Increased Frequency of Venous Thromboembolism With the Combination of Docetaxel and Thalidomide in Patients With Metastatic Androgen-Independent Prostate Cancer

McDonald K. Horne III, M.D., William D. Figg, Pharm.D., FCCP, Phil Arlen, M.D., James Gulley, M.D., Ph.D., Catherine Parker, R.N., Nehal Lakhani, M.D., Howard Parnes, M.D., William L. Dahut, M.D.

Disclosures

Pharmacotherapy. 2003;23(3) 

In This Article

Methods

This randomized phase II study evaluated the frequency of VTE in patients with prostate cancer who were treated with docetaxel alone or in combination with thalidomide. The protocol was approved by the institutional review board of the National Cancer Institutes. All patients gave written informed consent before participating in the study.

To be eligible for this trial, patients were required to have androgen-independent prostate cancer with progressive soft-tissue or bony metastases confirmed by computed tomography or bone scan, and/or a rising prostate specific antigen (PSA) level (two consecutive measurements > 5.0 ng/ml, at least 2 wks apart). Participants also had to have failed medical or surgical castration and antiandrogen withdrawal. Patients were allowed to continue receiving luteinizing hormone-releasing hormone agonists. Every attempt was made to exclude patients taking herbal therapies. History of deep vein thrombosis or VTE was not an exclusion criterion. No limit was placed on previous hormonal therapies, radiotherapy, or radioisotope administration, but patients were excluded if they had received chemotherapy or thalidomide before the start of the study. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0-1.

Each patient received one of two drug regimens: intravenous docetaxel 30 mg/m2/week for 3 consecutive weeks, followed by 1 week off, or the combination of continuous oral thalidomide 200 mg every evening plus the same docetaxel regimen. This 4-week cycle was repeated until there was evidence of excessive toxicity (grade 3 or higher) or disease progression (diagnosed by either computed tomography, bone scan, or PSA level). Twice as many patients were randomized to the thalidomide plus docetaxel arm as to the docetaxel alone arm. The frequency of VTE was analyzed statistically using the Fisher exact test.

All cases of clinically suspected VTE were confirmed with appropriate imaging studies. These studies were duplex ultrasonography (five cases), computed tomography (two cases), and ventilation-perfusion lung scanning (two cases).

Plasma samples that had been obtained and frozen before and during treatment with docetaxel or docetaxel plus thalidomide were tested for six parameters relevant to the homeostatic balance of coagulation: functional protein C, protein S, antithrombin, factor VIII, activated protein C resistance, and thrombin-antithrombin complex concentrations. The functional assays were performed using an STA Hemostasis System (Diagnostica Stago, Inc., Parsippany, NJ). Thrombin-antithrombin complex levels were measured with a commercial enzyme-linked immunosorbent assay (Enzygnost TAT micro; Dade Behring Diagnostics, Inc., San Jose, CA). The pre- and posttreatment test results were analyzed statistically using the nonparametric Wilcoxon signed rank test for paired comparisons. Because these tests were not included in the original clinical trial design and reflect six post hoc hypotheses, the significance level of was set at 0.0085.

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