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ANTICANCER RESEARCH 30: 5201-5206 (2010)

Ethinylestradiol Improves -specific Antigen Levels in Pretreated -resistant 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: was used as , 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 is useful for advanced PCa, its effects are development of combined 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 , 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 -based regimens were developed as survival rates. Results: All patients had already been treated standard 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 . 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 12 lymph node metastasis, 8 patients (33%) had both bone 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-, 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 . 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 5 (22%) patients underwent docetaxel-based chemotherapy (Table II).

Adverse events. Adverse events occurred in three patients, namely elevation of liver enzymes, anorexia, and heart Figure 2. A: Progression-free survival (PFS) and B: overall survival failure in 1 patient each. The patient who had elevation of (OS) in patients treated with ethinylestradiol as shown with Kaplan- liver enzymes has been mentioned already. Ethinylestradiol Meier analysis. was withdrawn 56 days after starting ethinylestradiol in the patient who had heart failure, and the dose of ethinylestradiol was decreased to 1.0 mg daily in the patient who had Table II. Additional and subsequent treatment. anorexia. Each adverse event was improved after withdrawal or a decrease in dose of ethinylestradiol. Patients, n 11

Treatment Discussion Fultamide 2 Dexamethasone 3 It is extremely difficult to cure CRPCa and there is no clear Prednisolone 2 consensus regarding the appropriate management strategy. Tegafur uracil 1 Yagoda et al. reported that among 1001 men with CRPCa Docetaxel 5 Zoledronic acid 6 who had received treatment in 26 chemotherapy trials, the Tranilast 3 objective response rate was only 8.7% and the median survival time was 6-10 months, with no clear survival benefit for any agent (16). Subsequently, two large randomized studies of chemotherapy including docetaxel for CRPCa were reported. The median survival time of CRPCa patients treated chemotherapy regimens significantly lengthened the OS with 75 mg/m2 docetaxel (DTX) every 3 weeks and daily compared with the control regimen of and prednisone was 18.9 months (TAX 327) (10), and the median prednisone, and was accepted as the standard form of therapy survival time with 60 mg/m2 DTX every 3 weeks and daily for advanced CRPCa. However, the incidence of adverse EMP on days 1 through 5 was 17.5 months (Southwest events, such as grade 3 and 4 neutropenia, was relatively Oncology Group 9916; SWOG 9916) (11). These DTX-based high. Therefore, it was necessary to develop new agents for

5203 ANTICANCER RESEARCH 30: 5201-5206 (2010) treatment of advanced CRPCa. Ethinylestradiol treatment was of the precise PFS and OS, and the incidence of adverse reported to cause considerable cardiovascular events; events. All patients were Japanese, so ethinylestradiol may however, comparable rates were reported in some studies not have the same effects in patients from other ethnic following placebo treatment of patients with PCa (12). In the backgrounds. In particular, cardiovascular events may be present study, the proportion of patients showing a PSA different between races. Larger international prospective response >50% was 70% and the median PFS was estimated studies with longer follow-up periods are needed to confirm to be 300 days. The proportion of PSA response >50% was our findings. reported to be 45% in TAX 327 and median PFS was reported Finally, although a decline in PSA >50% was achieved by to be 6.3 months in SWOG 9916. These data suggest that ethinylestradiol in 16 out of 23 patients, a continuous ethinylestradiol may be more beneficial than DTX-based increase in PSA was observed in two patients. It was unclear chemotherapy. Moreover, only one cardiovascular event (heart which factor(s) contributed to the good response to failure) occurred in the present study, and ethinylestradiol ethinylestradiol. Both the search for biomarkers that can treatment was successfully continued in 22 out of 24 patients predict the response to ethinylestradiol and examination of (92%). The incidence of cardiovascular events in the differences between the mechanisms of action of ethinylestradiol treatment may be lower than previously ethinylestradiol and other estrogens for CRPCa are needed. thought, and its safety and tolerability should be re-examined. Although this was a pilot study, the results suggested that However, care should be taken in comparing the present study ethinylestradiol could achieve a high PSA response rate and with TAX 327 and SWOG 9916. The results of this reasonable PFS and OS in patients with pretreated advanced comparison may not be correct because of the differences in CRPCa with a low adverse event rate. background between the present study and both TAX 327 and SWOG 9916. The baseline median PSA levels in TAX 327 References and SWOG 9916 were higher (84 and 114 ng/ml, respectively) than that in the present study (63.8 ng/ml). The 1 Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer lower baseline median PSA level in the present study may be statistics, 2009. CA Cancer J Clin 59: 225-249, 2009. a preferential factor regarding PSA response, PFS and OS. 2 Ferlay J, Parkin DM and Steliarova-Foucher E: Estimates of On the other hand, the median ages in the present study, TAX cancer incidence and mortality in Europe in 2008. Eur J Cancer 327, and SWOG 9916 were 75, 68, and 70 years, 46: 765-781, 2010. respectively. In addition, the proportion of cases with 3 Petrylak DP: Chemotherapy for advanced hormone refractory prostate cancer. Urology 54(6A Suppl): 30-35, 1999. Gleason’s score 8-10 (and poor differentiation) in the present 4 Oh WK: Chemotherapy for patients with advanced prostate study was higher (46%) than that in TAX 327 (31%). These carcinoma. A new option for therapy. Cancer 88(12 Suppl): data suggest the advantage of ethinylestradiol. 3015-3021, 2000. Furthermore, ethinylestradiol had antitumor effects in 5 Kojima S, Suzuki H, Akakura K, Shimbo M, Ichikawa T and Ito CRPCa patients who have experienced treatment failure with H: Alternative antiandrogens to treat prostate cancer relapse after DTX-based chemotherapy. The proportion of PSA response initial hormone therapy. J Urol 171(2 Pt 1): 679-683, 2004. >50% in phase 2 studies of , which is a 6 Hirano D, Minei S, Kishimoto Y, Yamaguchi K, Hachiya T, Yoshida T, Yoshikawa T, Endoh M, Yamanaka Y, Yamamoto T, selective inhibitor of CYP17, and MDV3100, which is an Satoh Y, Ishida H, Okada K and Takimoto Y: Prospective study androgen-, was reported to be 36% and of estramustine phosphate for hormone refractory prostate cancer 56%, respectively (17, 18). Ethinylestradiol may be a useful patients following androgen deprivation therapy. Urol Int 75: 43- candidate for salvage treatment after failure of treatment with 49, 2005. DTX-based chemotherapy. Interestingly, ethinylestradiol also 7 Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M, had antitumor effects in CRPCa patients who had experienced Tokizane T Fukui T, Ono Y, Inoue H, Shin M, Tsujimoto Y, treatment failure with estrogens, such as fosfestrol and EMP. Takayama H, Aozasa K and Okuyama A: Potential mechanism for the effects of dexamethasone on growth of androgen- It was reported previously that estrogens had a direct toxic independent prostate cancer. J Natl Cancer Inst 93: 1739-1746, effect on PCa cells by induction of apoptosis in addition to 2001. an indirect antitumor effect on these cells by down-regulation 8 Izumi K, Mizokami A, Li YQ, Narimoto K, Sugimoto K, of serum level (19). There may be some Kadono Y, Kitagawa Y, Konaka H, Koh E, Keller ET and differences between ethinylestradiol and other estrogens in Namiki M: Tranilast inhibits hormone refractory prostate cancer the mechanisms of their direct effects on PCa cells. Based on cell proliferation and suppresses transforming growth factor-β1- these data, ethinylestradiol may be an effective treatment with associated osteoblastic changes. Prostate 69: 1222-1234, 2009. 9 Izumi K, Mizokami A, Shima T, Narimoto K, Sugimoto K, reasonable tolerability in patients with advanced CRPCa. Kobori Y, Maeda Y, Konaka H, Koh E and Namiki M: The present study had some limitations. It was a Preliminary results of tranilast treatment for patients with retrospective study with one arm. Moreover, short follow- advanced castration-resistant prostate cancer. Anticancer Res 30: up and small sample size may have prevented determination 3077-3081, 2010.

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