Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials.
BACKGROUND
Venous thromboembolic events (VTEs) are a significant cause of death in patients with cancer. The incidence of VTE is not well characterized in early phase clinical trials of novel antineoplastic agents, or in hepatic dysfunction studies designed for patients with varying degrees of liver test abnormalities. We compared the incidences of VTE in phase 1 clinical trials (P1CTs) and hepatic dysfunction trials (HDCTs) sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) of the United States.


METHODS
We reviewed individual patient records of 1841 subjects for symptomatic VTE diagnosed while on study: 1328 subjects on 42 P1CTs, and 513 subjects on 9 HDCTs. The NCI's Organ Dysfunction Working Group definitions were used to categorize patients. The incidences of VTEs between patients were compared by the Chi square test. Confounders were evaluated with the Cochran-Mantel-Haenszel method.


CONCLUSIONS
There were 43 VTEs identified among all subjects (2.3%). There were significantly more VTE observed in the subjects on P1CTs (n=38, 2.9%) than in the subjects on HDCTs (n=5, 1.0%; RR 0.341, 95% 0.13-0.86, p=0.015). For patients on HDCTs, those with severe dysfunction had a high incidence of VTE (RR 10.5 (1.12-93.6), p=0.021) that remained significant in a multivariate model. VTEs were observed less frequently in patients who were enrolled in HDCT than those who were enrolled in P1CT; however, patients with severe hepatic dysfunction were more likely to experience VTE. Severe liver test abnormalities may not be protective against VTE in patients with malignancies receiving chemotherapy.
Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: mansfield.aaron@mayo.edu.
A S
AS
Mansfield
Vascular Medicine, Northshore University Health System, 2650 Ridge Avenue, Evanston, IL 60201, USA. Electronic address: atafur@northshore.org.
A J
AJ
Tafur
Theradex, 4365 Route 1 South, Princeton, NJ 08540, USA. Electronic address: DVulih@theradex.com.
D
D
Vulih
Clinical Trials Monitoring Branch, Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, USA. Electronic address: SmithG@ctep.nci.nih.gov.
G L
GL
Smith
Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, USA. Electronic address: harrispj@mail.nih.gov.
P J
PJ
Harris
Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, USA. Electronic address: ivyp@ctep.nci.nih.gov.
S P
SP
Ivy
D000368:Aged; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D054556:Venous Thromboembolism / Q000453:epidemiology*
Clinical trials, phase 1; Liver diseases; Neoplasms; Pulmonary embolism; Venous thrombosis