Antiangiogenic strategies

Bevacizumab. Tumor angiogenesis is likely to be an important biologic component of prostate cancer growth and progression. An elevated levels of the potent angiogenic molecule vascular endothelial growth factor (VEGF) have been shown to correlate with advanced clinical stage and survival. Microvessel density in clinically localized prostate cancer is an independent prognostic for progression and survival [87, 88]. Antiangiogenic agents using monoclonal antibodies to VEGF, such as bevacizumab (AvastinĀ®) have been studied in prostate cancer. Although single-agent studies have failed to demonstrate significant results, a phase II trial conducted by the CALGB added bevacizumab to docetaxel and estramustine in men with HRPC; 79% of patients had a greater than 50% decline in PSA level, median time to progression of 9.7 months, and overall median survival of 21 months [89]. On the basis of these promising results, a randomized, double-blind, placebo-controlled, phase III trial has been designed comparing docetaxel 75 mg/m2 every 3 weeks with prednisone 10 mg orally daily with either bevacizumab 15 mg/kg IV or placebo every 3 weeks (CALGB 90401]. The primary endpoint for this trial is overall survival, and secondary endpoints include progression-free survival, PSA reduction, and grade 3 toxicities. This trial opened in April 2005 and is actively accruing.

Thalidomide. Is a synthetic glutamic acid derivative. Thalidomide was noted to have anti-inflammatory, immunomodulatory and antiangiogenic effects. alone or in combination with docetaxel were studied in phase II trials with promising results. Microvessel density (MVD) has been reported to be higher in prostate cancer tissue than in adjacent hyperplastic or benign tissue [90]. Preclinical evidence also suggests that angiogenesis may play a key role in the development of aggressive prostate cancer lesion [91]. Clinical studies have observed a correlation between increased angiogenesis in primary tumor specimens and the future development of metastatic disease. The apparent importance of angiogenesis in the evolution of prostate cancer provides a rationale for the investigation of antiangiogenesis agents in CRPC. A phase II trial of thalidomide resulted in a > 40% fall in PSA levels in 27% of patients and improvement in clinical symptoms in all responding patients. PSA declines often resulted in striking reductions in measurable disease on positron emission tomographic scan. Thalidomide plus docetaxel versus docetaxel monotherapy, in a phase II trial in patients with metastatic CRPC, showed a >50% PSA decrease (53% versus 37%) and improvement in median overall survival (28.9 months versus 14.7 months) for patients in the thalidomide group [92, 93].

The combination of docetaxel, thalidomide, bevacizumab, and prednisolone was also evaluated in a phase II trial with a >50% PSA reduction in 89.6% of patients. The median time to progression was 18.3 months and the median overall survival was 28.2 months [93]. More studies are needed before prescribing angiogenesis inhibitors outside clinical trials.

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