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Ethinylestradiol Improves Prostate-Specific Antigen Levels in Pretreated Castration-Resistant Prostate Cancer Patients

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Ethinylestradiol Improves Prostate-Specific Antigen Levels in Pretreated Castration-Resistant Prostate Cancer Patients ANTICANCER RESEARCH 30: 5201-5206 (2010) Ethinylestradiol Improves Prostate-specific Antigen Levels in Pretreated Castration-resistant Prostate Cancer Patients KOUJI IZUMI, YOSHIFUMI KADONO, TAKASHI SHIMA, HIROYUKI KONAKA, ATSUSHI MIZOKAMI, EITETSU KOH and MIKIO NAMIKI Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan Abstract. Background: Ethinylestradiol was used as Europe, about 382,000 men (11.9% of all cancer) were palliative treatment for patients with advanced prostate diagnosed with prostate cancer in 2008 (2). Although cancer (PCa). However, its use has declined after the hormone therapy is useful for advanced PCa, its effects are development of combined androgen blockade. In the present limited because PCa changes to an androgen-independent study, we analyzed the effects of ethinylestradiol on phenotype over several years of therapy (3, 4). Recently, oral pretreated castration-resistant PCa patients. Patients and salvage therapies, e.g. alternative antiandrogens, estramustine Methods: Twenty-four Japanese patients were orally phosphate (EMP), dexamethasone, and tranilast for administered ethinylestradiol at a dose of 1.5 mg/day and castration-resistant PCa (CRPCa), have been reported (5-9). prostate-specific antigen (PSA) was examined. We However, as their effects do not last for a long time, new retrospectively analyzed the proportion of patients achieving agents are required for treatment of advanced CRPCa. a decline in PSA of >50% and progression-free and overall Although docetaxel-based regimens were developed as survival rates. Results: All patients had already been treated standard chemotherapy for CRPCa, high incidences of with combined androgen blockade followed by one or more adverse events were reported for these regimens (10, 11). salvage therapies. Median follow-up time was 227 (range: Treatment with ethinylestradiol was used as palliative 42-1490) days and median ethinylestradiol treatment time therapy in patients with advanced PCa in the 1980s. was 195 (range: 3-791) days. The proportion of patients However, ethinylestradiol treatment has become less achieving a decline in PSA >50% was 70%. Median common since the introduction of new forms of treatment, progression-free survival was estimated as 300 days. At the such as antiandrogens and luteinizing hormone-releasing end of the follow-up period, one patient had died from PCa. hormone agonists (12). One reason for this decline in use is Adverse events occurred in three patients, namely elevation the risk of cardiovascular events during treatment with of liver enzymes, anorexia, and heart failure in one patient estrogens. However, ethinylestradiol treatment is inexpensive each. Conclusion: Oral ethinylestradiol administration may and well-tolerated, and increases survival rate in patients be useful for treatment of advanced castration-resistant PCa with metastatic PCa (13). A small study of 1 mg oral after salvage therapy with a high PSA response rate and low ethinylestradiol combined with lanreotide acetate for CRPCa adverse event rate. patients showed a decline in prostate-specific antigen (PSA) of >50% in 9 out of 10 patients (14). Although Prostate cancer (PCa) is the most frequently diagnosed ethinylestradiol may be promising for treatment of CRPCa, cancer in men and the second leading cause of cancer-related there have been no reports regarding treatment with death in the USA. About 192,280 men (25.1% of male ethinylestradiol alone for CRPCa patients treated with more cancer cases) were estimated to have PCa in 2009 (1). In than one salvage therapy. In the present study, we analyzed the effects of ethinylestradiol in such pretreated CRPCa patients. Correspondence to: Yoshifumi Kadono, Department of Integrative Patients and Methods Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Patients with CRPCa in whom more than one salvage therapy had Ishikawa 920-8641, Japan. Tel: +81 762652393, Fax: +81 not been effective were orally administered ethinylestradiol at a dose 762226726, e-mail: [email protected] of 1.5 mg/day at Kanazawa University Hospital and associated institutions from October 2005 to May 2010. All patients had Key Words: Castration-resistant prostate cancer, ethinylestradiol, histologically confirmed adenocarcinoma of the prostate. Other new prostate-specific antigen. treatments were not started concomitant with ethinylestradiol except 0250-7005/2010 $2.00+.40 5201 ANTICANCER RESEARCH 30: 5201-5206 (2010) in one patient who received simultaneous zoledronic acid infusion. Table I. Patient characteristics. Additional treatments were started or ethinylestradiol was discontinued when the physician in charge judged that the state of Characteristic the PCa had deteriorated despite ethinylestradiol treatment or adverse events occurred. The primary study objective was determination of Patients, n 24 the proportion of patients achieving a decline in PSA >50% Median age at diagnosis, years 68 (54-84) according to the Prostate Specific Antigen Working Group 1 criteria Median PSA at diagnosis, ng/ml* 118 (6.8-1800) (PSA response) (15). The maximal decline was determined based on Median age at starting ethinylestradiol, years 75 (58-86) the value obtained >4 weeks after commencement of treatment. Time Median PSA at starting ethinylestradiol, ng/ml 63.8 (1.6-735) Median follow-up, days 227 (42-1490) to PSA progression was calculated for patients with PSA decline Median ethinylestradiol administration, days 195 (3-791) >50% from baseline at the time the PSA had increased to 50% above Gleason score the nadir and was >5 ng/ml. For those not meeting the PSA decline <7 or well-diffrentiated 2 criteria, time to PSA progression was the time at which PSA had =7 or moderately differentiated 8 increased by 25% from baseline. >7 or poorly differentiated 9 Statistical analysis was performed using commercially available Unknown 5 software (Prism; GraphPad Software, Inc., San Diego, CA, USA). T stage The crude probabilities of progression-free survival (PFS) and T1-2 6 overall survival (OS) were estimated using the Kaplan-Meier T3-4 11 method. To exclude the effects of other treatments, when PFS was Unknown 7 calculated, we regarded the time at which other new treatments were Regional node metastasis started as the time when the follow-up should end. No 13 Yes 7 Results Unknown 4 Distant metastasis Patient population. Twenty-four patients were enrolled in the No 9 present study. The median age and the median PSA at Bone 11 Other sites 1 commencement of ethinylestradiol treatment were 75 (range: Unknown 3 58–86) years and 63.8 (range: 1.6-735) ng/ml, respectively. Prior treatment The median follow-up period after starting ethinylestradiol Radical prostatectomy 5 and the median ethinylestradiol administration period were Brachytherapy 1 227 (range: 42-1490) days and 195 (range: 3-791) days, Castration** 24 Bicaltamide 24 respectively (Table I). On starting ethinylestradiol, 20 Fultamide 14 patients (83%) had bone metastasis, 10 patients (42%) had Chlormadinone acetate 12 lymph node metastasis, 8 patients (33%) had both bone Estramustine phosphate 21 metastasis and lymph node metastasis, and only 2 patients Fosfestrol 2 (8%) had no metastasis. Before starting ethinylestradiol, all Dexamethasone 4 Prednisolone 1 patients underwent combined androgen blockade by either Tegafur uracil 8 medical castration using luteinizing hormone-releasing Docetaxel 3 hormone agonist or surgical castration with oral Zoledronic acid 10 administration of anti-androgens, and subsequently one or Strontium 1 more salvage therapies were given. Docetaxel-based Tranilast 8 chemotherapy was given in only 3 patients (13%). Fosfestrol PSA: Prostate-specific antigen: Data in parentheses are ranges. *Omitting and EMP were given in 2 (8%) and 21 patients (88%), 4 patients with missing data. **Including 4 surgical castrations. respectively (Table I). PSA change. One patient was excluded from the analysis because of withdrawal of ethinylestradiol due to elevation of patients who did not undergo EMP showed 90%, 69%, and liver enzymes 3 days after starting ethinylestradiol treatment. 28% declines in PSA. Two of the three patients who PSA responses after starting ethinylestradiol treatment are underwent docetaxel-based chemotherapy showed declines shown in Figure 1. The number of patients achieving a of 60% and 57% in PSA, and one patient was excluded due decline in PSA >50% was 16 (70%). The number of patients to elevation of liver enzymes. with PSA decline compared with baseline was 21 (91%). The patient who underwent both zoledronic acid infusion and PFS and OS. Median PFS was estimated after 300 days ethinylestradiol treatment simultaneously showed a 69% (Figure 2A). Five out of six patients who underwent other decline in PSA. Two patients who received fosfestrol as prior new treatments in addition to ethinylestradiol had PSA treatment had declines of 72% and 51% in PSA. Three progression before starting new treatments. At the end of the 5202 Izumi et al: Ethinylestradiol for Castration-resistant Prostate Cancer Figure 1. Maximum changes in prostate-specific antigen (PSA) levels with ethinylestradiol are shown by waterfall plots. follow-up period, 22 out of 23 patients (96%) were alive and one patient had died from PCa (Figure 2B). Additional and subsequent treatment. After starting ethinylestradiol, other treatments were started in 11 patients (48%). Only
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