Major steps have been taken in the delineation of tumor-associated angiogenesis. In vitro data are accumulating to evaluate the role of the major ligands of the angiogenesis pathway, VEG-F (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) in prostate cancer cell lines.
Thalidomide is a glutamic acid derivative thought to have antiangiogenic activity. A randomized, phase II trial of 63 patients utilized low-dose (200 mg daily) and high-dose (up to 1200 mg daily) thalidomide in AIPC patients.47 Prior cytotoxic treatment was allowed. The high-dose arm was terminated early as none of the 13 patients enrolled had a ^50% reduction in PSA. The low-dose arm was then expanded to 50 patients. Nine patients (14%) had a ^50% decline in PSA. Four patients (6%) had a PSA decline of ^50% that was sustained for >150 days. No complete or partial responses were seen in patients with measurable disease on CT scan or bone scan. A total of 560 adverse events were reported. The most common complaints were fatigue, constipation and peripheral neuropathy. Median survival for all 63 patients is 15.8 months.
This study, while appearing to provide only a minor role for thalidomide in AIPC, must be viewed in the appropriate context. First, the mechanism of antiangiogenic agents could be to reduce the potential for metastatic growth. In comparison to chemotherapy, their role may be considered cytostatic as opposed to cytotoxic. Thalidomide and other antiangiogenesis agents may be best suited for patients with a low disease burden. In this study, however, patients had markedly advanced disease and were heavily pre-treated. Additionally, in vitro data have suggested that thalidomide may up-regulate the secretion of PSA in certain prostate cancer cell lines.48 If this holds true in vivo, even small declines in PSA may correlate to a significant amount of tumoricidal activity. Further studies in this area are eagerly awaited.
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