Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

INTRODUCTION: Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. PATIENTS AND METHODS: Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. RESULTS: The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. CONCLUSIONS: Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

Oncological outcome of neoadjuvant low-dose estramustine plus LHRH agonist/antagonist followed by extended radical prostatectomy for Japanese patients with high-risk localized prostate cancer: a prospective single-arm study.

BACKGROUND: Patients with advanced high-risk prostate cancer (PCa) are prone to have worse pathological diagnoses of positive surgical margins and/or lymph node invasion, resulting in early biochemical recurrence (BCR) despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether patients with high-risk PCa should undergo RP. The purpose of this study was to evaluate the efficacy of neoadjuvant chemohormonal therapy (NAC) followed by "extended" RP. METHODS: A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6 months of estramustine phosphate (EMP) 140 mg twice daily, along with a luteinizing hormone-releasing hormone agonist/antagonist. We developed our surgical technique to reduce the rate of positive surgical margins. We aimed to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum was exposed. RESULTS: More than 1 year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7 months. The 3-year BCR-free survival was 74.9%. Multivariate Cox-regression analysis revealed that a positive core ratio of 50% or greater and pathological stage of pT3 or greater were independent predictors for BCR. About 17 of 23 cases received salvage androgen deprivation therapy and concurrent external beam radiotherapy, and showed no progression after the salvage therapies. CONCLUSIONS: NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

Long responders to estramustine monophosphate. Report of two cases and literature review. / Repondedores a largo plazo a Estramustina monofosfato. A propósito de dos casos. Revisión bibliográfica.

OBJECTIVE: Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer. METHODS: We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase. RESULTS: To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate. CONCLUSIONS: We recognize that these clinical cases do not translate that estramustine acetate is a first line treatment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetate.

OBJETIVO: La estramustina es un conjugado estable de estradiol y una mostaza nitrogenada que tiene propiedades antimitóticas. Actualmente, con la aparición de la quimioterpia y las nuevas moléculas, el acetato de estramustina -no es un fármaco de elección en el cáncer de próstata resistente a castración.MÉTODO: Describimos dos pacientes con cáncer de próstata resistente a la castración en tratamiento con acetato de estramustina, y con una respuesta bioquímica completa y enfermedad estable. Revisamos la literatura para dilucidar si se debería retirar el acetato de estramustina y cambiar por las nuevas moléculas que han demostrado un aumento de supervivencia. RESULTADO: Hasta donde llega nuestro conocimiento, no hay datos en la literatura que resuelvan las dudas planteadas y tampoco que aporten luz en cuanto a la toxicidad acumulada por el uso prolongado del acetato de estramustina.CONCLUSIÓN: Somos conscientes de que estos casos clínicos no traducen que el acetato de estramustina sea un tratamiento de primera línea para los pacientes con cáncer de próstata resistente a la castración. Sin embargo, traducen la heterogeneidad del CPRC. Sería interesante investigar la combinación de los nuevos agentes con el acetato de estramustina así como la búsqueda de biomarcadores que permitan la selección de los candidatos que podrían responder al acetato de estramustina.

Long responders to estramustine monophosphate. Report of two cases and literature review / Repondedores a largo plazo a Estramustina monofosfato. A propósito de dos casos. Revisión bibliográfica

Objective: Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer. Methods: We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase. Results: To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate. Conclusions: We recognize that these clinical cases do not translate that estramustine acetate is a first line treat ment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetat. Conclusions: We recognize that these clinical cases do not translate that estramustine acetate is a first line treat

OBJETIVO: La estramustina es un conjugado estable de estradiol y una mostaza nitrogenada que tiene propiedades antimitóticas. Actualmente, con la aparición de la quimioterpia y las nuevas moléculas, el acetato de estramustina -no es un fármaco de elección en el cáncer de próstata resistente a castración. MÉTODO: Describimos dos pacientes con cáncer de próstata resistente a la castración en tratamiento con acetato de estramustina, y con una respuesta bioquímica completa y enfermedad estable. Revisamos la literatura para dilucidar si se debería retirar el acetato de estramustina y cambiar por las nuevas moléculas que han demostrado un aumento de supervivencia. RESULTADO: Hasta donde llega nuestro conocimiento, no hay datos en la literatura que resuelvan las dudas planteadas y tampoco que aporten luz en cuanto a la toxicidad acumulada por el uso prolongado del acetato de estramustina. CONCLUSIÓN: Somos conscientes de que estos casos clínicos no traducen que el acetato de estramustina sea un tratamiento de primera línea para los pacientes con cáncer de próstata resistente a la castración. Sin embargo, traducen la heterogeneidad del CPRC. Sería interesante investigar la combinación de los nuevos agentes con el acetato de estramustina así como la búsqueda de biomarcadores que permitan la selección de los candidatos que podrían responder al acetato de estramustina

Cost-effectiveness comparison between neoadjuvant chemohormonal therapy and extended pelvic lymph node dissection in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis.

The aim of the present study was to assess the cost-effectiveness of extended pelvic lymph node dissection (ePLND) compared to neoadjuvant chemohormonal therapy using gonadotropin-releasing hormone agonist/antagonist and estramustine. We retrospectively analyzed data within Michinoku Urological Cancer Study Group database containing 2971 PC patients treated with radical prostatectomy (RP) at four institutes between July 1996 and July 2017. We identified 237 and 403 high-risk patients who underwent RP and ePLND (ePLND group), and neoadjuvant chemohormonal therapy followed by RP and limited PLND (neoadjuvant group), respectively. The oncological outcomes and cost-effectiveness were compared between groups. Medical cost calculation focused on PC-related medication and adjuvant radiotherapy. Biochemical recurrence-free and overall survival rates in the neoadjuvant group were significantly higher than those in the ePLND group. Significantly higher number of patients progressed to castration-resistant PC in the ePLND group than in the neoadjuvant group. Background-adjusted multivariate Cox regression analysis using inverse probability of treatment weighting (IPTW) revealed that neoadjuvant chemohormonal therapy independently reduced the risk of biochemical recurrence after RP. The 5-year cost per person was significantly higher in the ePLND group than in the neoadjuvant group. Although the present study was retrospective, neoadjuvant chemohormonal therapy followed by RP as a concurrent strategy has potential to improve oncological outcome and cost-effectiveness.

[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.

[Primary breast diffuse large B-cell lymphoma developing subsequent to estramustine therapy for prostate cancer].

An 85-year-old male presented with 1-year history of a right breast mass. Needle biopsy of the mass revealed diffuse proliferation of large lymphoid cells that were positive for CD20, BCL2, BCL6, and MUM1 and negative for CD5, CD10, MYC, and EBER. The patient was diagnosed as having diffuse large B-cell lymphoma, a type of primary breast lymphoma (PBL). Sex hormone imbalance, which causes conditions such as gynecomastia, is associated with PBL development in males. Estramustine is a nitrogen mustard moiety linked to estradiol. For 5 years, the patient underwent estramustine therapy for treating prostate cancer. Our case suggests an important role of estrogen in PBL development.

Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice.

Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC) has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen (PSA). However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.

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.

[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.

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902.

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

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.

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

BACKGROUND: 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. METHODS: EMP was given orally at a dose of 140 mg daily. Treatment discontinuation rates due to progressive disease/toxicity and response rates were assessed. RESULTS: 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. CONCLUSION: 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.

Quimioterapia con estramustina en el manejo del cáncer de próstata resistente a la castración: metaanálisis de ensayos controlados aleatorizados / Chemotherapy Plus Estramustine for Management of Castration-Resistant Prostate Cancer: Meta-Analysis of Randomized Controlled Trials

Objetivo: La estramustina, un agente con efectos tanto hormonales como no hormonales en los hombres, se supone que es eficaz en el tratamiento de cáncer de próstata resistente a la castración. Sin embargo, estudios previos han notificado resultados contradictorios. Hemos llevado a cabo este metaanálisis para evaluar la eficacia y la toxicidad de estramustina adicional a la quimioterapia. Métodos: Se realizaron búsquedas en las bases de datos, incluyendo PubMed, Medline, EMBASE y Cochrane Controlled Trials Register, para identificar los ensayos controlados aleatorizados potencialmente relevantes. Se analizaron la respuesta del antígeno prostático específico (PSA), la supervivencia global y la toxicidad de grado 3 a 4. Resultados: Siete ensayos controlados aleatorizados, un total de 839 pacientes, fueron incluidos. La odds ratio combinada para la respuesta de PSA fue de 3,02 (IC 95% = 1,69-5,39, p = 0,0002); el cociente de riesgos instantáneos agrupado de supervivencia global fue de 0,95 (IC 95% = 0,80-1,14, p = 0,58); la odds ratio combinada para náuseas/vómitos y toxicidad cardiovascular fue de 3,90 (IC 95% = 1,05-14,45, p = 0,04) y 2,22 (IC 95% = 1,15-4,30, p = 0,02). No se detectó ninguna diferencia significativa para neutropenia, anemia, trombocitopenia, diarrea, fatiga o neuropatía (p > 0,05). Conclusiones: Según este metaanálisis la quimioterapia con estramustina adicional aumentaba la tasa de respuesta del PSA. Sin embargo, aumentaba el riesgo de efectos adversos de grado 3 o 4 como náuseas/vómitos y los episodios cardiovasculares, y la supervivencia global no mejoró en los pacientes con cáncer de próstata resistente a la castración

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 = 0.0002); the pooled hazard ratio for overall survival was 0.95 (95% CI = 0.80-1.14, P = 0.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI = 1.05-14.45, P = 0.04) and 2.22 (95% CI = 1.15-4.30, P = 0.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P > 0.05). 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

Chemotherapy and its evolving role in the management of advanced prostate cancer.

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer (CRPC). Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing 'level-1 evidence' that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. abiraterone and enzalutamide) have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include: how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.

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.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Hormonal treatment in prostate cancer]. / Le traitement hormonal du cancer de la prostate.

AIM: To describe drugs used in the hormonal treatment (hormonotherapy) of prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: LHRH analogs and the antiandrogens remain the cornerstone in the treatment of locally advanced and metastatic prostate cancer. New therapeutic classes emerged recently (inhibitor of the synthesis of the androgen, the new antiandrogens) and allowed to grow again the limits of the hormone resistance and define the concept castration-resistant prostate cancer. CONCLUSION: The hormonal treatment of the prostate cancer grew rich of new therapeutic classes which are going to change the medical care of the prostate cancer in the coming years and the urologist must play its full part.

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.

Changes in fPSA level could discriminate tPSA flare-up from tPSA progression in patients with castration-refractory prostate cancer during the initial phase of docetaxel-based chemotherapy.

PURPOSE: To evaluate whether changes in fPSA level could predict tPSA flare-up in patients with castration-refractory prostate cancer during the initial phase of docetaxel-based chemotherapy. METHODS: We retrospectively identified 79 consecutive patients who received docetaxel-based chemotherapy at our institution. The treatment protocols included docetaxel 75 mg/m² every 21 days, with either prednisone 5 mg twice daily or estramustine 280 mg three times daily on days 1-5; treatment with dexamethasone preceded docetaxel therapy. All PSA values were determined before every cycle of docetaxel-based treatment. RESULTS: According to changes in tPSA level, 79 patients were divided into 3 groups: response (group 1), progression (group 2) and flare-up (group 3). fPSA and tPSA levels showed different patterns in groups 1, 2 and 3. Changes in fPSA level were independent of the changes in tPSA level in group 3, which decreased during chemotherapy. However, comparing with fPSA changes in group 3, changes in fPSA level were in accordance with tPSA changes in groups 1 and 2. Estimated median survival in groups 1, 2 and 3 was 23, 13 and 21 months, respectively. Median survival for patients in groups 1 (P = 0.008 vs group 2) and 3 (P = 0.029 vs group 2) is significantly longer than for patients who experienced progressive disease under therapy. However, there was no statistically significant difference in survival between groups 1 and 3. CONCLUSIONS: In the present study, we observed that changes in fPSA level could possibly discriminate tPSA flare-up from tPSA progression in patients with castration-refractory prostate cancer during the initial phase of docetaxel-based chemotherapy.