Estramustine Phosphate Research Articles

Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science.

Background:Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL).Methods:This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010.Results:Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population.Conclusions:Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

Outcome of Combination Chemotherapy with Docetaxel, Estramustine Phosphate, and Carboplatin after Docetaxel and Prednisolone Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer

We retrospectively reviewed the outcome of docetaxel, EMP, and carboplatin (DEC) as second-line chemotherapy in castration-resistant prostate cancer (CRPC) patients previously treated with docetaxel-prednisolone (DP). Nineteen patients pretreated with DP received a DEC regimen which consisted of a 28-day cycle of docetaxel [60 mg/m2 intravenously (IV) on day 1)], carboplatin (IV to an area under the curve of 5 on day 1), and EMP (560 mg orally daily). The DEC therapy was continued intermittently after two consecutive courses. End points were DEC effect on prostate-specific antigen (PSA), radiographic response, progression-free survival (PFS), and overall survival (OS). All patients received DP before DEC administration with a median of 6 cycles (range, 1 - 12). Mean follow-up duration was 19.0 months after starting DEC therapy; median total number of the therapy cycles was 2 (range, 1 - 11). Thirteen patients (68.4%) showed a PSA decrease; 6 (31.6%) showed a decrease in the PSA level of ≥50%, including 4 with no PSA response to DP. Grade 3/4 neutropenia and febrile neutropenia were observed in 13 (68.4%) and 2 (10.5%) patients, respectively. The median PFS following DEC was 3.7 months. The median OS was 18.0 months. In univariate analyses, patients with ≤12 months from CRPC to DEC had shorter PFS and OS, whereas PSA response to DP was not associated with PFS or OS in CRPC patients treated with DEC after DP. In conclusion, DEC retains some clinical benefits for CRPC patients pretreated with DP, even in patients without any response to DP. Therefore, they may be an effective and feasible treatment option for CRPC patients after first-line docetaxel therapy, particularly for those deemed unfit for novel endocrine and chemotherapeutic drugs.

Effective and Safe Administration of Low-Dose Estramustine Phosphate for Castration-Resistant Prostate Cancer

BackgroundWe evaluated the efficacy and safety of low-dose estramustine phosphate (EMP) in Japanese patients with castration-resistant prostate cancer (CRPC). Patients and MethodsThe present study was a single-arm, nonrandomized prospective study in which all patients received EMP orally twice daily for a total dose of 280 mg/day. A total of 31 patients with CRPC were enrolled from December 2009 to December 2012 at 5 institutions in Japan. The primary endpoint was the prostate-specific antigen (PSA) response, defined as a 50% decline in the serum PSA level, confirmed ≥ 3 weeks later. The secondary endpoints included the objective response rate, interval to PSA progression, PSA response duration, progression-free survival, disease-specific survival, overall survival, safety, and quality-of-life assessment using the Functional Assessment of Cancer Therapy-Prostate scores. ResultsTen patients (32%) had a PSA response, and no patient had an objective response. The treatment was well tolerated, and the most frequent toxicities were grade 1 to 2 nausea/vomiting, anorexia, and gynecomastia. The median interval to PSA progression was 140 days (95% confidence interval [CI], 117-260 days). The PSA response duration was 119 days (95% CI, 49-219 days). The median progression-free survival was 213 days (95% CI, 167-422 days). The 3-year disease-specific survival and overall survival rates were 68.6% (median not reached; 95% CI, 33 months to not available) and 59.9% (median 42 months, 95% CI, 28 months to not available), respectively. ConclusionLow-dose EMP seems to be a safe treatment option with some efficacy in patients with CRPC.

Prospective clinical phase-II trial on docetaxel and estramustine with or without epoeitin-α in patients with metastatic castration-resistant prostate cancer (mCRPC).

e16064 Background: Docetaxel (DOC) and estramustine phosphate (EMP) have shown to exert a survival benefit in mCRPC. Anemia is one of the significant side effects associated the DOC with negative e...

MP87-02 PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND ESTABLISHMENT OF NOVEL RISK STRATIFICATION MODEL IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH DOCETAXEL CHEMOTHERAPY

You have accessJournal of UrologyProstate Cancer: Advanced III1 Apr 2015MP87-02 PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND ESTABLISHMENT OF NOVEL RISK STRATIFICATION MODEL IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH DOCETAXEL CHEMOTHERAPY Yoshihiro Nakagami, Jun Nakashima, Yoshio Ohno, Ohori Makoto, and Masaaki Tachibana Yoshihiro NakagamiYoshihiro Nakagami More articles by this author , Jun NakashimaJun Nakashima More articles by this author , Yoshio OhnoYoshio Ohno More articles by this author , Ohori MakotoOhori Makoto More articles by this author , and Masaaki TachibanaMasaaki Tachibana More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1947AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel (DTX) therapy is the standard treatment for castration-resistant prostate cancer (CRPC). The present study was undertaken to investigate independent prognostic factors and develop a stratification model of survival in CRPC patients treated with DTX therapy. METHODS The present study included 101 CRPC patients treated with DTX therapy from December 2003 to October 2013 in a single institution. We used the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone every 3 weeks. Associations of clinical factors with survival were analyzed using univariate and multivariate analyses. RESULTS The average number of treatment courses was 11. Median overall survival (OS) time was 21 months. In univariate analyses, patients with pain, impaired performance status, hemoglobin (Hb) ≤ 11 mg/dl, neutrophil-to-lymphocyte ratio (NLR) ≥ 2.6, lactate dehydrogenase ≥ 230 IU/L, PSA (at the initiation of DTX therapy) ≥ 110 ng/ml, alkaline phosphatase ≥ 650 IU/L and C-reactive protein (CRP) ≥ 2 mg/dl showed significantly lower survival rates than their respective counterparts. On the other hand, bone metastasis, age, PSA doubling time and lymph node metastasis were not significantly associated with OS. Multivariate analysis showed that presence of pain (hazard ratio [HR] 3.60, p < 0.001), CRP ≥ 2 mg/dl (HR 3.49, p = 0.002), impaired performance status (HR 2.75, p = 0.004), Hb ≤ 11 mg/dl (HR 1.93, p = 0.021), and NLR ≥ 2.6 (HR 1.98, p = 0.031) were independent predictors of OS. Using these 5 statistically significant variables, patients were stratified into 3 risk groups: low (HR = 1 – 3.60), intermediate (HR = 3.82 – 34.55), and high (HR = 34.68 – 132.03). The differences among the three groups were statistically significant CONCLUSIONS Elevation of NLR was an independent prognostic factor as were presence of pain, elevated CRP, impaired performance status and low Hb and the combination of these factors can stratify OS risks in CRPC patients treated with DXT therapy. Our risk stratification model may be useful to identify patients with poor prognosis, who might be good candidates for innovative treatment. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1084 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshihiro Nakagami More articles by this author Jun Nakashima More articles by this author Yoshio Ohno More articles by this author Ohori Makoto More articles by this author Masaaki Tachibana More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Low-Dose Estramustine Phosphate and Concomitant Low-Dose Acetylsalicylic Acid in Heavily Pretreated Patients With Advanced Castration-Resistant Prostate Cancer

BackgroundThe aim of this phase 2 study was to evaluate the activity and tolerability of low-dose estramustine phosphate (EMP) with concomitant low-dose acetylsalicylic acid (ASA) as a thromboprophylactic agent in heavily pretreated patients with advanced castration-resistant prostate cancer. MethodsPatients received 420 mg of oral EMP twice daily and oral ASA 100 mg once daily. The primary endpoint was prostate-specific antigen response. All of the patients had been previously treated with docetaxel and abiraterone acetate, and 12 had also received cabazitaxel. ResultsThirty-one patients were enrolled. Prostate-specific antigen response was observed in 9 patients (29.0%; 95% confidence interval [CI], 14-48). Median progression-free survival was 3.6 months (95% CI, 2.2-5.6), and median overall survival was 7.6 months (95% CI, 6.9-9.7). Treatment was generally well tolerated, and no grade 3/4 toxicity was observed. Ten patients (32.2%) had grade 2 nausea and vomiting. No cardiovascular event and no major bleeding occurred. No venous thromboembolism event was observed. ConclusionLow-dose EMP with concomitant low-dose ASA seems to be a safe treatment option with some activity for patients with advanced castration-resistant prostate cancer who have been heavily pretreated.

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca. The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS. The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110). Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

Concurrent chemoradiation for high-risk prostate cancer.

There are estimated to be 220800 cases of prostate cancer diagnosed in 2015, making up 26% of all cancer diagnoses. Fortunately, adenocarcinoma of the prostate is often a highly treatable malignancy. Even though the majority of prostate cancer patients present with localized disease, prostate cancer still accounts for over 27000 deaths a year. There is a subset of patients that are likely to recur after locoregional treatment that is thought of as a "high-risk" population. This more aggressive subset includes patients with clinical stage greater than T2b, Gleason score greater than 7, and prostate specific antigen greater than 20 ng/dL. The rate of biochemical relapse in this high risk group is 32%-70% within five years of definitive focal therapy. Given these discouraging outcomes, attempts have been made to improve cure rates by radiation dose escalation, addition of androgen depravation therapy, and addition of chemotherapy either sequentially or concurrently with radiation. One method that has been shown to improve clinical outcomes is the addition of chemotherapy to radiotherapy for definitive treatment. Concurrent chemoradiation with 5-fluorouracil, estramustine phosphate, vincristine, docetaxel, and paclitaxel has been studied in the phase I and/or II setting. These trials have identified the maximum tolerated dose of chemotherapy and radiation that can be safely delivered concurrently and established the safety and feasibility of this technique. This review will focus on the addition of concurrent chemotherapy to radiotherapy in the definitive management of high-risk prostate cancer.

Both radical prostatectomy following treatment with neoadjuvant LHRH agonist and estramustine and radiotherapy following treatment with neoadjuvant hormonal therapy achieved favorable oncological outcome in high-risk prostate cancer: a propensity-score matching analysis.

BackgroundTo date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT).MethodsWe studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70 to 76 Gy administered at 2 Gy/fraction.ResultsPropensity-score matching identified 78 matched pairs of patients. The 3-year overall survival rates were 98.3% and 92.1% in the RP and RT groups, respectively (P = 0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P = 0.878).ConclusionsOur study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have an important impact on decision making in treatment of high-risk Pca.

Estramustine phosphate sodium in heavily pretreated patients with metastatic breast cancer: a retrospective consecutive case series.

Estramustine phosphate sodium (EMP) is an oral agent poorly developed--although active--in patients with metastatic breast cancer (MBC). To resume interest in EMP in MBC, we analyzed a retrospective series of consecutive patients with estrogen receptor-positive disease. EMP was given orally at a dose of 140 mg daily. Treatment discontinuation rates due to progressive disease/toxicity and response rates were assessed. Twenty postmenopausal patients with mainly visceral disease were treated with EMP, in five cases in combination with other anticancer drugs. Median numbers of previous chemotherapies and hormonal treatments were six and four, respectively. From the entire cohort, one complete response and four partial responses were observed. The proportions of patients free of progression at 6 and 12 months were 39 and 8 %, respectively. Six patients discontinued EMP, three each for toxicity and adverse events. Good disease control was obtained in heavily pretreated MBC patients receiving EMP. Toxicity was manageable and reversible although treatment discontinuation has to be considered. A prospective study should be encouraged to identify the optimal use of the drug.

Interstitial fibrosis in radical prostatectomy specimen treated with neoadjuvant therapy and its relationship to biochemical outcome and castration-resistant status in high-risk prostate cancer.

251 Background: Interstitial fibrosis (IF) have been known to occur in radical prostatectomy specimens treated with hormonal therapy. We previously reported that neoadjuvant therapy for high-risk prostate cancer (Pca) with luteinizing hormone-releasing hormone (LHRH) agonist and low-dose estramustine phosphate (EMP) (LHRH + EMP) significantly improved biochemical recurrence (BCR) free survival. In this study, we quantified IF in radical prostatectomy specimens treated with neoadjuvant LHRH + EMP, and we examined whether degree of IF has impact on BCR free survival or subsequent castration-resistant status. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study from July 2005 to August 2010. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone (&lt; 50 ng/dL). A quantitative analysis of IF was performed using computer-assisted imaging. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). All patients completed six months of LHRH + EMP neoadjuvant therapy with no delays in the radical prostatectomy. At a median follow-up period of 64.0 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). The average IF rate was 0.43 (0.33–0.55). The five year BCR-free survival rates for the groups with IF rates less than 0.42 and greater than 0.42 were 74.7% and 50.0%, respectively. The log-rank test was significantly different between the two groups (p = 0.010). We could not identify CRPC in the patients with IF rates less than 0.42. Conclusions: Although the present study was small and preliminary, the IF rate may have a predictive potential for biochemical outcome and the occurrence of CRPC after neoadjuvant therapy for high-risk Pca. Further study is warranted to elucidate its clinical significance.

Oncologic outcomes of radical prostatectomy with neoadjuvant LHRH agonist/estramustine and radiotherapy with neoadjuvant hormonal therapy for high-risk prostate cancer.

259 Background: To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT). Methods: We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70–76 Gy administered at 2 Gy/fraction. Results: Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival (OS) rates were 98.3% and 92.1% in the RP and RT groups, respectively (P = 0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P = 0.878). Conclusions: Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have important impact on decision making of treatment in high-risk Pca.

Meta-analysis of randomized trials to study the impact of prednisone on toxicities and survival in metastatic castration-resistant prostate cancer.

28 Background: The impact of daily oral prednisone (P) on toxicities and outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) is unclear. We conducted a meta-analysis of randomized trials comparing regimens that included P in only one arm. Methods: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2013. Eligible studies were selected in an unbiased manner and limited to randomized trials enrolling patients with mCRPC and comparing regimens administering P in only one arm. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Arms containing P were compared with arms without P for severe toxicities grade 3 or higher and overall survival (OS). Results: Five randomized trials were published or presented with P in only one arm: by Scher and colleagues comparing docetaxel (D) plus P versus D plus DN101 (n=953), by Higano and colleagues comparing DP versus GVAX (n=621), by Small and colleagues comparing DP versus GVAX plus D (n=394), by Fossa and colleagues comparing P versus flutamide (n=201) and by Petrylak and colleagues comparing mitoxantrone plus P versus D plus estramustine phosphate (n=770). The total number of patients was 2,939, of whom 1,471 received therapy not containing P and 1,468 received therapy containing P. All five trials were eligible for analysis of toxicities, but the Fossa trial was excluded for the OS analysis due to lack of required parameters. There was no difference between the non-P and P groups for severe toxicities (incidence rate ratio [IRR] = 0.82, p = 0.712, I2 = 97.9%). When examining toxicities as a reason for discontinuing therapy, the non-P groups were not different from the P groups (relative risk [RR] = 1.24, p = 0.413, I2 = 86.8%). The non-P groups demonstrated no difference in OS compared to the P groups (HR = 1.09, p = 0.531, I2= 79.7%). The meta-analysis is limited by the trial level design and small number of patients and does not exclude a favorable palliative impact of P. Conclusions: This meta-analysis of randomized trials in mCRPC suggests no significant impact on severe toxicities and OS with the use of daily oral prednisone.

The efficacy of ethinylestradiol for castration-resistant prostate cancer

We analyzed the efficacy of ethinylestradiol as estrogen therapy on Castration-resistant Prostate Cancer (CRPC). The study was conducted on 14 patients who were diagnosed as having CRPC and who were being prescribed ethinylestradiol (1.5-2.0 mg/day) with aspirin (100 mg/day) and an LH-RH agonist in our hospital from August 2011. All patients had already been treated with a combined androgen blockade (CAB), 8 patients had been treated with docetaxel, 9 patients with tegafur-uracil, 4 patients with estramustine phosphate sodium. Age and prostate-specific antigen (PSA) at prescription of ethinylestradiol was 55-85 (median 75.5) and 0.784-508.7 ng/ml (median 4.842 ng/ml). Thirteen patients (92.9%) achieved a decline in PSA, 8 patients (57.1%) achieved a decline in PSA > 50%. Time to progression was 0-18 months (median 7 months), and there were no severe adverse events including venous thromboembolic diseases. Oral ethinylestradiol administration may have efficacy for CRPC without severe adverse events. Ethinylestradiol may be one of the selective drugs for CRPC patients who do not wish to undergo intravenous chemotherapy or become resistant to docetaxel.

Efficacy of tegafur–uracil (UFT) administration in castration-resistant prostate cancer patients with a history of both alternative antiandrogen therapy and estramustine phosphate sodium hydrate therapy

The purpose of this study was to evaluate the efficacy of tegafur-uracil (UFT) administration as a fourth-line therapy in patients with castration-resistant prostate cancer (CRPC) who had already received combined androgen blockade (CAB) therapy (first-line), alternative antiandrogen therapy (second-line), and estramustine phosphate sodium hydrate (EMP) therapy (third-line), in order to determine who would benefit from UFT therapy. UFT was administered at a daily dose of 300 mg/m(2) to 26 patients, and the response to UFT 4 weeks after its induction and its toxicity were evaluated. A reduction in the serum prostate-specific antigen (PSA) value was observed in 12 patients (46.2 %), while two cases (7.7 %) achieved more than 50 % reduction in PSA. Two patients (7.7 %) required discontinuation of UFT administration because of side effects (grade 2 exanthema in one patient and grade 2 nausea in one patient). A PSA response to UFT was observed, especially in patients older than 75 years and/or whose Gleason score was 8 or less. Our data indicate that UFT administration as a fourth-line therapy was tolerable and effective to some degree in patients with CRPC who had already received CAB therapy, alternative antiandrogen therapy, and EMP therapy. It can be used, even in patients aged more than 75 years old, without any loss of efficacy or effect on their activities of daily life, and can be regarded as a treatment option for patients with advanced prostate cancer.

Efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in castration-resistant prostate cancer patients: report of 102 cases and review of literature

This retrospective chart review study was conducted to evaluate the efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC) and to determine who would benefit from EMP therapy. EMP was administered at a daily dose of 560 mg to 102 patients as a third-line therapy, who had already received combined androgen blockade (CAB) and subsequent alternative antiandrogen therapy. The responses to EMP after its induction and its toxicity were evaluated. We also analyzed the association between the clinicopathological factors of the patients and their responses to EMP therapy. A reduction in the serum prostate-specific antigen (PSA) 4 weeks after induction was observed in 70 patients (68.6%), while 30 cases (29.4%) achieved more than 50% reduction of PSA. Long-term reduction of PSA from baseline for more than 6 months was observed in 31 patients (30.4%). EMP treatment was discontinued in 11 patients (10.8%) because of side effects (nausea in six patients, gynecomastia in three patients, eruption in one patient, and liver dysfunction in one patient). Multivariate analysis demonstrated that long duration of prior hormonal therapy was an independent favorable factor for reduced PSA levels, long responses, and overall survival. The data suggest that oral EMP administration as a third-line monotherapy is well tolerated and effective to some degree in patients with CRPC who have already received CAB and subsequent alternative antiandrogen therapy. Thus, EMP can be regarded as one treatment option, especially for patients whose prior duration of hormonal therapy was long.

Clinical outcomes and toxicity of estramustine phosphate (EP) addition to docetaxel (D) as first-line therapy for castration-resistant prostate cancer (CRPC): A cumulative analysis on 243 patients (pts) from two randomized phase II trials.

208 Background: Although EP exerts a synergism with D and a meta-analysis suggested a survival advantage in combining EP to chemotherapy, D+EP combination is usually discouraged due to a marginal improvement in disease control at cost of an enhanced toxicity compared to D alone. In order to assess the role of EP added to D we have analyzed data from pts enrolled in two randomized trials with D ± EP conducted by our group (BJU Int 2008 – ASCO GU 2012). Methods: All patients received D 70 mg/m2IV q 3 wks ± E 280 mg/TID PO for 5 days starting 1 day prior to D. Ninety-five pts of the first study (started in 2002) were treated until progression; 148 pts of the second study received 8 D courses in continuous or intermittent fashion. We evaluated PSA response, PFS according to PCWG2, OS and toxicity. Results: We shared the clinical data from all 243 pts (123 D, 120 D+EP): the median baseline PSA values were 53 and 60 respectively; 49.5% and 59.1% of the D and D+EP pts presented visceral metastases, respectively. Clinical outcomes and main toxicities are summarized in the Table. Conclusions: The addition of EP to D was tolerable with a mild toxicity profile; it was able to double the biochemical responses which did not translate in any PFS or OS advantage. From our data the addition of EP addition to D should not further role in first line of CRPC, while it may help to overcome D resistance in selected cases according to our previously published data (Urol Oncol 2010). However, this statement should be critically considered at the light of new drugs availabile and active after D failure. Clinical trial information: 2006-005728-17. [Table: see text]

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

Radical prostatectomy (RP) has limited cancer control potential for the patient with high-risk prostate cancer (Pca). We prospectively examined the efficacy and safety of neoadjuvant therapy with luteinizing hormone-releasing hormone (LHRH) agonist + low-dose estramustine phosphate (EMP) (LHRH+EMP) followed by RP. High-risk Pca was defined by the D'Amico stratification system. A total of 142 patients with high-risk Pca were enrolled in this trial from September 2005 to March 2011. The LHRH+EMP therapy included administration of LHRH agonist and 280 mg day(-1) EMP for 6 months before RP. Pathological cancer-free (pT0) rate on the surgical specimen was the primary end point. Secondary end points were PSA-free survival and toxicity. The average patient age was 67.4 years (interquartile range (IQR) 72, 65) and the median initial PSA level was 14.80 ng ml(-1) (IQR 26.22, 7.13). The median Gleason score was 9 (IQR 9, 7) and 97 patients (68.3%) had clinical stage T2c or T3. All patients completed 6 months of LHRH+EMP neoadjuvant therapy with no delays in RP. Seven patients (4.9%) achieved pT0. Surgical margins were negative in 125 patients (87.0%). At a median follow-up period of 34.9 months, PSA-free survival was 84.3%. No serious adverse events were reported during the study and there were no toxicity-related deaths. Six months of LHRH+EMP neoadjuvant therapy followed by RP is safe and oncological outcomes are acceptable. Although this study was a single-arm trial with a relatively short follow-up, this treatment may have a potential to improve PSA-free survival in high-risk Pca patients. Further clinical trials are warranted.

Ablation of the ATP-binding cassette transporter, Abca2 modifies response to estrogen-based therapies

The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein expressed in oligodendrocytes and Schwann cells, prostate, ovary and macrophages. In cell cultures, ABCA2 over-expression has been linked with resistance to the anticancer agent, estramustine phosphate (EMP; a nor-nitrogen mustard conjugate of estradiol). The present study shows that Abca2 knockout (KO) mice have greater sensitivity to a variety of side effects induced by EMP treatment. Chronic EMP (12×100mg/kg body weight) produced mortality in 36% of KO mice, but only 7% of age-matched wild type (WT). Side effects of the drug were also more prevalent in the KO mouse. For example, during the first week of EMP treatments, 67% of KO males (compared to 6% of WT males) responded with episodic erectile events. In WT mice, ABCA2 protein localized within pene corpuscles, (which rely on modified Schwann cells for amplification of tactile signals) suggesting that the transporter may function in the erectile process. Endothelial nitric oxide synthase (eNOS; a source of nitric oxide during erectile response) levels were similar in WT and KO male penile tissue. Treatment with 100mg/kg EMP (once daily for four days) elevated serum estradiol and estrone in both WT and KO. However, the circulating levels of these estrogens were higher in KO mice implying a reduced plasma clearance of estrogens as a consequence of ABCA2 ablation. Consistent with the pro-convulsant effects of estrogens, KO mice also displayed an increased incidence of seizures following EMP (14% vs. 0%). Taken together, these data indicate that ABCA2 deficiency renders mice more sensitive to EMP treatment-induced effects implying that the transporter has a role in regulating EMP transport and/or metabolism.

Weekly low-dose docetaxel combined with estramustine and dexamethasone for Japanese patients with metastatic castration-resistant prostate cancer

A low-dose chemotherapy consisting of docetaxel, estramustine and dexamethasone was investigated for its beneficial effect and feasibility in Japanese patients with metastatic castration-resistant prostate cancer (CRPC). Seventy-two Japanese patients with metastatic CRPC were enrolled to receive docetaxel (25 mg/m(2) on days 2 and 9), estramustine phosphate (280 mg orally twice daily from day 1 to day 3 and from day 8 to day 10) and dexamethasone (0.5 mg orally twice daily) every 21 days. The median age of the patients was 72 years and 64 patients (89 %) had ≥grade 1 anemia at entry. The median total number of courses administered was 8.5 (range 1-93). Forty-two patients (58 %) had a prostate-specific antigen (PSA) decline of ≥50 %. The median progression-free survival and overall survival were 6 and 23 months, respectively. Fifteen patients (21 %) improved and 53 patients (74 %) were stable in their performance status. Of the 40 patients with bone pain, 25 patients (63 %) showed pain reduction. Among 71 patients assessable for their hemoglobin levels, 21 patients (30 %) achieved an increase of at least 1.0 g/dl. Of the 5 patients who terminated treatment because of ≥grade 3 toxicity, 4 patients had pneumonitis and one patient had anemia. Only one patient developed ≥grade 3 neutropenia. The low-dose combination of docetaxel, estramustine and dexamethasone is active and tolerable with beneficial effects on serum PSA levels, performance status, anemia and bone pain in Japanese patients with CRPC. This regimen is a reasonable option for elderly patients with bone disease at risk of hematologic toxicity.