Docetaxel and Estramustine Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer

Columbia University, Herbert Irving Comprehensive Cancer Center, New York, USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2004; 351(15):1513-20. DOI: 10.1056/NEJMoa041318
Source: PubMed


Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer.
We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels.
Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups.
The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

  • Source
    • "CRPC progression is a complex process by which PCa cells acquire the ability to survive and proliferate in the absence of androgens. Unfortunately, currently effective chemotherapeutic agents available for CRPC improve the mean survival time of patients by only a few months91011. Therefore, investigating the many diverse mechanisms involved in the progression of aggressive PCa or CRPC is essential in order to identify new therapeutic targets. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PCa) is the leading type of cancer diagnosed in men. Studies on tumour-related extracellular vesicles (EVs) suggest that exosomes play a significant role in paracrine signaling pathways thus potentially influencing cancer progression via different mechanisms.During last decade numerous studies have revealed the role of EVs in the progression of various pathological conditions including cancer. We have previously described the role of exosomes as potential biomarkers for PCa. Differences in proteomic, lipidomic, and cholesterol content of exosomes derived from PCa cell lines versus benign prostate cell lines confirmed that exosomes are good candidates for future biomarker studies. Our extensive proteomic analysis completed alongside with the evidence of exosome uptake into a local tumour microenvironment have encouraged us to further examine the role of these vesicles in distinct mechanisms involved in the progression of PCa and castration resistant PCa.In this study, we hypothesize that exosomes play a pivotal role in cell-cell communication in the local tumour microenvironment, conferring activation of numerous survival mechanisms during PCa progression and development of therapeutic resistance. Our in vitro results demonstrate that PCa derived exosomes significantly reduce apoptosis in LNCaP and RWPE-1 cells increase cancer cell proliferation and induce cell migration. Consistently with our in vitro findings, we have demonstrated that exosomes increase tumor volume and PSA level in vivo when xenograft bearing mice were administered intravenously with DU145 exosomes.This research suggests that exosomes derived from PCa cells, regardless of the androgen receptor phenotype, attribute positively the of mechanisms that contribute to PCa progression.
    Full-text · Article · Jan 2016 · Oncotarget
  • Source
    • "Chemotherapeutic drugs such as cyclophosphamide, doxorubicin, paclitaxel or docetaxel (16) were reported to possess immunomodulatory activities and appeared to be suitable for chemoimmunotherapy (17,18). Docetaxel is a widely used chemotherapeutic drug and represents a first-line chemotherapy for metastatic castrationresistant prostate cancer (19,20). The autologous dendritic cell-based vaccines are intensively studied as an immunotherapy for prostate cancer, and the first cellular immunotherapy based on activated peripheral blood mononuclear cells, Sipuleucel T, has been FDA-approved (21). "
    [Show abstract] [Hide abstract]
    ABSTRACT: High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality.
    Full-text · Article · Dec 2015 · International Journal of Oncology
  • Source
    • "However, most patients progress to castration-resistant prostate cancer (CRPC) at varying intervals following ADT [2]. For such patients, docetaxel (DCT)–based chemotherapy has been established as first-line treatment [3] [4]. More recently, new classes of treatments, such as second-line taxane cytotoxic agent [5], androgen-targeted therapies [6] [7], or immunotherapy [8], have been approved for patients with CRPC following DCT-based chemotherapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To identify pretreatment prognostic factors for patients with castration-resistant prostate cancer (CRPC) undergoing docetaxel (DCT) chemotherapy. We retrospectively analyzed 102 patients with CRPC who underwent DCT chemotherapy (dosage: 60-75mg/m(2)) from December 2001 to August 2013. The parameters evaluated as prognostic factors were as follows: age, body mass index, Gleason score, clinical TNM stage, prior radical prostatectomy, prior radiation therapy, performance status, presence of pain, laboratory results at the start of DCT, and prostate-specific antigen (PSA) kinetics during prior androgen deprivation therapy (ADT), including PSA level at the start of ADT (PSA-ADT), PSA half-time (PSAT1/2), time to nadir, PSA level at nadir (PSA-Nadir), duration of nadir, PSA doubling time (PSADT), and PSA level at the start of DCT (PSA-DCT). Univariate and multivariate analyses were performed to identify independent prognostic factors. Median cancer-specific survival (CSS) duration following CRPC diagnosis was 28.0 months. In univariate analyses, performance status, serum albumin, serum creatinine, PSAT1/2, time to nadir, PSA-Nadir, duration of nadir, PSADT, and PSA-DCT showed a potential association with prognosis (P<0.001-0.077). Multivariate analyses of these parameters showed that performance status (hazard ratio [HR] = 0.046; P = 0.046), serum creatinine (HR = 3.028; P = 0.036), PSAT1/2 (HR = 0.172; P = 0.007), PSA-Nadir (HR = 4.884; P = 0.033), PSADT (HR = 0.148; P<0.001), and PSA-DCT (HR = 5.222; P = 0.004) remained independent predictors of CSS in CRPC. PSA kinetic parameters measured during prior ADT are significant surrogate markers predicting CSS in patients undergoing DCT chemotherapy for CRPC. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Urologic Oncology
Show more