Radical Prostatectomy With and Without Neoadjuvant Chemohormonal Pretreatment for High-Risk Localized Prostate Cancer: A Comparative Propensity Score Matched Analysis.

BACKGROUND: To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP). PATIENTS AND METHODS: Our NCHT protocol involved complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) plus estramustine phosphate (560 mg). NCHT was provided to 60 patients with PCa before RP, and we compared the clinical and pathologic outcomes with those of 349 patients with high-risk PCa who underwent RP alone using propensity score matching. The data for those who underwent RP alone were obtained from the Michinoku Japan Urological Cancer Study Group database. RESULTS: In the NCHT group, 10.0% experienced pathologic complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien-Dindo grade III or higher) after RP. The median follow-up duration was 42.5 months, and the 5-year biochemical recurrence (BCR)-free survival was 60.1%. In multivariate analysis, pN+ was an independent prognostic factor for BCR (hazard ratio = 5.251, 95%CI 1.300-21.201; P = .020). In propensity score matching, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = .021). In subgroup analyses, the BCR rate in patients with a single high-risk factor was significantly lower in the NCHT group than in the RP-alone group (P = .027). CONCLUSION: NCHT before RP can reduce the risk of BCR in patients with high-risk PCa, particularly if a single high-risk factor is present. However, the potential for perioperative complications should be considered.

Phase 2 Study of Cyclophosphamide, Etoposide, and Estramustine in Patients With Castration-Resistant Prostate Cancer.

BACKGROUND: There are no effective chemotherapies for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has failed to respond to taxanes or patients who do not wish to receive intravenous drugs. We hypothesized that low doses of multiple medications with prolonged exposure would result in a high response rate and low toxicity. PATIENTS AND METHODS: Patients with mCRPC were eligible for this phase 2 trial. The primary endpoint was a prostate-specific antigen decrease of more than 50%. CEE consisted of cyclophosphamide (50 mg/m2), etoposide (50 mg/m2), and estramustine 280 mg provided orally once a day for 14-day cycles every 28 days. RESULTS: Fifty-two patients were enrolled and included in all evaluations. The prostate-specific antigen response rate was 46% in all patients, 53% in chemotherapy-naive subjects, and 31% after docetaxel chemotherapy. Thirty subjects had measurable lesions, 1 (3%) had complete response, 2 (7%) partial response, and 22 (73%) stable disease, for a clinical benefit of 83%. Sixty percent experienced an improvement in their performance status, and 65% reported improvement in their pain. The median overall survival was 18.6 months in all patients, 20.4 months in chemotherapy-naive patients and 11.3 months in patients whose disease progressed while receiving docetaxel therapy. Grade 3/4 treatment-related toxicities included 20% neutropenia, 10% thrombocytopenia, 10% deep-vein thrombosis, 8% anemia, 8% fatigue, 4% death, and 2% anorexia and stomatitis. CONCLUSION: CEE was an all-oral, easy-to-administer, and effective triple-drug therapy for patients with mCRPC.

The efficacy and safety comparison of docetaxel, cabazitaxel, estramustine, and mitoxantrone for castration-resistant prostate cancer: A network meta-analysis.

AIMS: The aim of this study was to compare the efficacy and safety of docetaxel, cabazitaxel, docetaxel + estramustine, mitoxantrone in the management of castration-resistant prostate cancer (CRPC). METHODS: Electronic databases including PubMed, Cochrance Library and Embase were searched for studies published from when the databases were established to January 1st, 2018. Randomized controlled trials (RCTs) that compared docetaxel + prednisone (DP), cabazitaxel + prednisone (CP), docetaxel + estramustine + prednisone (DEP), and mitoxantrone + cabazitaxel + prednisone (MP) for CRPC treatment were identified. The network meta-analysis was conducted with software R 3.3.2. We analyzed the main outcomes, including the overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) response, tumor response and severe adverse events (AEs). Ranking of the chemotherapeutic agents was based on probabilities of interventions for each of the outcomes that were performed. The consistency of direct and indirect evidence was assessed by node splitting. RESULTS: 10 RCTs, with 3590 patients, were analyzed. The network meta-analysis results revealed that CP significantly increased OS, PFS, PSA response, tumor response, and severe AEs compared to MP. DP showed similar results with CP except for tumor response, where it showed slight inferiority in effectiveness. DEP was associated with clearly improved outcomes in PFS, PSA response and tumor response compared to those of MP, but this was not the case for OS benefit and severe AEs. No significant difference was detected in DP, CP and DEP except for the outcomes of severe AEs. MP was less effective in survival and clinical benefit, but much safer in safety outcomes than other chemotherapy agents. The probabilities of rank plots showed that CP ranked first in OS and tumor response; DEP ranked first in PFS time and PSA response; MP was the best treatment mode for safety. CONCLUSIONS: DP and CP survival benefit (OS, PFS) and clinical benefit (PSA response and tumor response) were comparable, as well as their associated AEs. DEP was associated with less survival benefit, similar clinical improvement and more AEs than DP or CP. MP had the lowest survival and clinical benefit but excellent safety than other agents. Based on evidences of current results, we recommended CP as the most suitable chemotherapy agent for CRPC patients, followed by DP, MP as third, and DEP as the last choice. However, considering limitations of our network meta-analysis, additional high-quality studies are needed for further evaluation.

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.

Dendrimer conjugated estramustine nanocrystalline 'Dendot': An effective inhibitor of DMBA-TPA induced papilloma formation in mouse.

Clinically approved anticancer drug estramustine mediates its function by impairing microtubule polymerization. However, the low aqueous solubility and high toxicity limit its anticancer activity via the oral route. Previously, efforts have been made to develop an enhanced water soluble form of estramustine as estramustine phosphate (EM) but acidic gastrointestinal pH breaks the phosphate derivative via oral administration. As an alternative approach, we have made an effort to enhance solubility and minimize toxicity in vivo by conjugating EM to a poly(amidoamine) (PAMAM) dendrimer, which generated the sustained release of dendrimer conjugate (DEM). To the best of our knowledge, for the first time, we report the direct proof of the nano-crystalline 'DenDot' of DEM on TEM image. The toxicity study showed that both EM and DEM were nontoxic up to 20mg/kg. A comparative anti-papilloma study was also performed with EM and dendrimer conjugates (DEM) using a two-stage mouse skin carcinogenesis model. We found that DEM was more effective in inhibiting skin tumor formation than EM. Histopathology and immunohistochemistry studies further indicated that DEM treatment increased cell apoptosis, and reduced epithelial hyperplasia, cell proliferation and inflammation in skin tissues of mice. In addition, the synthetic DEM conjugate inhibited skin tumor progression more effectively than EM.

Overall survival of high-risk prostate cancer patients who received neoadjuvant chemohormonal therapy followed by radical prostatectomy at a single institution.

BACKGROUND: The optimal treatment for high-risk prostate cancer (PCa) remains to be established. We previously reported favorable, biochemical recurrence-free survival in high-risk PCa patients treated with a neoadjuvant gonadotropin-releasing hormone agonist or antagonist and estramustine phosphate (EMP) (chemohormonal therapy; CHT) followed by radical prostatectomy (RP). We conducted a retrospective study to elucidate the clinical benefit of neoadjuvant CHT for high-risk PCa patients. METHODS: We reviewed the clinical and pathological records of 1254 PCa patients who underwent RP and bilateral pelvic lymphadenectomy between July 1996 and April 2016 at Hirosaki University. According to the D'Amico risk classification, we focused on 613 patients in the high-risk group. The high-risk PCa patients were further divided into two groups based on whether the patients received neoadjuvant CHT before RP (EMP group) or not (non-EMP group). The endpoint was overall survival (OS) after surgery. RESULTS: The 5- and 10-year OS rates were 98.5 and 92.6%, respectively. The 10-year OS rate in the EMP group was significantly higher compared to the non-EMP group (P = 0.021). In multivariate analysis, administration of neoadjuvant CHT, lymph node involvement, and castration-resistant PCa status were significantly associated with OS. CONCLUSIONS: RP with neoadjuvant CHT using EMP for high-risk PCa patients provided excellent long-term OS.

[Low-Dose Estramustine Phosphate Monotherapy in Castration-Resistant Prostate Cancer Patients].

We retrospectively evaluated the efficacy and toxicity of low-dose estramustine phosphate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC). We administered EMP at 140 or 280 mg/day to 89 patients between January 2003 and December 2012. None of the patients were receiving concomitant dexamethasone and none had ever been treated with docetaxel. Fifty-three patients (59.6%) experienced a decline in prostate-specific antigen (PSA) levels, including 20 (22.5%) with a decline of more than 50%. The median time to PSA progression was 90 days. PSA-progression-free survival was significantly longer in patients treated with EMP 140 mg compared with patients treated with EMP 280 mg, and there was no significant difference in the incidence of adverse events between the two groups. The most frequent toxicities were nausea and anorexia. Two patients had grade 3 adverse events of pulmonary embolism and liver dysfunction. EMP treatment was discontinued in nine patients (10.1%) because of side effects (nausea and anorexia in 7, liver dysfunction and lacunar infarction in 1). Low-dose EMP monotherapy is well tolerated and can effectively reduce PSA levels.

Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: a single-center study.

PURPOSE: The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) for high-risk Pca patients treated with neoadjuvant therapy comprising a luteinizing hormone-releasing hormone agonist plus low-dose estramustine (LHRH + EMP) prior to radical prostatectomy (RP). In the present study, we evaluated the efficacy of neoadjuvant therapy comprising a gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate (GnRH + EMP) in patients with high-risk Pca. METHODS: Between September 2005 and March 2016, we identified 406 high-risk Pca patients of whom 136 received neoadjuvant GnRH + EMP (GnRH group) and 270 received LHRH + EMP (LHRH group) before RP. We retrospectively evaluated the clinical and pathological covariates between the two groups. The endpoint was the rate of pathological T0 status. RESULTS: The rates of pathological T0 status were 11.0 and 8.9% in the GnRH group and LHRH group, respectively (P = 0.490). The 2-year BRFS rates were 97.8% in the GnRH group and 87.8% in the LHRH group (P = 0.027). CONCLUSION: Our findings suggest that neoadjuvant GnRH antagonist + EMP followed by RP may improve the pathological outcomes and reduce the risk of biochemical recurrence in patients with high-risk Pca. Further prospective studies to confirm these findings are warranted.

The impact of extended lymph node dissection versus neoadjuvant therapy with limited lymph node dissection on biochemical recurrence in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis.

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. The current guidelines recommend extended pelvic lymph node dissection (e-PLND) for selected intermediate- and high-risk patients treated with RP. However, the indications, optimal extent, and therapeutic benefits of e-PLND remain unclear. The aim of this study was to assess whether e-PLND confers an oncological benefit for high-risk Pca compared to neoadjuvant luteinizing hormone-releasing hormone and estramustine (LHRH + EMP). The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at four institutes between March 2000 and December 2014. In the e-PLND group, we identified 238 high-risk Pca patients who underwent RP and e-PLND, with lymphatic tissue removal around the obturator and the external iliac regions, and hypogastric lymph node dissection. The neoadjuvant therapy with limited PLND (l-PLND) group included 280 high-risk Pca patients who underwent RP and removal of the obturator node chain between September 2005 and June 2014 at Hirosaki University. The outcome measure was BRFS. The 5-year biochemical recurrence-free survival rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9 and 54.7%, respectively (P < 0.0001). The operative time was significantly longer in the e-PLND group compared to that of the neoadjuvant therapy with l-PLND group. Grade 3/4 surgery-related complications were not identified in both groups. Although the present study was not randomized, neoadjuvant LHRH + EMP therapy followed by RP might reduce the risk of biochemical recurrence.

Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Recently, increasing relevant studies researched the efficacy of castration resistant prostate cancer (CRPC) patients using chemotherapy with or without estramustine, in order to assess the efficacy and toxicity of combining estramustine with chemotherapy for the treatment of CRPC. METHODS: Relevant randomized clinical trials were systematically searched from the databases Pubmed, Embase, and Web of science up to April 1, 2016. Data were centrally extracted and analyzed from the previous studies by 2 independent reviewers. The primary endpoint was overall survival (OS) with pooled hazard ratios. Secondary endpoints were prostate-specific antigen (PSA) response and grade 3 or 4 toxicity using pooled odds ratios. Stata version 12.0 software was used for statistical analysis. RESULTS: Overall, this meta-analysis identified 9 eligible articles, including a total of 956 patients, who had been accrued between January 1, 1993 and December 1, 2010 and randomly divided into chemotherapy with estramustine and without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, epirubicin, and vinblastine. Patients who received chemotherapy with estramustine had a better improvement in PSA response rate, comparing those without estramustine (OR = 1.84, 95% CI = 1.20-2.80). However, OS between the 2 groups indicated no significant differences (HR = 0.90, 95% CI = 0.77-1.05). Besides, these results of meta-analysis showed no obvious differences between these 2 groups in grade 3 or 4 adverse effects, including anemia (OR = 0.78, 95% CI = 0.38-1.57), neutropenia (OR = 0.91, 95% CI = 0.59-1.43), thrombocytopenia (OR = 0.68, 95% CI = 0.19-2.42), nausea (OR = 2.34, 95% CI = 0.81-6.72), vomiting (OR = 2.43, 95% CI = 0.69-8.51), diarrhea (OR = 3.45, 95% CI = 0.93-12.76), fatigue (OR = 0.67, 95% CI = 0.32-1.41), neuropathy (OR = 0.54, 95% CI = 0.21-1.44), allergic reaction (OR = 1.60, 95% CI = 0.37-6.84), thromboembolic event (OR = 2.18, 95% CI = 0.86-5.51), and edema (OR = 1.02, 95% CI = 0.18-5.95). CONCLUSIONS: This meta-analysis indicated chemotherapy with additional estramustine increased the PSA response rate. However, OS and grade 3 or 4 toxicity were not improved for these patients with CRPC.

Identifying Severe Adverse Event Clusters Using the National Cancer Institute's Common Terminology Criteria for Adverse Events.

PURPOSE: Exploring the relationships among adverse events is important because those that arise from a common mechanism are amenable to a common intervention, which can improve symptom management, quality of life, and treatment adherence. To date, symptom cluster studies have used patient-reported data, which are not always available in clinical trials. In this study, we proposed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) to identify adverse event clusters because the CTCAE data are collected as standard practice and can therefore be used when patient-reported outcomes are unavailable. METHODS: The CTCAE data from a randomized clinical trial conducted by SWOG that compared docetaxel plus estramustine versus mitoxantrone plus predinsone in patients with advanced prostate cancer were used to identify severe adverse event clusters. A variable based hierarchical cluster analysis was conducted using the CTCAE for the 323 patients who experienced at least one grade 3 or higher adverse event. RESULTS: A total of 109 adverse event types were captured using the CTCAE. Four clusters had moderate associations: nausea, vomiting, and anorexia (n = 35, r = 0.45); joint/bone(myalgia, arthralgia, and arthritis) and muscle weakness (n = 26, r = 0.29); anemia and transfusion (n = 20, r = 0.38); and neutrophils/granulocytes, febrile neutropenia, and leukocytes/lymphopenia (n = 114, r = 0.29). Two clusters had weak associations: fatigue/malaise/lethargy and dehydration (n = 66, r = 0.12); and constipation, infection without neutropenia, and abdominal pain/cramping (n = 35, r = 0.13). CONCLUSION: Several severe adverse event clusters were identified in patients with advanced prostate cancer. Identifying adverse event clusters using CTCAE data from clinical trials is feasible.

Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial.

PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.

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

UNLABELLED: Despite the favorable toxicity profile at the standard dose of 560 mg daily, the tolerability and toxicology of estramustine phosphate (EMP) have been a cause for concern at administration. Moreover, we do not know whether a lower dose of 280 mg of EMP daily can be administered with some efficacy and fewer side effects. The results of our phase II study suggest that low-dose EMP is a safe treatment option with the same efficacy in patients with castration-resistant prostate cancer. BACKGROUND: We evaluated the efficacy and safety of low-dose estramustine phosphate (EMP) in Japanese patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: The 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. RESULTS: Ten 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. CONCLUSION: Low-dose EMP seems to be a safe treatment option with some efficacy in patients with CRPC.

Tissue Chromogranin A Expression during Prostate Cancer Progression: Prediction of Chemosensitivity.

PURPOSE: We investigated the clinical significance of chromogranin A (CgA) expression as a neuroendocrine (NE) marker during prostate cancer (PCa) progression, especially as a potential predictor of chemotherapeutic response in castration-resistant PCa (CRPC) patients based on immunohistochemical findings. MATERIALS AND METHODS: Sixteen CRPC patients who underwent combination (docetaxel/estramustine/ carboplatin; DEC) chemotherapy were retrospectively studied. Immunostaining of CgA was performed using prostate biopsy samples obtained at the initial PCa diagnosis, during androgen deprivation therapy, at the time of CRPC diagnosis, and after 2 cycles of DEC therapy. The positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells. Differences in positive rates among the treatment courses were compared using a Mann-Whitney test. RESULTS: The mean percentage of CgA-positive PCa cells increased in a stepwise manner until CRPC development and then significantly decreased after DEC therapy. Subanalysis of CgA at CRPC diagnosis showed a more evident reduction of CgA expression after DEC therapy in patients who also had a high level of CgA as compared to those with a low CgA level (P = .003). Likewise, longer prostate-specific antigen progression-free survival was related to CRPC and high CgA (P = .028). CONCLUSION: NE differentiation of PCa cells is accelerated despite androgen deprivation and reaches a peak at the time of CRPC diagnosis. Although further studies using larger samples are needed, CgA expression in CRPC may be a candidate tissue biomarker to reflect the chemotherapy sensitivity of individual PCa cells.

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.

BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

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

BACKGROUND: The 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. METHODS: Patients 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. RESULTS: Thirty-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. CONCLUSION: Low-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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Long-term oncological outcomes of a phase II trial of neoadjuvant chemohormonal therapy followed by radical prostatectomy for patients with clinically localised, high-risk prostate cancer.

OBJECTIVE: To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer. PATIENTS AND METHODS: In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only. RESULTS: In all, 34 patients were enrolled and followed for a median of 13.1 years. Within 10 years most patients had biochemical recurrence (BCR-free probability 22%; 95% confidence interval [CI] 10-37%). However, the probability of disease-specific survival at 10 years was 84% (95% CI 66-93%) and overall survival was 78% (95% CI 60-89%). The CHT group had higher-risk features than the comparison group (123 patients), with an almost doubled risk of calculated preoperative 5-year BCR (69% vs 36%, P < 0.01). After adjusting for these imbalances the CHT group had trends toward improvement in BCR (hazard ratio [HR] 0.76, 95% CI 0.43-1.34; P = 0.3) and metastasis-free survival (HR 0.55, 95% CI 0.24-1.29; P = 0.2) although these were not statistically significant. CONCLUSIONS: Neoadjuvant CHT followed by RP was associated with lower rates of BCR and metastasis compared with the RP-only group; however, these results were not statistically significant. Because this treatment strategy has known harms and unproven benefit, this strategy should only be instituted in the setting of a clinical trial.

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.

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 to 76 Gy administered at 2 Gy/fraction. RESULTS: Propensity-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). 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 an important impact on decision making in treatment of high-risk Pca.

Chemotherapy plus estramustine for management of castration-resistant prostate cancer: meta-analysis of randomized controlled trials.

OBJECTIVE: Estramustine, an agent with both hormonal and non-hormonal effects in men, is supposed to be effective in treating castration-resistant prostate cancer. However, previous studies have reported conflicting results. We conducted this meta-analysis to evaluate the efficacy and toxicity of additional estramustine to chemotherapy. METHODS: Data sources including PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. Prostate specific antigen (PSA) response, overall survival, and grade 3 to 4 toxicity were analyzed. RESULTS: Seven randomized controlled trials, a total of 839 patients, were enrolled. The pooled odds ratio for PSA response was 3.02 (95% CI=1.69-5.39, P=.0002); the pooled hazard ratio for overall survival was .95 (95% CI=.80-1.14, P=.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI=1.05-14.45, P=.04) and 2.22 (95% CI=1.15-4.30, P=.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P>.05). CONCLUSIONS: According to this meta-analysis, chemotherapy with additional estramustine increased the PSA response rate. However, it increased the risk of grade 3 or 4 adverse effects such as nausea/vomiting and cardiovascular events, and the overall survival was not improved for castration-resistant prostate cancer patients.