estramustine and bicalutamide

Urologists often are faced with challenges in treating men with metastatic prostate cancer. Although historically chemotherapy has had limited utility in treating this disease, therapeutic nihilism surrounding its use is no longer warranted, as demonstrated by results of 2 recent randomized clinical trials showing that docetaxel-based chemotherapy improves survival in patients with hormone-refractory prostate cancer (HRPC). Although the survival benefit was a modest 2 months, the results hold the promise that docetaxel-based treatment in earlier-stage disease may provide a longer survival advantage. The Cancer and Leukemia Group B (CALGB) 90203 and TAX 3501 studies are phase 3 neoadjuvant and adjuvant radical prostatectomy trials designed to assess the role of docetaxel in patients with high-risk localized disease. These 2 trials, along with the Southwest Oncology Group (SWOG) 9921 trial, which will assess the potential for adjuvant mitoxantrone, are paving the way for earlier systemic treatment. The need for better therapies for patients routinely seen in the urology clinic and the potential for improvements with chemotherapy necessitate an increasing collaboration between urologists and oncologists. Referral to a medical oncologist for a full discussion of treatment options is in the best interest of patients with HRPC, and patients at high-risk for treatment failure should be encouraged to consider clinical trial enrollment.

Topics: Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Nitriles; Prednisone; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids; Tosyl Compounds

To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR).. Treatment was 4 cycles of docetaxel (70 mg/m(2)) every 3 weeks and estramustine 280 mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate-specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration-resistant prostate cancer (CRPC), and overall survival (OS).. Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths.. Chemotherapy plus ADT for BR resulted in durable (>5 years) complete responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Therapy, Combination; Estramustine; Follow-Up Studies; Goserelin; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Retrospective Studies; Taxoids; Time Factors; Tosyl Compounds; Treatment Outcome

Prostate-specific antigen progression (PSA-P) is an indicator of progression in hormone-sensitive (HS) and castration-resistant (CR) prostate cancer (PC). We evaluated different definitions of PSA-P as predictors of overall survival (OS).. A total of 1,078 patients with HSPC who were on hormones (Southwest Oncology Group [SWOG] trial 9346 [S9346]) and 597 patients with CRPC who were treated with chemotherapy (SWOG trial 9916 [S9916]) were eligible for this analysis. PSA-P definitions tested included the following: PSA Working Group, Prostate Cancer Working Group (PCWG 2008), and other definitions. A time-varying approach analyzed associations between PSA-P at any time and OS. A landmark analysis examined the relationship between PSA-P status at 7 months for S9346, or 3 months for S9916, and subsequent OS.. In the time-varying analysis, both working groups definitions were strongly associated with OS (P < .001) in both study settings. In patients enrolled onto S9346, both definitions predicted a 2.4-fold increased risk of death (ROD) and a greater than four-fold increased ROD if PSA-P occurred in the first 7 months. In S9916, they predicted a 40% increase in ROD and a two-fold increase in ROD if PSA-P occurred at 3 months. In landmark analyses of patients on S9346 by using the PCWG 2008 definition of PSA-P, median subsequent OS was 10 months versus 44 months in patients who did or did not have PSA-P by 7 months, respectively; in S9916, data were 11 months versus 18 months for patients who did or did not have PSA-P by 3 months, respectively.. PSA-P, defined as an increase of > or = 25% greater than the nadir and an absolute increase of at least 2 or 5 ng/mL, predicts OS in HSPC and CRPC and may be a suitable end point for phase II studies in these settings.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Docetaxel; Estramustine; Goserelin; Humans; Male; Middle Aged; Mitoxantrone; Nitriles; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tosyl Compounds

To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa).. Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed.. No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease.. We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

Topics: Aged; Androgens; Anilides; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Estramustine; Female; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Survival Rate; Taxoids; Tosyl Compounds; Treatment Outcome

Our study and previous reports suggest that castration results in increased bone turnover and lowered BMD and that these changes might be attenuated by anti-androgens, such as BL and EMP.. Recent studies have shown that castration for PC decreases bone mineral density (BMD), while estrogen therapy or bicalutamide (BL) monotherapy maintains BMD. However, the effect of combined androgen blockade (CAB) on bone turnover is not well studied.. A total of 204 men were evaluated in the study (control group: n = 56, castration group: n = 102, 'CAB with BL' group: n = 22, 'CAB with estramustine phosphate (EMP)' group: n = 24). We measured steroid hormone levels, BMD (measured at one-third distal radius), bone turnover markers (levels of urinary N-telopeptide cross links of type 1 collagen (u-NTx) and deoxypyridinoline (u-DPD), serum concentrations of osteocalcin (OC)) in order to assess differences between groups.. The BMD % Z score of the castration group was significantly lower than that of the control group or the 'CAB with EMP' group (90.6% vs. 95.5%, 98.6%; p < 0.042, p < 0.044, respectively). Levels of u-NTx, u-DPD, OC of the castration group were the highest followed by the control group, then the 'CAB with BL' group and the 'CAB with EMP' group.. Our study and previous reports suggests that castration results in increased bone turnover and lowered BMD and that these changes might be attenuated by anti-androgens, such as BL and EMP.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Amino Acids; Androgen Antagonists; Anilides; Biomarkers; Bone Density; Collagen Type I; Combined Modality Therapy; Estramustine; Humans; Male; Middle Aged; Neoplasm Staging; Nitriles; Orchiectomy; Osteocalcin; Peptides; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds

A 52-year-old man presented to his urologist with hematuria and symptoms of frequency and incomplete voiding. The patient received antibiotics without symptom resolution. His prostate-specific antigen (PSA) level was 6.6 ng/ml and digital rectal examination revealed a normal-sized firm prostate gland. Biopsy obtained by transurethral resection revealed poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. Pure small-cell cancer or poorly differentiated prostate cancer may secrete little or no PSA. One should be alerted to this phenotype in a patient with large volume disease on biopsy or examination and a low PSA or PSA not in proportion to tumor burden.. Digital rectal examination, laboratory tests, cystoscopy, prostatic chips obtained from transurethral resection, prostate biopsy, bone scan, CT scan of the chest, abdomen and pelvis.. Poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features.. Transurethral resection, androgen blockade with a gonadotropin-releasing hormone analog and antiandrogen flutamide, oral bicalutamide, docetaxel and oral estramustine. Total pelvic exenteration with ileal conduit urinary diversion and permanent end-colostomy formation, percutaneous nephrostomy placement, cisplatin combined with etoposide.

Topics: Adenocarcinoma; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Docetaxel; Estramustine; Etoposide; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Nephrostomy, Percutaneous; Nitriles; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tosyl Compounds; Transurethral Resection of Prostate; Urinary Diversion

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer.

Topics: Androgen Antagonists; Androgens; Anilides; Animals; Base Sequence; Dihydrotestosterone; Estradiol; Estramustine; Flutamide; Humans; Ligands; Male; Molecular Sequence Data; Nitriles; Phosphorylation; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; RNA, Messenger; Tosyl Compounds; Tumor Cells, Cultured