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Journal of Translational Medicine Feb 2010To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899.
BACKGROUND
To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).
METHODS
70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).
RESULTS
The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).
CONCLUSIONS
Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.
CLINICAL TRIALS REGISTRATION NUMBER
CDR0000067865.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Interferons; Isotretinoin; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Survival Rate; Teratogens; Treatment Outcome; Vinblastine; Vinorelbine
PubMed: 20178647
DOI: 10.1186/1479-5876-8-20 -
Biochemical Pharmacology Oct 1999Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of...
Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5-15 microM) and PSC 833 (5 microM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5-15 microM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.
Topics: Antineoplastic Agents, Hormonal; Cyclosporins; Drug Synergism; Estramustine; HeLa Cells; Humans; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Receptors, Androgen; Tumor Cells, Cultured
PubMed: 10484069
DOI: 10.1016/s0006-2952(99)00210-5 -
British Journal of Cancer Feb 1993Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The...
Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours.
Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Carrier Proteins; Ependymoma; Estramustine; Estrone; Female; Glioma; Humans; Immunohistochemistry; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Secretory Proteins
PubMed: 8431366
DOI: 10.1038/bjc.1993.65 -
The Oncologist 2002Initial therapy for advanced prostate cancer includes androgen ablation by surgical or medical castration. Still, nearly all men with metastases will progress to... (Review)
Review
Initial therapy for advanced prostate cancer includes androgen ablation by surgical or medical castration. Still, nearly all men with metastases will progress to hormone-refractory prostate cancer (HRPC). Current U.S. Food and Drug Administration-approved agents for the treatment of HRPC include mitoxantrone and estramustine, although the vinca alkaloids and the taxanes have shown promising activity in single-agent phase II trials. Combinations of these agents induce a biochemical response in greater than 50% of patients, but the median duration of response is approximately 6 months. Overall survival of patients treated with these combinations is approximately 18-24 months. Studies are ongoing to develop novel therapies that target specific molecular pathways or mechanisms of chemotherapy resistance. Novel agents under development include growth factor receptor inhibitors, antisense oligonucleotides, bisphosphonates, and cell differentiating agents. Evaluation and incorporation of these agents into existing treatment regimens will guide us in the development of more active regimens in the treatment of HRPC.
Topics: Antineoplastic Agents, Hormonal; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Review Literature as Topic; Treatment Outcome; United States
PubMed: 12185298
DOI: 10.1634/theoncologist.7-4-360 -
BMC Cancer May 2006Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually... (Review)
Review
Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group.
BACKGROUND
Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases?
METHODS
A systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus.
RESULTS
Of the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results.
CONCLUSION
Docetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Evidence-Based Medicine; Hormones; Humans; Male; Microtubules; Neoplasm Metastasis; Ontario; Prostatic Neoplasms
PubMed: 16670021
DOI: 10.1186/1471-2407-6-112 -
Annals of Oncology : Official Journal... Dec 2000A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer during the last ten years.... (Review)
Review
BACKGROUND AND PURPOSE
A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer during the last ten years. The aims of the present review were to assess their impact on management of the disease and on survival of patients.
METHODS
The review of full published reports was facilited by the use of a MEDLINE computer search.
RESULTS
Clinical research studies have focused on defining guidelines for eligibility criteria and accurate endpoints for patients to be enrolled onto clinical trials and developing new agents or combination of drugs including estramustine phosphate. Any combination of current chemotherapy has no impact on overall survival of patients. Among drugs in development, only the promising activity observed with docetaxel deserves randomized trials to assess its impact on survival. The major innovative advance of the 90s is the demonstration of the impact of chemotherapy (mitoxantrone + prednisone) on quality of life as compared to prednisone alone. A greater and longer-lasting improvement in quality of life along with a concomitant decrease in costs was observed.
CONCLUSIONS
At the present time, chemotherapy should be considered as a palliative treatment in patients with symptomatic androgen-independent disease. The enrollment of patients into clinical trials dealing with quality of life as primary endpoint is strongly solicited. A standard methodology should be used in phase II trials with a primary goal of selection of agents which should progress to randomized trials using survival as an endpoint. Hopefully new specific strategies targeted to reverse the molecular changes that underlie prostate tumorigenesis should rapidly impact the multimodality management of AIPC in the third millenium.
Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Paclitaxel; Palliative Care; Prednisolone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Taxoids
PubMed: 11205458
DOI: 10.1023/a:1008394823889 -
Health Technology Assessment... Jan 2007A systematic review was undertaken and an economic model constructed to evaluate the clinical effectiveness and cost-effectiveness of docetaxel (Taxotere,... (Review)
Review
A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.
OBJECTIVES
A systematic review was undertaken and an economic model constructed to evaluate the clinical effectiveness and cost-effectiveness of docetaxel (Taxotere, Sanofi-Aventis) in combination with prednisone/prednisolone for the treatment of metastatic hormone-refractory prostate cancer (mHRPC). The main comparators considered were other established chemotherapy regimens and best supportive care.
DATA SOURCES
Twenty-one resources (including MEDLINE, EMBASE and the Cochrane Library) were searched to April 2005.
REVIEW METHODS
Two reviewers independently assessed studies for inclusion. Data from included studies were extracted and quality assessed. Where appropriate, outcomes were synthesised using formal analytic approaches. A new economic model was developed in order to establish the cost-effectiveness of docetaxel compared with a range of potential comparators. A separate review was undertaken to identify sources of utility data required to estimate quality-adjusted life-years (QALYs). Sensitivity analyses were also undertaken to explore the robustness of the main analysis to alternative assumptions related to quality of life. Monte Carlo simulation was used to propagate uncertainty in input parameters through the model in such a way that the results of the analysis could be presented with their uncertainty. The impact of uncertainty surrounding the decision was established using value of information and implementation approaches.
RESULTS
Seven randomised controlled trials were identified that met the inclusion criteria. A direct comparison of docetaxel plus prednisone versus mitoxantrone plus prednisone in an open-label randomised trial showed improved outcomes for docetaxel plus prednisone in terms of overall survival, quality of life, pain and prostate-specific antigen decline. Two other chemotherapy regimens that included docetaxel: docetaxel plus estramustine and docetaxel plus prednisone plus estramustine, also showed improved outcomes in comparison with mitoxantrone plus prednisone. Indirect comparison suggested that docetaxel plus prednisone seems to be superior to corticosteroids alone in terms of overall survival. Conclusions on cost-effectiveness were primarily informed by the results of the in-house model. This indicated that mitoxantrone plus a corticosteroid is probably cheaper and more effective than corticosteroid alone. Compared with mitoxantrone plus prednisone/prednisolone, the use of docetaxel plus prednisone/prednisolone (3-weekly) appears cost-effective only if the NHS is prepared to pay 33,000 pounds per QALY. The incremental cost-effectiveness ratio associated with docetaxel plus prednisone (3-weekly) remained fairly robust to these variations with estimates ranging from 28,000 pounds to 33,000 pounds per QALY. Value of information analysis revealed that further research is potentially valuable. Given a maximum acceptable ratio of 30,000 pounds per QALY, the expected value of information was estimated to be approximately 13 million pounds.
CONCLUSIONS
This systematic review of the research suggests that docetaxel plus prednisone seems to be the most effective treatment for men with mHRPC. The economic model suggests that treatment with docetaxel plus prednisone/prednisolone is cost-effective in patients with mHRPC provided the NHS is prepared to pay 33,000 pounds per additional QALY. Future research should include the direct assessment of quality of life and utility gain associated with different treatments, including the effect of adverse events of treatment, using generic instruments, which are suitable for the purposes of cost-effectiveness analyses.
Topics: Antineoplastic Agents; Docetaxel; Drug Therapy, Combination; Glucocorticoids; Humans; Male; Models, Economic; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Quality-Adjusted Life Years; Taxoids; Treatment Outcome; United Kingdom
PubMed: 17181985
DOI: 10.3310/hta11020 -
British Journal of Cancer Sep 2004There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy... (Review)
Review
There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy with mitoxantrone and prednisone. This treatment is well tolerated, even by elderly patients, although the cumulative dose of mitoxantrone is limited by cardiotoxicity. Treatment with docetaxel or paclitaxel, with or without estramustine, appears to convey higher rates of prostate-specific antigen response in phase II trials, but is more toxic. Large phase III trials comparing docetaxel with mitoxantrone have completed accrual. There is no role for chemotherapy in earlier stages of disease except in the context of a well-designed clinical trial.
Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Estramustine; Estrogens; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Taxoids
PubMed: 15150548
DOI: 10.1038/sj.bjc.6601850 -
Annals of Oncology : Official Journal... May 2001The quality of life (QoL) of 44 men with HRPC and 37 partners (primary caregivers, most residing with the patient) was assessed in a multicenter Phase II trial of... (Clinical Trial)
Clinical Trial
The impact of docetaxel, estramustine, and low dose hydrocortisone on the quality of life of men with hormone refractory prostate cancer and their partners: a feasibility study.
OBJECTIVES
The quality of life (QoL) of 44 men with HRPC and 37 partners (primary caregivers, most residing with the patient) was assessed in a multicenter Phase II trial of docetaxel, estramustine and low dose hydrocortisone (CALGB 9780). A secondary objective was to test the feasibility of assessing partners' QoL in a cooperative group setting.
PATIENTS AND METHODS
Patients and partners were separately interviewed by telephone at baseline, two, four and six months by a single trained research interviewer. Patients' QoL was measured by the FACT-P, Mental Health Inventory-17 (MHI-17), Brief Pain Inventory (BPI), a two-day log of pain medications, and the OARS for co-morbid conditions. Partners' QoL was measured by the MHI-17, Caregiver Burden Interview, and co-morbid conditions.
RESULTS
The QoL study refusal rates were low for patients (4%) and partners (3%). Although patients tended to experience greater treatment side effects in the first two months (FACT Physical Well-Being item, P = 0.057), their cancer-specific emotions (e.g., worrying about worsening health) significantly improved at two and four months (FACT-Emotional Well-Being, P = 0.003, P = 0.03, respectively), as did their prostate cancer-specific physical problems (e.g., urination, pain), at two and four months (FACT-P, P = 0.001, P = 0.005, respectively). Partners' anxiety significantly decreased over time (MHI, P < 0.05). Patients' quality of life at two months was significantly related to their clinical response (FACT-P total and prostate cancer-specific problems, P < 0.05), and their clinical response was significantly related to a decrease in their partners' anxiety at two months (MHI, P < 0.05).
CONCLUSIONS
Despite feeling worse from side effects, patients' prostate cancer-specific problems and emotional state significantly improved in the first four months of treatment. With treatment significantly affecting both patients' and partners' lives. and the successful assessment of partners' QoL, QoL of both patients and partners could be used as important endpoints in selected clinical trials.
Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Anxiety; Docetaxel; Drug Resistance, Neoplasm; Emotions; Estramustine; Feasibility Studies; Female; Health Status; Humans; Hydrocortisone; Infusions, Intravenous; Male; Mental Health; Middle Aged; Paclitaxel; Pain; Prostatic Neoplasms; Quality of Life; Sexual Behavior; Spouses; Taxoids
PubMed: 11432621
DOI: 10.1023/a:1011102619058 -
Anticancer Research Feb 2009The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC). (Clinical Trial)
Clinical Trial
UNLABELLED
The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC).
PATIENTS AND METHODS
Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients.
RESULTS
A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients.
CONCLUSION
The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Taxoids; Vinblastine; Vinorelbine
PubMed: 19331234
DOI: No ID Found