Estramustine Phosphate Research Articles

Dose compliance of estramustine phosphate in neoadjuvant chemohormonal therapy combined with degarelix acetate predicts the biochemical recurrence in patients with very high-risk prostate cancer who underwent robot-assisted radical prostatectomy.

The objective of this study is to evaluate the safety and efficacy of neoadjuvant degarelix acetate and low-dose estramustine phosphate for high-/very high-risk prostate cancer. Overall, 187 patients diagnosed with National Comprehensive Cancer Network high-/very high-risk cTanyN0M0 localized prostate cancer who consented to undergo robot-assisted radical prostatectomy after receiving neoadjuvant chemohormonal therapy for 6 months were prospectively enrolled between December 2017 and March 2023. Adverse events, perioperative and histopathological outcomes, and biochemical recurrence-free survival rates were examined. Survival analysis compared the estramustine phosphate completion and reduction groups. Thirty-six patients discontinued neoadjuvant therapy in <5 months owing to adverse events (n = 34) or other reasons (n = 2). Eleven were excluded for being in the postoperative castration range. Of the 140 patients who underwent surgery, 124 continued with two tablets of estramustine phosphate and 16 with one tablet. Overall, 82 patients were very high-risk. Histopathological outcomes were significantly worse in the very high-risk group than those in the high-risk group. Very high-risk status and estramustine phosphate reduction were significant factors in biochemical recurrence in multivariate analysis. The biochemical recurrence-free survival rate in very high-risk patients was significantly lower in the estramustine phosphate dose reduction group than in the completion group but not significant in high-risk patients. Major adverse events were anemia (n = 174), elevated transaminase levels (n = 68), and deep vein thrombosis (n = 24). Severe adverse events included acute coronary syndrome (n = 4) and pulmonary embolism (n = 3). Dose compliance with estramustine phosphate predicted biochemical recurrence in patients with very high-risk prostate cancer undergoing robot-assisted radical prostatectomy with neoadjuvant chemohormonal therapy.

Gösta Jönsson (1909-1978): A pioneer in the hormonal treatment of prostate cancer in Sweden.

Treatment of castration-resistant prostate cancer is and has been a challenge. In 1957, the chemist Imre Könyves came to Sweden as a refugee from Hungary and started to work at AB Leo, a pharmaceutical company in Helsingborg. In 1961, he started to synthesize compounds where the oestrogens were linked to a mustard group by a carbamate. This resulted in estramustine phosphate, which was initially tested against mammary cancer with disappointing results. He then started a cooperation with urology professor Gösta Jönsson, Head of the Department of Urology at the Lund University Hospital, to test estramustine phosphate against prostate cancer. Jönsson started clinical estramustine phosphate tests in 1966. His studies were one-armed and consecutive, with a "favourable response" in 83% of previously untreated patients. These favourable results could not be reproduced in later randomized controlled studies suggesting that estramustine phosphate as primary treatment was not better than conventional estrogenic treatment. Conclusions: Even if the results of Gösta Jönsson's studies could not be confirmed, the subsequent randomized studies of estramustine phosphate may hide the desired action of estramustine phosphate in a subgroup of patients. It has still not been elucidated whether estramustine phosphate has effects in this subgroup of patients with ostrogen-resistant prostate cancer.

Abstract 5447: Microtubule-associated protein MAP2 promotes drug resistance and cancer stemness in hepatocellular carcinoma through integrin dysregulation

Abstract Integrins are adhesion molecules that mediate mechanical and chemical signal transduction pathways to support cell survival and proliferation. Dysregulated integrin signaling empowers tumor cells to drive oncogenic stemness functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to therapies. However, the interplay between cancer stemness and integrin signaling in hepatocellular carcinoma (HCC) remains poorly understood. HCC cells marked by CD133 represent an important functional subset of HCC tumors, displaying a dedifferentiated status with stem cell traits. In this study, transcriptome profiling reveals specific downregulation of integrin α family genes and integrin signaling in ‘HCC’ CD133+ cells isolated from NRAS+AKT-driven HCC, but not epithelial-specific ‘normal’ CD133+ cells isolated from regenerating liver. Of note, one of the most differentially upregulated genes identified in CD133+ HCC cell profiling, microtubule-associated protein MAP2, demonstrates the ability to suppress integrin expression. MAP2 overexpression is frequently observed in HCC and correlates with aggressive clinical and stemness features, including survival, tumor stage, and stemness signatures. Epigenetic modifications by H3K27Ac contribute to MAP2 upregulation. Functionally, MAP2 promotes cancer stemness and cell invasion, and confers resistance to the targeted therapy sorafenib. Mechanistically, the inhibition of collagen-binding integrin α subunits by MAP2 subsequently ablates integrin β1-mediated cell adhesion and FAK signaling. Estramustine Phosphate (EMP), previously reported to inhibit the interaction of MAP2 with actin filaments, attains a synergistic effect in suppressing tumor initiation and growth of HCC cell lines, HCC patient-derived organoids and NRAS+AKT HCC mouse model when used in combination with sorafenib. In summary, MAP2 inhibition may represent a potential novel therapy for HCC by targeting its cancer stemness roots and altering integrin signaling. Ongoing work is focused on the study of MAP2 regulation of integrin signaling and cell behaviours in the maintenance of a more stemness state in HCC. Citation Format: Ut Kei Lou, Ka-Hei Lam, Huajian Yu, Jia Jian Loh, Ki-Fong Man, Lei Zhou, Yuan Gao, Tin-Lok Wong, Cheng-Han Yu, Stephanie Ma. Microtubule-associated protein MAP2 promotes drug resistance and cancer stemness in hepatocellular carcinoma through integrin dysregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5447.

Theranostic inorganic-organic hybrid nanoparticles with a cocktail of chemotherapeutic and cytostatic drugs.

Theranostic inorganic-organic hybrid nanoparticles (IOH-NPs) with a cocktail of chemotherapeutic and cytostatic drugs and a composition Gd23+[(PMX)0.5(EMP)0.5]32-, [Gd(OH)]2+[(PMX)0.74(AlPCS4)0.13]2-, or [Gd(OH)]2+[(PMX)0.70(TPPS4)0.15]2- (PMX: pemetrexed, EMP: estramustine phosphate, AlPCS4: aluminum(III) chlorido phthalocyanine tetrasulfonate, TPPS4: tetraphenylporphine sulfonate) are presented for the first time. These IOH-NPs are prepared in water (40-60 nm in size) and have a non-complex composition with outstanding drug loading (71-82% of total nanoparticle mass) of at least two chemotherapeutic or a mixture of cytostatic and photosensitizing agents. All IOH-NPs show red to deep-red emission (650-800 nm) to enable optical imaging. The superior performance of the IOH-NPs with a chemotherapeutic/cytostatic cocktail is validated based on cell-viability assays and angiogenesis studies with human umbilical vein endothelial cells (HUVEC). The synergistic anti-cancer effect of the IOH-NPs with a chemotherapeutic cocktail is shown in a murine breast-cancer cell line (pH8N8) and a human pancreatic cancer cell line (AsPC1), whereas the synergistic cytotoxic and phototoxic efficacy is verified in response to illumination of HeLa-GFP cancer cells, MTT assays with human colon cancer cells (HCT116), and normal human dermal fibroblasts (NHDF). HepG2 spheroids as 3D cell cultures prove the effective uptake of the IOH-NPs with high uniform distribution and the release of the chemotherapeutic drugs with the strong synergistic effect of the cocktail of drugs.

Significance of pelvic lymph node dissection during radical prostatectomy in high-risk prostate cancer patients receiving neoadjuvant chemohormonal therapy

We aimed to determine the survival and staging benefit of limited pelvic lymph node dissection (PLND) during radical prostatectomy (RP) in high-risk prostate cancer (PC) patients treated with neoadjuvant chemohormonal therapy. We retrospectively analyzed 516 patients with high-risk localized PC (< cT4N0M0) who received neoadjuvant androgen-deprivation therapy plus estramustine phosphate followed by RP between January 2010 and March 2020. Since we stopped limited PLND for such patients in October 2015, we compared the surgical outcomes and biochemical recurrence-free survival (BCR-FS) between the limited-PLND group (before October 2015, n = 283) and the non-PLND group (after November 2015, n = 233). The rate of node metastases in the limited-PLND group were 0.8% (2/283). Operation time was significantly longer (176 vs. 162 min) and the rate of surgical complications were much higher (all grades; 19 vs. 6%, grade ≥ 3; 3 vs. 0%) in the limited-PLND group. The inverse probability of treatment weighting-Cox analysis revealed limited PLND had no significant impact on BCR-FS (hazard ratio, 1.44; P = 0.469). Limited PLND during RP after neoadjuvant chemohormonal therapy showed quite low rate of positive nodes, higher rate of complications, and no significant impact on BCR-FS.

Erratum to: 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 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.

Estramustine Phosphate Monotherapy in Castration-Resistant Prostate Cancer Patients Who Cannot Receive Cytotoxic Chemotherapy

Purpose To investigate whether estramustine phosphate (EMP) monotherapy is applicable to castration-resistant prostate cancer (CRPC) patients who cannot receive cytotoxic chemotherapy. Materials and Methods This retrospective single-arm study was conducted in CRPC patients who had not experienced cytotoxic chemotherapy and received EMP monotherapy (560 mg/day) at 2 institutions from 2008 to 2017. We analyzed prostate-specific antigen (PSA) responses, overall survival, and adverse effects of EMP treatment. Results A total of 28 patients were analyzed. A reduction in serum PSA was observed in 11 patients (39.3%). Seven cases (25.9%) achieved more than 25% reduction of PSA, and 5 of them (18.5%) experienced more than 50% reduction. Median overall survival was 23 months (interquartile range, 10–60 months). Multivariable analyses demonstrated that low level of PSA at diagnosis of CRPC and long duration of prior androgen deprivation therapy were independent favorable factors predicting long-term overall survival. Adverse effects were edema (n=2; grade 2), nausea/vomiting (n=1; grade 2), gynecomastia (n=1; grade 2), and dyspnea (n=1; grade 1). Neither throm-boembolic event nor grade 3–5 toxicity was observed. There was no discontinuation caused by side effects of EMP. Conclusions EMP monotherapy could be considered as a safe treatment option with some effectiveness for CRPC patients who did not undergo cytotoxic chemotherapy. EMP is not generally recommended anticancer drug in the current guidelines for CRPC, but EMP monotherapy is thought to have an alternative role when a standard treat-ment cannot be selected due to patient's age, health condition, or comorbidity. Key Words: Castration-resistant prostatic neoplasm; Estramustine.

MP74-05 OUTCOMES OF NEOADJUVANT CHEMOHORMONAL THERAPY WITH COMPLETE ANDROGEN BLOCKADE, FOLLOWED BY TREATMENT WITH DOCETAXEL AND ESTRAMUSTINE PHOSPHATE BEFORE RADICAL PROSTATECTOMY IN PATIENTS WITH HIGH-RISK LOCALIZED PROSTATE CANCER: A PROPENSITY-SCORE MATCHING ANALYSIS

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy IV (MP74)1 Apr 2020MP74-05 OUTCOMES OF NEOADJUVANT CHEMOHORMONAL THERAPY WITH COMPLETE ANDROGEN BLOCKADE, FOLLOWED BY TREATMENT WITH DOCETAXEL AND ESTRAMUSTINE PHOSPHATE BEFORE RADICAL PROSTATECTOMY IN PATIENTS WITH HIGH-RISK LOCALIZED PROSTATE CANCER: A PROPENSITY-SCORE MATCHING ANALYSIS Shintaro Narita*, Hiromi Sato, Mizuki Kobayashi, Akane Kikuchi, Taketoshi Nara, Sohei Kanda, Kazuyuki Numakura, Atsushi Koizumi, Ryuhei Yamamoto, Mitsuru Saito, Takamitsu Inoue, Shigeru Satoh, Koji Mitsuzuka, Norihiko Tsuchiya, Chikara Ohyama, Yoichi Arai, Hiroshi Nanjo, and Tomonori Habuchi Shintaro Narita*Shintaro Narita* More articles by this author , Hiromi SatoHiromi Sato More articles by this author , Mizuki KobayashiMizuki Kobayashi More articles by this author , Akane KikuchiAkane Kikuchi More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Sohei KandaSohei Kanda More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Atsushi KoizumiAtsushi Koizumi More articles by this author , Ryuhei YamamotoRyuhei Yamamoto More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , Koji MitsuzukaKoji Mitsuzuka More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Chikara OhyamaChikara Ohyama More articles by this author , Yoichi AraiYoichi Arai More articles by this author , Hiroshi NanjoHiroshi Nanjo More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000960.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP). METHODS: Our NCHT protocol involved complete androgen blockade (CAB) followed by 6 cycles of docetaxel (30 mg/m2) plus estramustine phosphate (560 mg). NCHT was given to 60 patients with PCa before RP, and we compared the clinical and pathological outcomes with those of 349 patients with high-risk PCa who underwent RP alone, using propensity score matching (PSM). 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% achieved pathological complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien–Dindo grade ≥III) 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 = 5.25, 1.30–21.20; P = 0.020). In PSM, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = 0.021). 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 = 0.027). CONCLUSIONS: 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. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1133-e1133 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita* More articles by this author Hiromi Sato More articles by this author Mizuki Kobayashi More articles by this author Akane Kikuchi More articles by this author Taketoshi Nara More articles by this author Sohei Kanda More articles by this author Kazuyuki Numakura More articles by this author Atsushi Koizumi More articles by this author Ryuhei Yamamoto More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Shigeru Satoh More articles by this author Koji Mitsuzuka More articles by this author Norihiko Tsuchiya More articles by this author Chikara Ohyama More articles by this author Yoichi Arai More articles by this author Hiroshi Nanjo More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...

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.

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. A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6months of estramustine phosphate (EMP) 140mg 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. More than 1year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7months. 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. NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

Estramustine Phosphate Inhibits TGF-β-Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production.

Transforming growth factor-beta (TGF-β) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF-β regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF-β-induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-β. Moreover, EP greatly reduced the capacity of TGF-β to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF-β-induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-β.

Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels.

Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels.

Extended radical prostatectomy following neoadjuvant chemohormononal therapy (low dose estrmustine + LHRH agonist/antagonist) contributes to good cancer control for patients with high risk localized prostate cancer.

185 Background: Patients with high-risk prostate cancer (PCa) according to D’Amico risk categories are prone to a pathological diagnosis of positive margins or lymph node invasion and biochemical recurrence, despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether RP should be done for high risk PC patients. Methods: 87 high-risk PCa patients prospectively underwent ‘extended’ RP following neoadjuvant chemohormonal therapy (NAC); primarily 6 months of estramustine phosphate 280 mg bid, along with a LH-RH agonist/antagonist. Our surgical technique was developed to reduce the rates of positive surgical margins. The goal is 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 is exposed. The procedure was safely performed as a result of good recognition of the structure between the perineal body and the rectal surface. We also performed extended lymphadenectomy if the patients meet two or more of D’Amico risk categories Results: More than 1 year had elapsed after surgery in 69 of the 87 patients with the median follow-up period of 36.2 months. Among those 69 patients, 18 (26.1%) experienced PSA failure. Kaplan-Meier analyses revealed that significant poorer PSA progression-free survival were observed in patients with higher positive biopsy core ratio, lymph node metastasis, and higher pathological stage (pT3a/b). Multivariate Cox-regression analysis revealed that higher pathological stage (pT3a/b) was the only independent valuable for predicting PSA progression failure. These 18 cases received salvage androgen deprivation therapy followed-by external beam radiotherapy and showed no progression after the salvage therapies (median follow-up period, 34.6 months after PSA progression). Conclusions: NAC concordant with extended RP is feasible and contributes to negative surgical margins that might provide good cancer control for patients with high-risk PCa.

Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels.

Prostate cancer seriously threats to patient's life and health. Estramustine phosphate (EP) is one of the most important drugs in the clinical treatment of prostate cancer. This study aims to explore the molecular mechanism of estramustine phosphate in regulating PC3 cell growth and survive through mediating miR-31. Estramustine phosphate was used to treat prostate cancer cell line PC3. Flow cytometry was applied to detect PC3 cell growth and apoptosis. RT-PCR was performed to test miR-31 level. Prostate cancer tissue and paracarcinoma tissue were collected to test miR-31 level. PC3 cells were transfected with miR-31 or control microRNA by lipofectamine, and followed treated by estramustine phosphate. PC3 cell appeared growth restrain and apoptosis after treated by estramustine phosphate. MiR-31 level decreased after estramustine phosphate treatment. Prostate cancer tissue presented higher miR-31 level than paracarcinoma tissue. MiR-31 over-expression inhibited estramustine phosphate induced PC3 cell apoptosis. Estramustine phosphate induces prostate cancer cell line PC3 apoptosis through reducing miR-31.

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.

PD10-03 EXTENDED RADICAL PROSTATECTOMY FOLLOWING NEOADJUVANT CHEMOHORMONONAL THERAPY (LOW DOSE ESTRMUSTINE + LHRH AGONIST/ANTAGONIST) CONTRIBUTES TO GOOD CANCER CONTROL FOR PATIENTS WITH HIGH RISK LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy I1 Apr 2017PD10-03 EXTENDED RADICAL PROSTATECTOMY FOLLOWING NEOADJUVANT CHEMOHORMONONAL THERAPY (LOW DOSE ESTRMUSTINE + LHRH AGONIST/ANTAGONIST) CONTRIBUTES TO GOOD CANCER CONTROL FOR PATIENTS WITH HIGH RISK LOCALIZED PROSTATE CANCER Hideki Enokida, Shuichi Tatarano, Hiroaki Nishimura, Akihiko Mitsuke, Hirofumi Yoshino, Ryosuke Matsushita, and Masayuki Nakagawa Hideki EnokidaHideki Enokida More articles by this author , Shuichi TataranoShuichi Tatarano More articles by this author , Hiroaki NishimuraHiroaki Nishimura More articles by this author , Akihiko MitsukeAkihiko Mitsuke More articles by this author , Hirofumi YoshinoHirofumi Yoshino More articles by this author , Ryosuke MatsushitaRyosuke Matsushita More articles by this author , and Masayuki NakagawaMasayuki Nakagawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.566AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with high-risk prostate cancer (PCa) according to D′Amico risk categories are prone to a pathological diagnosis of positive margins or lymph node invasion and biochemical recurrence, despite having undergone radical prostatectomy (RP). METHODS 84 high-risk PCa patients prospectively underwent ′extended′ RP following neoadjuvant chemohormonal therapy (NCH); primarily 6 months of estramustine phosphate 280 mg bid, along with a LH-RH agonist/antagonist. Our surgical technique was developed to reduce the rates of positive surgical margins. The goal is 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 is exposed. The procedure was safely performed as a result of good recognition of the structure between the perineal body and the rectal surface. We also performed extended lymphadenectomy if the patients meet two or more of D′Amico risk categories RESULTS Pathological analysis revealed that positive surgical margins were found in only two patients. More than 1 year had elapsed after surgery in 64 of the 84 patients with the median follow-up period of 36.1 months. Among those 64 patients, 12 (18.8%) experienced PSA recurrence (Table 1). Kaplan-Meier analyses revealed that significant poorer PSA progression-free survival were observed in patients with younger age, higher positive biopsy core ratio, positive extra-prostate extension (EPE), lymph node metastasis, and higher pathological stage (pT3a/b). Multivariate Cox-regression analysis revealed that higher pathological stage (pT3a/b) was the only independent valuable for predicting PSA progression failure (Table 2). These 12 cases received salvage androgen deprivation therapy followed-by external beam radiotherapy and showed no progression after the salvage therapies (median follow-up period, 22.9 months after PSA progression). CONCLUSIONS NCH concordant with extended RP is feasible and contributes to negative surgical margins that might provide good cancer control for patients with high-risk PCa. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e199-e200 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hideki Enokida More articles by this author Shuichi Tatarano More articles by this author Hiroaki Nishimura More articles by this author Akihiko Mitsuke More articles by this author Hirofumi Yoshino More articles by this author Ryosuke Matsushita More articles by this author Masayuki Nakagawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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.

e543 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 neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low-dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). The aim of this study was to assess whether neoadjuvant LHRH+EMP confers an oncological benefit for high-risk Pca compared to extended lymph node dissection (e-PLND). Methods: The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at 4 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 neoadjuvant LHRH+EMP therapy included the administration of 280 mg/day of LHRH and EMP for 6 months before RP. The outcome measure was BRFS. Results: The 5-year BRFS rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9% and 54.7%, respectively ( P &lt; 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. Conclusions: Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP might reduce the risk of biochemical recurrence.

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

e542 Background: 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 agonist + 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 antagonist + 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 antagonist + EMP and 270 received LHRH agonist + EMP before RP. We retrospectively evaluated the clinical and pathological covariates between the two groups. The primary endpoint was the rate of pathological ≤ T2 status, and the secondary endpoint was BRFS. Results: The rates of pathological ≤ T2 status were 80.2% and 61.5% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P &lt; 0.001). The 3-year BRFS rates were 97.8% and 85.2% in the GnRH antagonist + EMP and LHRH agonist + EMP groups, respectively ( P = 0.021). Multivariate analysis revealed that biopsy Gleason score, GnRH antagonist + EMP, and clinical T stage were independent predictors of pathological ≤ T2 status in surgical specimens. Conclusions: 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.

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

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. 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. 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). 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.

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.

P021 - Long-term outcomes of androgen deprivation therapy plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: A randomized study

P021 - Long-term outcomes of androgen deprivation therapy plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: A randomized study