Purpose: In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups.
Materials and methods: Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2.
Results: Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2.
Conclusion: Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of patient selection, study 3 has been successfully launched on September 2005 with high drug compliance. Better clinical results are being accumulated.