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.

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    • "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. "
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    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.
    Urologic Oncology 02/2015; 33(5). DOI:10.1016/j.urolonc.2015.01.017 · 2.77 Impact Factor
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    • "Ultimately, patients relapse, signalled by a rise in PSA, and develop CRPC. Docetaxel (Taxotere) was the first chemotherapy drug to show improved survival for patients with CRPC, compared to the then standard of care, mitoxantrone [6, 7]. More recently, cabazitaxel was FDA-approved for patients who fail docetaxel therapy on the basis of prolonged survival [8]. "
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    ABSTRACT: The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.
    BioMed Research International 09/2014; 2014. DOI:10.1155/2014/981434 · 3.17 Impact Factor
    • "PSA partial response (PR) was defined as a 50% or greater decrease in serum PSA compared with the last value assessed prior to initiation of chemotherapy (Petrylak et al, 2004; Tannock et al, 2004). PSA progressive disease (PD) was defined as an increase in PSA value by 425% over the baseline, and stable disease (SD) was defined as a value 40.5 but o1.25 times the baseline value (Petrylak et al, 2004; Tannock et al, 2004). Overall survival was calculated from the date of the baseline biomarker blood draw to the date of death or last follow-up. "
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    ABSTRACT: Background: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. Results: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). Conclusions: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
    British Journal of Cancer 08/2014; 111(9). DOI:10.1038/bjc.2014.463 · 4.84 Impact Factor
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