted this population-level baseline study of gemcitabine toxicity signals. The present analysis uses only publicly available, de-identified FAERS data; institutional clinical experience motivates but does not validate the signals reported here. Methods: Four-metric disproportionality analysis (ROR primary, PRR, IC BCPNN, EBGM MGPS) of FAERS 2014-2026 (18.37M reports) across five non-exclusive gemcitabine groups (monotherapy, +ICI, +TKI, triple, BTC/PDAC disease-specific). Liver toxicity stratified into three MedDRA PT groups; fatal toxicity analyzed with dual definitions. BTC/PDAC queried via correct patient.drug.drugindication field. BH-FDR post hoc. EBGM used two implementations: a non-standard single-pair gamma(1,1) closed-form approximation (positivity-screening column in S1) and the standard openEBGM two-component MGPS. Complete-MGPS EB05 > 2 is the primary Bayesian criterion (10/17 pass); closed-form count (12/17) is labeled non-standard. Results: 14/17 exposure-AE combinations passed the three frequentist criteria (ROR/PRR/IC lower bounds); 10/17 additionally passed complete-MGPS EB05 > 2 (standard openEBGM caers fit). The non-standard closed-form count (12/17) is a labeled approximation only. Myelosuppression is the most consistent signal across all regimens (ROR 3.35-7.74); under complete MGPS the sparse all-role triple-combination cell had EB05=1.59. Triple combo liver toxicity (ROR=10.32, a=28, n=181 all-role) is driven by the Severe failure/hepatitis PT group (ROR=23.51); this cell is unstable under primary-suspect restriction (ROR=1.62, a=0, n=31; Supplementary S9) and is hypothesis-generating. Restricted to expanded fatal bridge: triple ROR 1.62 to 4.64 (zero overlap verified). BTC/PDAC thrombocytopenia (ROR=19.36) was independently reproduced at 19.70 after deduplication/PS filtering; PPV=94%. Conclusions: This study establishes baseline gemcitabine toxicity signals from a largely sea-level FAERS population. The fatal-liver-failure bridge and PT-stratified liver toxicity are hypothesis-generating signals. High-altitude hypotheses are mechanistic and not FAERS-testable; they require prospective validation.