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

Discussion

We observed an increased frequency of VTE in patients receiving the combination of thalidomide and docetaxel for androgen-independent prostate cancer, making prostate cancer the third malignancy (along with multiple myeloma and renal cell carcinoma) in which thalidomide has been associated with thrombosis. The frequency of VTE in patients receiving both drugs was significantly greater (19%) than in those receiving docetaxel alone (0%) (p=0.025). Furthermore, it greatly exceeded the frequency of 1-2% reported in other patients with advanced prostate cancer.[16,17] However, in our study, all of the patients with a history of previous VTE had been randomized to the thalidomide arm. Since approximately one fourth of patients with VTE have a recurrent event, this skewed distribution may have contributed to the increased frequency of thrombosis that we observed.[18] Of the four patients who had a history of previous VTE, three developed recurrent VTE while receiving docetaxel and thalidomide. However, the recurrent VTE episodes in two of these patients perhaps should be considered as first-time VTEs, since their previous VTE episodes had occurred 8 and 9 years earlier, respectively.

We were unable to find biochemical clues to suggest how a prothrombotic effect of thalidomide might be mediated. The only measured factor that fell appreciably after starting thalidomide plus docetaxel was protein C. This reduction was not observed in the men taking docetaxel alone, suggesting that it was related to thalidomide. Although the change in protein C was statistically significant (p=0.003), it was not great enough to account for the increased risk of thrombosis.

It has been suggested, however, that the prothrombotic effect of thalidomide may result from endothelial damage.[19] Agents used in combination with thalidomide that are toxic to endothelium (e.g., doxorubicin) may expose subendothelial tissue to the prothrombotic effect of the antiangiogenic agent. Docetaxel has antiangiogenic effects in vitro,[20] and one report associates mesenteric venous thrombosis with this drug.[21] Therefore, perhaps docetaxel and thalidomide act synergistically to damage endothelium in vivo and thus stimulate thrombosis.

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