Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials

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.

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.

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.