[Efficacy and Prognostic Factors of Estracyt ® in Patients with Castration-Resistant Prostate Cancer (CRPC) : From the Data Analysis of Estracyt ® Special Drug Use Investigation].

Estracyt○R (estramustine phosphate) is a medical drug for prostate cancer with cytotoxic activity causing disruption of microtubule organization and indirect androgen production suppressing activity by its metabolite, estradiol. Based on the data obtained from the Estracyt○R Special Drug Use Investigation which surveyed the clinical efficacy and safety of Estracyt○R in patients with prostate cancer whose relapse of prostate cancer after combined androgen blockade (CAB) therapy was confirmed, we evaluated the progression-free survival, prognostic factor, decrease in prostate specific antigen (PSA) level and safety. This surveillance was conducted at 147 institutions nationwide between October, 2010 and September, 2013 and clinical efficacy was evaluated in 239 cases and safety in 329 cases. The median duration of progression-free survival, PSA progression-free survival and PSA response were 169 days (95%CI, 142-190), 197 days (95%CI, 169-267) and 385 days, respectively. The decrease in PSA level was observed in 125 cases (52.3%). Rate of PSA decline ＞50 and ＞25% were 18.4 and 43.1, respectively, and rate of PSA best response (PSA decline ＞ 50%) was 32.6%. Multivariate analysis demonstrated that long duration of prior CAB therapy, Estracyt○R - pretreatment PSA value and bone metastasis influenced progression-free survival significantly. Adverse events were observed in 127 cases (38.6%). The major adverse events were anorexia which was observed in 35 cases (10.9%), gastrointestinal disorders observed in 32 cases (9.7%), abnormal laboratory test values observed in 31 cases (9.4%) and gynecomastia observed in 16 cases (4.9%). These results suggest the clinical efficacy and safety of Estracyt○R for chemotherapy-naïve castration-resistant prostate cancer (CRPC), and Estracyt○R is regarded as one of the treatment options for patients with CRPC, especially for patients who had long duration of prior CAB therapy.

Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment.

BACKGROUND: We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard-dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression-free and overall survival were analyzed in each group. RESULTS: Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline ≥ 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). CONCLUSION: For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events.

Docetaxel in combination with estramustine and prednisolone for castration-resistant prostate cancer.

BACKGROUND: The aim of this study was to investigate the efficacy and toxicity of docetaxel-based chemotherapy, and to investigate pretreatment factors that can predict overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). METHODS: From June 2005 to July 2010, 70 patients with CRPC underwent docetaxel-based chemotherapy at Wakayama Medical University and related hospitals. Docetaxel was given at a dose of 70 mg/m(2) once every 3 weeks or 35 mg/m(2) twice every 3 weeks. Oral estramustine 560 mg was given concurrently for five consecutive days during weeks 1 and 2 of each cycle, and prednisolone 10 mg was given every day. Dexamethasone 8 mg was premedicated intravenously before docetaxel administration. RESULT: The patients received a median of four cycles of treatment (range 1-31). In the serum prostate-specific antigen response, 13 (18.6%) patients achieved a complete response and 29 (41.4%) achieved a partial response. Median OS and time to progression were 14 months and 6 months, respectively. Median follow-up period was 9.5 months. Two independent pretreatment risk factors that predicted OS were visceral metastasis including lymph node metastasis and anemia. Grade 3/4 neutropenia and anemia occurred in 25.7 and 8.6% of the patients, respectively. Four treatment-related deaths were seen during the observation period. CONCLUSION: The combination of docetaxel, estramustine and prednisolone was effective in Japanese patients with CRPC; however, this combination therapy should be carefully indicated to elderly and/or poor performance status patients due to its toxicity. Visceral metastasis and anemia were identified as independent risk factors which could predict OS.

Quality of life associated with treatment of castration-resistant prostate cancer: a review of the literature.

The development of new therapies for castration-resistant prostate cancer (CRPC) has increasingly focused on improving patient quality of life, mainly because of limited survival gains and continuing high morbidity burden from disease progression or the adverse effects of treatments. However, there is no generally accepted quality of life instrument for use with this patient group. This paper objectively reviews the existing literature and assesses the impact of CRPC treatments on patients' quality of life. The review also provides a narrative description of the evolving role of quality of life measures in clinical trials, and critiques the most widely used instruments.

The use of estramustine phosphate in the modern management of advanced prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Estramustine phosphate has anti-tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as docetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low-molecular-weight heparin support its use as a second-line treatment in hormone-resistant prostate cancer. OBJECTIVES: • Estramustine phosphate is a nitrogen mustard derivative of estradiol-17ß-phosphate and has anti-tumour properties. • Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel. PATIENTS AND METHODS: • Relevant clinical studies using chemotherapy combinations including estramustine are discussed. • Efficacy and safety outcomes are summarized. RESULTS: • Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine. • Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events. CONCLUSIONS: • The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low-molecular-weight heparins support the use of estramustine as an effective second-line treatment strategy in hormone-resistant prostate cancer. • These promising findings warrant further investigation in a randomized clinical trial.

Survival benefit during zoledronic acid and docetaxel-based chemotherapy in metastatic hormone-refractory prostate cancer patients: an institutional report.

PURPOSE: To assess the overall survival (OS) of metastatic hormone-refractory prostate cancer (mHRPC) patients when treated with zoledronic acid (ZOL) in combination with docetaxel-based chemotherapy (docetaxel combined with estramustine or oxaliplatin or gemcitabine). METHODS: A retrospective chart review of mHRPC patients in our clinic was performed. At the time of data collection, 23 patients with mHRPC were identified, of which 15 were still alive at data analysis. Survival data was analyzed through Kaplan-Meier methodology. OS stratification by prostatic specific antigen (PSA) response (50% and 80% decline) and multivariate analysis of prognostic variables were also conducted. RESULTS: 182 cycles of chemotherapy (mean 8.27 cycles, range 1-23) were recorded. Median OS was 26 months (range 5-56; 95% CI: 4.0-48.0). No patient achieved complete response (CR), 5 (21.7%) showed partial response (PR), 2 (8.7%) minor response (MR), 7 (30.4%) stable disease (SD) and 9 (39.1%) progressive disease (PD). Twelve (52.2%) patients exhibited a decrease in PSA levels >50% (9 of 12 >80%). No association of age, PSA response, or tumor response with OS could be demonstrated. The most frequent toxicities were anaemia (52.1%) and neutropenia (26%). CONCLUSION: In our clinical setting, ZOL and docetaxel- containing chemotherapy was a beneficial therapeutic scheme for the patients in terms of safety and survival.

A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer.

Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

Combination chemotherapy with weekly paclitaxel or docetaxel, carboplatin, and estramustine for hormone-refractory prostate cancer.

Paclitaxel (PTX) and docetaxel (DTX) have been reported to be effective for treating hormone-refractory prostate cancer (HRPC). The objective of this study was to examine the efficacy of weekly DTX (PTX)-based chemotherapy and compare weekly DTX-based chemotherapy with triweekly (once every 3 weeks) DTX-based chemotherapy. We performed a combination chemotherapy on a weekly cycle with an i.v. PTX 100 mg/m(2) or i.v. DTX 30 mg/m(2) (days 1, 8, 15, and 22), i.v. carboplatin (CBDCA) (day 1, area under the plasma concentration time curve = 6), and oral estramustine phosphate 10 mg/kg daily for 10 HRPC patients. In addition, we investigated the patient characteristics and treatment efficacy and toxicity. Among all cases, serum prostate-specific antigen (PSA) decreased by 50% or more in 90% of patients, by 75% or more in 70%, and 90% or more in 40% after chemotherapy. The effectiveness of weekly DTX-based chemotherapy was comparable with previous reports, and we showed no toxicity serious enough to require cancellation of chemotherapy. In conclusion, weekly DTX-based chemotherapy was no less effective and less toxic than triweekly DTX-based chemotherapy for HRPC patients and therefore can be useful as the first-line chemotherapy regimen for HRPC patients, especially the elderly or those with a poor performance status.

Safety and efficacy of docetaxel, estramustine phosphate and hydrocortisone in hormone-refractory prostate cancer patients.

OBJECTIVE: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone-refractory prostate cancer (HRPC). METHODS: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate-specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. RESULTS: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3-4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4-5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. CONCLUSIONS: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.

[Effect of the 5-HT3 receptor antagonist granisetron on estramustine phosphate sodium (Estracyt)-induced emesis in ferrets].

Estracyt(R) is an antimitotic drug used for the treatment of prostate cancer, and its most common adverse effects are nausea and vomiting. In this study, we investigated the effect of a 5-HT3 receptor antagonist, granisetron, on emesis induced in ferrets by estramustine phosphate sodium (EMP), the active ingredient of Estracyt. To clarify the mechanism of action of EMP-induced emesis, we also investigated the effect of EMP on the release of serotonin (5-HT) in the isolated rat ileum. EMP (3 mg/kg, per os) induced 75.3+/-10.2 retching episodes and 7.5+/-1.3 vomiting episodes during a 2-h observation period. The latency to the first emetic response was 58.0+/-13.5 min. Granisetron (0.1 mg/kg, per os) administered 1 h before the administration of EMP reduced the number of EMP-induced retching and vomiting episodes to 1.3+/-1.3 and 1.0+/-1.0, respectively, and prolonged the latency by a factor of almost two. EMP (10-5 and 10-4 M) increased 5-HT release from isolated rat ileum, and 10 -7 M granisetron almost completely inhibited the increase induced by 10-4 M EMP. These results suggest that EMP induces nausea and vomiting via 5-HT release from the ileum, and that 5-HT3 receptor antagonists may be useful to prevent gastrointestinal adverse effects that occur during treatment with Estracyt.

[Two cases of pellagra associated with chemotherapy of docetaxel, estramustine, dexamethasone].

An 81-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone as an outpatient. After 4 courses of chemotherapy, he was admitted to our hospital in December 2007 because of general fatigue, appetite loss and erythema of the back of hands and face. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. An 80-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone without admission. After 8 courses of the chemotherapy, appetite loss appeared. In January 2008, medical examinations revealed nails peeling off, facial erythema and erosion of the back of his hands. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. Pellagra, a nicotinic acid deficiency disease, is rarely observed clinically nowadays. However, it may occur in the patients, undergoing chemotherapy without admission.

[Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy for hormone-refractory prostate cancer].

The objective of this study was to evaluate the efficacy and safety of low-dose docetaxel, estramustine and dexamethasone combination chemotherapy in patients with hormone-refractory prostate cancer (HRPC). Sixty-nine patients with HRPC were enrolled. Docetaxel was given at a dose of 25 mg/m(2) on days 1 and 8 every 3 weeks, oral estramustine 280 mg twice daily on days 1 to 3 and 8 to 10, and oral dexamethasone 1 mg daily throughout the course. Cycles were repeated every 21 days. Treatment was continued until disease progression or excessive toxicity. Patients were evaluated for response and toxicity. Patients received a median of eleven cycles (range : 1-25). Prostatic-specific antigen (PSA) was decreased greater than 50% in 53 (77%) out of 69 patients and median duration of PSA response was 10.2 months. Median time to progression and overall survival 10.2 and 24 months, respectively. Grade 1-2 fatigue was the most common toxicity observed in 10 (15%) patients. Grade 3-4 toxicities were observed in five (7%) patients (2 thrombosis, 2 bilirubin elevation, and 1 aspartate transaminase/alanine transaminase elevation). Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy is an effective and well tolerated treatment for Japanese HRPC patients.

Long-term Castration-related Outcomes in Patients With High-risk Localized Prostate Cancer Treated With Androgen Deprivation Therapy With or Without Docetaxel and Estramustine in the UNICANCER GETUG-12 Trial.

INTRODUCTION: Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects. PATIENTS AND METHODS: Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected. RESULTS: Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms. CONCLUSION: Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.

A phase I/II trial of fixed-dose docetaxel plus irinotecan and escalating doses of estramustine phosphate for second-line or greater treatment of selected advanced solid tumors.

This phase I/II study evaluated the safety of the combination of irinotecan, docetaxel, and estramustine for selected advanced solid tumors and also obtained initial efficacy data. Twenty-two patients were enrolled in the study. The regimen consisted of docetaxel 30 mg/m(2) and irinotecan 60 mg/m(2) both given intravenously on days 1 and 8 every 21 days in combination with escalating doses of estramustine (500 mg/m(2)/day escalated to 750 mg/m(2)/day on days 0, 1, 2, 7, 8, and 9 given every 21 days) during phase I. Dose escalation was continued until the maximum planned dose level of estramustine (750 mg/m(2)/day) was reached. After the appropriate phase II dose of estramustine was found additional patients were enrolled. Twenty-one of the 22 patients were evaluable for toxicity and 17 for tumor response. The recommended phase II dose of estramustine was found to be 750 mg/m(2)/day orally on days 0, 1, 2, 7, 8, and 9 given every 21 days. Hematologic toxicity was fairly mild, with only one episode of grade 3 neutropenia. Diarrhea was the most common nonhematologic toxicity with grade 3 toxicity occurring in five of 21 patients. Only one episode of venous thrombosis was observed. Objective response rate was 15.8%, overall clinical benefit rate was 63%, and median time to progression was 15 weeks. Estramustine in combination with the doublet of docetaxel and irinotecan is a well-tolerated regimen with minimal hematologic toxicity, mild to moderate nonhematologic toxicity, and promising initial antitumor activity in previously treated patients with advanced solid tumors.

Combination chemotherapy with docetaxel, vinorelbine and estramustine phosphate in metastatic androgen-resistant prostate cancer: a single institution experience.

UNLABELLED: The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC). PATIENTS AND METHODS: Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients. RESULTS: A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients. CONCLUSION: The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.

Single nucleotide polymorphisms of 17beta-hydroxysteroid dehydrogenase type 7 gene: mechanism of estramustine-related adverse reactions?

OBJECTIVES: To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17beta-hydroxysteroid dehydrogenase (HSD17B7) gene. METHODS: Luciferase reporter genes containing a 5'-flanking of the HSD17B7 gene, as well as the sequence around the SNP, were transfected into LNCaP and DU145 cells. Then, luciferase assays were carried out. RESULTS: The presence of the G allele resulted in an increase of transcriptional activity derived from the 5'-flanking region of the HSD17B7 gene by 270% and 370% in LNCaP and DU145 cells, respectively. Transcriptional activity of the HSD17B7 gene containing the G allele was higher than that of the C allele. CONCLUSIONS: The transcriptional activity of the HSD17B7 gene containing the G allele is higher than that of the C allele. This difference in HSD17B7 expression may regulate the risk of peripheral edema as an adverse reaction induced by estramustine phosphate sodium.

Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy.

OBJECTIVES: The intention of this study is to describe the impact and underlying potential basis of the prostate-specific antigen (PSA) flare-up phenomenon in patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel-based chemotherapy. METHODS: We retrospectively identified 74 consecutive patients who received docetaxel/estramustine-based chemotherapy at our institution. Patients were evaluated based on modified criteria from the Prostate-Specific Antigen Working Group regarding survival and toxicity. Additionally, two androgen receptor mutations derived from patients with advanced disease were analyzed for promiscuous transactivation activity. RESULTS: The 74 patients were stratified into four groups: response, partial response, flare-up-initial PSA elevation, and progression. Median survival in the flare-up group (n=8) was 20 months and did not differ from the response group (p=0.564). The flare-up group showed a maximum PSA elevation from baseline between 3.4 and 28.3% (between three and six weeks) followed by PSA decline >or=50% from the baseline level in seven of the eight patients. The androgen receptor mutations AR(877) and AR(715) displayed a 37.5- and 5.2-fold increase in transactivation activity by progesterone and a 12.6- and 5.4-fold increase by estrogen compared to the AR(WT), respectively. CONCLUSIONS: A considerable portion of HRPC patients experience an initial PSA flare-up under systemic chemotherapy. In this study, occurrence of flare-up phenomenon did not impact survival. Chemotherapy should be continued a minimum of six weeks before removing patients from a docetaxel-based regimen. We showed evidence that co-medication with dexamethasone/prednisolone and/or estramustine itself can induce an initial PSA flare-up via androgen receptor mutations.

[Estramustine phosphate withdrawal syndrome in relapsed prostate cancer: two case reports].

The decrease of the level of serum prostate specific antigen (PSA) after discontinuation of estramustine phosphate (EMP) has rarely been reported. We report 2 cases in whom EMP withdrawal syndrome was encountered. Case 1 was a 68-year-old man with a complaint of paresis of lower limbs. He was diagnosed with prostate cancer with multiple bone metastases. The serum PSA level was 9,300 ng/ml. He was treated with luteinizing hormone-releasing hormone agonist (LH-RHa) and bicalutamide (BCL). Six months later, EMP was started against PSA failure. During the 3-year treatment with EMP, PSA decreased to the nadir of 0.7 ng/ml and gradually increased to 14 ng/ml. After withdrawal of EMP, PSA decreased to 0.3 ng/ml (97.9% decline) and remained at this level for 4 months. Case 2 was a 61-year-old man who visited our hospital with gross hematuria. Transurethral bladder biopsy and transrectal prostate biopsy were performed. The diagnosis was moderately differentiated adenocarcinoma of the prostate that invaded to the bladder. Computed tomography (CT) showed a lymph node metastasis. He was treated with LH-RHa and BCL. The treatment was changed to EMP after PSA failure. EMP was withdrawn when PSA was 30 ng/ml. Then PSA decreased to less than 0.2 ng/ml (99% decline) and remained at this level for 9 months. We consider that in patients with EMP-resistant progression, EMP withdrawal syndrome should be checked.

Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data.

BACKGROUND: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer. METHODS: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used. FINDINGS: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275). INTERPRETATION: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.

INTRODUCTION: This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest. RESULTS: Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant. CONCLUSION: The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.