Thalidomide Antiangiogenesis Explored in Prostate Cancer Studies

BETHESDA, Md—Thalidomide (Thalomid) appears to inhibit angiogenesis (the recruitment of new blood vessels by the tumor). Clinically, thalidomide has been shown to lower PSA levels in some patients with androgen-independent prostate cancer. Using an LNCaP in vitro model, thalidomide has been shown to slightly increase the amount of PSA per cell number. "Some drugs appear to upregulate the expression of PSA and some downregulate it," William Dahut, MD, of the National Cancer Institute, said at an NCI conference on urologic oncology. This is clearly the case for carboxyamidotriazole (CAI) and TNP-470, both angiogenesis inhibitors, he said. CAI has been shown to downregulate PSA, whereas TNP-740 upregulated it.

In 1995, a phase II trial was conducted in androgen-independent metastatic prostate cancer patients. Patients were randomized to a low dose of thalidomide (200 mg/d) or a high dose (escalating up to 1,200 mg/d). Patients could not tolerate the high-dose levels and that arm was stopped. Of the other patients, 30% showed a 40% or greater decline in PSA.

"We saw no correlation between markers of angiogenesis—vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF)—and PSA decline," Dr. Dahut said. "Either there was a low response rate or we were looking at the wrong endpoints." He noted that serial PET scans of six patients found 100% agreement between scan changes and PSA changes (ie, the PET image showed increased activity with an increase in PSA and vice versa).

Dr. Dahut is currently testing thalidomide in asymptomatic prostate cancer patients receiving intermittent hormonal therapy. All patients receive 6 months of leuprolide (Lupron) hormonal therapy. Treatment is then stopped. Patients whose PSA is less than 5 ng/mL are randomized to placebo or thalidomide. They are kept on the drug until their PSA returns to the starting value or to 5 ng/mL. Then they are restarted on hormonal therapy for 6 months, after which they are crossed over to the other arm. The goal is to increase the break period between hormonal treatments.

In another early clinical trial in 49 patients, Dr. Dahut’s team is exploring evidence of antiangiogenic synergy using a combination of weekly thalidomide and docetaxel (Taxotere) therapy. The regimen is given for 3 weeks of a 4-week cycle. To date, study results suggest that thalidomide may be enhancing the PSA decline rate, he said.