title: Prevalence and incidence of liver enzyme elevations in a pooled oncology clinical trial cohort.
abstract: Few epidemiologic studies describe longitudinal liver chemistry (LC) elevations in cancer patients. A population-based retrospective cohort was identified from 31 Phase 2-3 oncology trials (excluding targeted therapies) conducted from 1985 to 2005 to evaluate background rates of LC elevations in patients (n = 3998) with or without liver metastases. Patients with baseline liver metastases (29% of patients) presented with a 3% prevalence of alanine transaminase (ALT) ≥ 3x upper limits normal (ULN) and 0.2% prevalence of bilirubin ≥ 3xULN. During follow-up, the incidence (per 1000 person-months) of new onset ALT elevations ≥3xULN was 6.1 (95% CI: 4.5, 8.0) and 2.2 (95% CI: 0.9, 4.5) in patients without and with liver metastases, respectively. No new incident cases of ALT and bilirubin elevations suggestive of severe liver injury occurred among those with liver metastases; a single case occurred among those without metastasis. Regardless of the presence of liver metastases, LC elevations were rare in cancer patients during oncology trials, which may be due to enrollment criteria. Our study validates uniform thresholds for detection of LC elevations in oncology studies and serves as an empirical referent point for comparing liver enzyme abnormalities in oncology trials of novel targeted therapies. These data support uniform LC stopping criteria in oncology trials.
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Gateway West, Singapore. Electronic address: sumitra.y.shantakumar@gsk.com.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Shantakumar
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Stockley Park, United Kingdom. Electronic address: sarah.h.landis@gsk.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Landis
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline, Stockley Park, United Kingdom. Electronic address: andy.m.lawton@gsk.com.
authors.forename: Andy
authors.initials: A
authors.lastname: Lawton
authors.affiliation: Department of Veterans Affairs, Durham VA Medical Center, North Carolina, USA. Electronic address: christine.hunt@va.gov.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hunt
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology*; D004796:Clinical Enzyme Tests; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology* / Q000556:secondary; D011237:Predictive Value of Tests; D015995:Prevalence; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D000410:Alanine Transaminase; D001663:Bilirubin
keywords: Alanine aminotransferase; Bilirubin; Clinical trial; Hepatotoxicity; Liver enzyme; Liver injury; Metastasis; Oncology; Truncated robust multivariate outlier detection