estramustine and Prostatic-Neoplasms

Cancer of the prostate are cancers in which most incidences are slow-growing, and in the U.S., a record of 1.2 million new cases of prostate cancer occurred in 2018. The rates of this type of cancer have been increasing in developing nations. The risk factors for prostate cancer include age, family history, and obesity. It is believed that the rate of prostate cancer is correlated with the Western diet. Various advances in methods of radiotherapy have contributed to lowering morbidity. Therapy for hormone- refractory prostate cancer is making progress, for almost all men with metastases will proceed to hormone-refractory prostate cancer. Smoking cigarettes along with the presence of prostate cancer has been shown to cause a higher risk of mortality in prostate cancer. The serious outcome of incontinence and erectile dysfunction result from the cancer treatment of surgery and radiation, particularly for prostate- specific antigen detected cancers that will not cause morbidity or mortality. Families of patients, as well as patients, are profoundly affected following the diagnosis of prostate cancer. Poor communication between spouses during prostate cancer increases the risk for poor adjustment to prostate cancer. The use of serum prostate-specific antigen to screen for prostate cancer has led to a greater detection, in its early stage, of this cancer. Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and about 13% of all cancer deaths. A shortened course of hormonal therapy with docetaxel following radical prostatectomy (or radiation therapy) for high-risk prostate cancer has been shown to be both safe and feasible. Patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50%. Cancer vaccines are an immune-based cancer treatment that may provide the promise of a non-toxic but efficacious therapeutic alternative for cancer patients. Further studies will elucidate improved methods of detection and treatment.

Topics: Age Factors; Antineoplastic Agents; Biomarkers, Tumor; Cancer Vaccines; Docetaxel; Drug Therapy, Combination; Estramustine; Humans; Incidence; Male; MicroRNAs; Mortality; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Treatment Outcome

Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer.. We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase.. To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate.. We recognize that these clinical cases do not translate that estramustine acetate is a first line treatment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetate.. La estramustina es un conjugado estable de estradiol y una mostaza nitrogenada que tiene propiedades antimitóticas. Actualmente, con la aparición de la quimioterpia y las nuevas moléculas, el acetato de estramustina -no es un fármaco de elección en el cáncer de próstata resistente a castración.MÉTODO: Describimos dos pacientes con cáncer de próstata resistente a la castración en tratamiento con acetato de estramustina, y con una respuesta bioquímica completa y enfermedad estable. Revisamos la literatura para dilucidar si se debería retirar el acetato de estramustina y cambiar por las nuevas moléculas que han demostrado un aumento de supervivencia.. Hasta donde llega nuestro conocimiento, no hay datos en la literatura que resuelvan las dudas planteadas y tampoco que aporten luz en cuanto a la toxicidad acumulada por el uso prolongado del acetato de estramustina.CONCLUSIÓN: Somos conscientes de que estos casos clínicos no traducen que el acetato de estramustina sea un tratamiento de primera línea para los pacientes con cáncer de próstata resistente a la castración. Sin embargo, traducen la heterogeneidad del CPRC. Sería interesante investigar la combinación de los nuevos agentes con el acetato de estramustina así como la búsqueda de biomarcadores que permitan la selección de los candidatos que podrían responder al acetato de estramustina.

Topics: Antineoplastic Agents, Alkylating; Estramustine; Humans; Male; Prostatic Neoplasms

Estramustine, an agent with both hormonal and non-hormonal effects in men, is supposed to be effective in treating castration-resistant prostate cancer. However, previous studies have reported conflicting results. We conducted this meta-analysis to evaluate the efficacy and toxicity of additional estramustine to chemotherapy.. Data sources including PubMed, Medline, EMBASE, and Cochrane Controlled Trials Register were searched to identify potentially relevant randomized controlled trials. Prostate specific antigen (PSA) response, overall survival, and grade 3 to 4 toxicity were analyzed.. Seven randomized controlled trials, a total of 839 patients, were enrolled. The pooled odds ratio for PSA response was 3.02 (95% CI=1.69-5.39, P=.0002); the pooled hazard ratio for overall survival was .95 (95% CI=.80-1.14, P=.58); the pooled odds ratio for nausea/vomiting and cardiovascular toxicity were 3.90 (95% CI=1.05-14.45, P=.04) and 2.22 (95% CI=1.15-4.30, P=.02). No significant difference was detected for neutropenia, anemia, thrombocytopenia, diarrhea, fatigue, or neuropathy (P>.05).. According to this meta-analysis, chemotherapy with additional estramustine increased the PSA response rate. However, it increased the risk of grade 3 or 4 adverse effects such as nausea/vomiting and cardiovascular events, and the overall survival was not improved for castration-resistant prostate cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Combined Modality Therapy; Docetaxel; Epirubicin; Epothilones; Estramustine; Fatigue; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Orchiectomy; Paclitaxel; Peripheral Nervous System Diseases; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

To describe drugs used in the hormonal treatment (hormonotherapy) of prostate cancer.. Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned.. LHRH analogs and the antiandrogens remain the cornerstone in the treatment of locally advanced and metastatic prostate cancer. New therapeutic classes emerged recently (inhibitor of the synthesis of the androgen, the new antiandrogens) and allowed to grow again the limits of the hormone resistance and define the concept castration-resistant prostate cancer.. The hormonal treatment of the prostate cancer grew rich of new therapeutic classes which are going to change the medical care of the prostate cancer in the coming years and the urologist must play its full part.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Combined Modality Therapy; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Estrogens, Non-Steroidal; Flutamide; Gonadotropin-Releasing Hormone; Humans; Imidazolidines; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Nitriles; Oligopeptides; Phenylthiohydantoin; Prostatectomy; Prostatic Neoplasms

The development of new therapies for castration-resistant prostate cancer (CRPC) has increasingly focused on improving patient quality of life, mainly because of limited survival gains and continuing high morbidity burden from disease progression or the adverse effects of treatments. However, there is no generally accepted quality of life instrument for use with this patient group. This paper objectively reviews the existing literature and assesses the impact of CRPC treatments on patients' quality of life. The review also provides a narrative description of the evolving role of quality of life measures in clinical trials, and critiques the most widely used instruments.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Progression; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Survival; Taxoids

If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Cancer Vaccines; Denosumab; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Zoledronic Acid

What's known on the subject? and What does the study add? Estramustine phosphate has anti-tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as docetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low-molecular-weight heparin support its use as a second-line treatment in hormone-resistant prostate cancer.. •  Estramustine phosphate is a nitrogen mustard derivative of estradiol-17β-phosphate and has anti-tumour properties. •  Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.. •  Relevant clinical studies using chemotherapy combinations including estramustine are discussed. •  Efficacy and safety outcomes are summarized.. •  Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine. •  Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.. •  The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low-molecular-weight heparins support the use of estramustine as an effective second-line treatment strategy in hormone-resistant prostate cancer. •  These promising findings warrant further investigation in a randomized clinical trial.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Nausea; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Taxoids; Thromboembolism; Treatment Outcome; Vomiting

To assess the efficacy and toxicity of the addition of estramustine to docetaxel-based chemotherapy for the treatment of castration-resistant prostate cancer.. We systematically searched, without language restrictions, for randomized clinical trials that compared docetaxel-based chemotherapy with or without estramustine in patients with histologically proven prostate cancer. The primary end point was overall survival (OS). Secondary endpoints were prostate-specific antigen (PSA) response rate and grade 3 or 4 toxicity. Data was extracted from the studies by 2 independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, Texas, USA).. Four randomized clinical trials (totally 400 patients) were eligible. Meta-analysis showed that there was significant improvement in PSA response rate in docetaxel-based therapy with estramustine group, compared with docetaxel-based therapy group (OR = 1.55, 95% CI = 1.10-2.18, P = 0.012). With regard to OS (HR = 0.873, 95% CI = 0.55-1.40, P = 0.572), grade3 or 4 neutropenia (OR = 1.27, 95% CI = 0.61-2.7), anemia (OR = 1.04, 95% CI = 0.07-16.3), thrombocytopenia (OR = 0.87, 95% CI = 0.13-5.7), diarrhea (OR = 2.3, 95% CI = 0.36-14.9), nausea (OR = 1.14, 95% CI = 0.16-8.35), mucositis (OR = 1.66, 95% CI = 0.50-5.52) , and vomiting (OR = 1.53, 95% CI = 0.23-10.3), and there were no significant differences between the two groups.. This was the first meta-analysis of docetaxel-based therapy with estramustine versus docetaxel-based chemotherapy in the treatment of castration-resistant prostate cancer. Our meta-analysis did not support the addition of estramustine to docetaxel-based chemotherapy for the treatment of castration- resistant prostate cancer, based on no gain in survival.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

The decrease of the level of serum prostate specific antigen (PSA) after discontinuation of estramustine phosphate (EMP) has rarely been reported. We report 2 cases in whom EMP withdrawal syndrome was encountered. Case 1 was a 68-year-old man with a complaint of paresis of lower limbs. He was diagnosed with prostate cancer with multiple bone metastases. The serum PSA level was 9,300 ng/ml. He was treated with luteinizing hormone-releasing hormone agonist (LH-RHa) and bicalutamide (BCL). Six months later, EMP was started against PSA failure. During the 3-year treatment with EMP, PSA decreased to the nadir of 0.7 ng/ml and gradually increased to 14 ng/ml. After withdrawal of EMP, PSA decreased to 0.3 ng/ml (97.9% decline) and remained at this level for 4 months. Case 2 was a 61-year-old man who visited our hospital with gross hematuria. Transurethral bladder biopsy and transrectal prostate biopsy were performed. The diagnosis was moderately differentiated adenocarcinoma of the prostate that invaded to the bladder. Computed tomography (CT) showed a lymph node metastasis. He was treated with LH-RHa and BCL. The treatment was changed to EMP after PSA failure. EMP was withdrawn when PSA was 30 ng/ml. Then PSA decreased to less than 0.2 ng/ml (99% decline) and remained at this level for 9 months. We consider that in patients with EMP-resistant progression, EMP withdrawal syndrome should be checked.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prostatic Neoplasms; Substance Withdrawal Syndrome

Chemotherapy treatment for patients with prostate cancer has advanced considerably during the past decade. The first demonstration of the efficacy of palliative chemotherapy in patients with hormone-resistant prostate cancer was followed by FDA approval of mitoxantrone in this setting and by studies showing the usefulness of several different drugs in these patients. Docetaxel became the standard treatment for them. The development of new cytotoxic molecules and targeted therapies as well as the evaluation of the efficacy of docetaxel in earlier stages of prostate cancer, with many ongoing studies, are the current lines of research for improving management of these hormone-refractory patients.

Topics: Antineoplastic Agents; Calcitriol; Chemotherapy, Adjuvant; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Neoadjuvant Therapy; Prostatic Neoplasms; Taxoids; Vitamins

In this paper, we summarize the options of conservative systemic medical therapy in elderly patients with prostate cancer. Treatment was classified into three categories: 1) endocrine therapy, 2) systemic chemotherapy, and 3) treatment using other drugs. 1) The common endocrine therapy called CAB (combined androgen blockade) consisting of androgen ablation with medical or surgical castration using anti-androgen agents will be considered first. It is important to minimize or eliminate the side effects of hormonal therapy in elderly patients. Therefore,monotherapy with anti-androgen agents, intermittent CAB, watchful waiting and delayed CAB, sequential usage with LH-RH (luteinizing hormone-releasing hormone) and anti-androgens will be considered. In hormone refractory prostate cancer, estramustine may be administered as an estrogen effect is expected. 2) Recently, systemic chemotherapy such as docetaxel regimens has prolonged survival and chemotherapy should be considered as the next step. There are, however, a variety of controversial issues in elderly patients such as the suitable timing of induction and the optimal dose, interval and schedule. It is also unclear whether docetaxel alone should be administered or combined with estramustine, steroid or bisphosphonate. We have performed intermittent chemotherapy, consisting of docetaxel with estramustine, and this regimen has been tolerated well and resulted in a good quality of life. 3) Additional therapy such as steroids and bisphosphonate may be administered to improve the quality of life. We have listed the major treatment options for prostate cancer, reviewed the expectation induced by each treatment and outlined key issues pertaining to usage in elderly patients.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Diphosphonates; Docetaxel; Drug Administration Schedule; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Quality of Life; Risk; Taxoids

Androgen deprivation in patients with metastatic prostate cancer produces palliation of symptoms, PSA decrease and tumoral regression in most patients. After a brief period of disease regression lasting 18 to 24 months nearly all pts will progress to androgen independence disease (HRPC) with progressive clinical deterioration and ultimately death. Chemotherapy with mitoxantrone has been shown to palliate symptoms but did not extend survival. Two large randomized trials showed a survival benefit for pts with HRPC treated with docetaxel with a reduction risk of death by 21-24%, and significant improvement in palliation of symptoms and quality of life. New agents targeting angiogenesis, apoptosis, signal transduction pathway, used alone or in combination with docetaxel currently are under trial in an attempt to provide much needed improvements in outcome. Questions remains in suspend when and who need to be treated, earlier, in high risk as in adjuvant setting? Current data have demonstrated that neoadjuvant or adjuvant chemotherapy is relatively safe and feasible. Further investigation through prospective randomize trials is critical to define the precise role of this modality in high risk populations.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer.. We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used.. The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275).. In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Castration; Disease-Free Survival; Drug Resistance, Neoplasm; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate

Chemotherapy is one the therapeutic options in prostate cancer. Docetaxel once every three weeks is the current standard for castration-refractory disease with cancer-related symptoms. The docetaxel plus estramustine association is likely more active than docetaxel alone. Docetaxel is currently tested in early stages: first results of phase III trials are expected by 2009-2010.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Taxoids

The use of cytotoxic chemotherapy in advanced prostate adenocarcinoma has been validated by the recent demonstration of survival benefit in two large randomized phase III trials. Before publication of these landmark trials, SWOG 9916 and TAX 327, no chemotherapeutic regimen had shown survival benefit in the treatment of androgen independent prostate cancer (AIPC). These trials provide new encouragement for the use of chemotherapy in all stages of disease. Improved communication between medical and urologic oncologists and early patient referral for clinical trial participation remains essential for identifying new chemotherapeutic regimens with improved activity in AIPC and for defining the role of chemotherapy in earlier-stage disease. This article discusses the role of chemotherapy as the current standard of care for the treatment of AIPC and provides a historical perspective of the trials that preceded the development of current docetaxel-based regimens.

Topics: Androgens; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Prostatic Neoplasms; Taxoids

This review describes the current state of chemotherapy for androgen-independent prostate cancer. Landmark clinical trials, including TAX 327, a randomized trial comparing docetaxel and prednisone with mitoxantrone and prednisone, and SWOG 9916, a randomized clinical trial comparing docetaxel and estramustine with mitoxantrone and prednisone, are reviewed. Novel combination therapies, involving taxane administered with compounds such as calcitrol and thalidomide, newer cytotoxic agents, vaccine therapies, and targeted modalities are also detailed. This review mainly focuses on agents with activity in phase II/III clinical trials.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Atrasentan; Bevacizumab; Cancer Vaccines; Chemotherapy, Adjuvant; Clinical Trials as Topic; Docetaxel; Endothelin-1; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Pyrrolidines; Randomized Controlled Trials as Topic; Taxoids; Tubulin Modulators; Vascular Endothelial Growth Factor A

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Dexamethasone; Drug Resistance, Neoplasm; Estramustine; Etoposide; Gonadotropin-Releasing Hormone; Growth Substances; Humans; Leuprolide; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Orchiectomy; Osteoblasts; Osteoclasts; Paracrine Communication; Peptides, Cyclic; Prospective Studies; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Androgen; Salvage Therapy; Somatostatin; Survival Analysis; Triptorelin Pamoate

The clinical significance of chemotherapy for patients with hormone refractory prostate cancer(HRPC) is still controversial. Some randomized-controlled trials represented that mitoxantrone combined with prednisone (or hydrocortisone) provided palliative benefit to patients with HRPC. These treatments are well tolerated by elderly patients. On the other hand, the high PSA response rates have been observed in trials with both estramustine and taxane, however, higher toxicity was also recognized. The most relevant endpoint is not only palliative efficacy but also survival in these trials. Recently, the improvement of survival with docetaxel-based chemotherapy was reported. Further studies with chemotherapeutic agents will be needed to provide patients of HRPC good quality of life and longer survival.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bridged-Ring Compounds; Docetaxel; Drug Resistance; Drug Therapy, Combination; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Palliative Care; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Taxoids

Although prostate cancer patients with metastatic lesion initially respond to androgen ablation therapy, almost patients develop to hormone-refractory states. The optimal treatment for men with hormone refractory prostate cancer (HRPC) has not been established. Docetaxel is a semisynthetic taxane that inhibit tumor growth by induction of microtubule stabilization and promotion of bcl-2 inactivation, which induce apoptosis. Docetaxel as single agent has significant anti-tumor effect in HRPC patients. Docetaxel combined with estramustine or other antimicrotubular agents have shown further significant cytotoxicity in HRPC patients. In the United States, Food and Drug Administration (FDA) approved docetaxel, injection in combination with prednisone for the treatment of patients with advanced metastatic prostate cancer in 2004.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Dexamethasone; Docetaxel; Estramustine; Gene Silencing; Genes, bcl-2; Humans; Male; Microtubules; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

2004 was a critical year for advances in prostate cancer treatment. The results from two pivotal multicenter phase III randomized studies are the first to demonstrate a survival benefit associated with chemotherapeutic treatment interventions in patients with hormone-refractory prostate cancer. This review will focus on an interpretation of the data from these two studies, the emerging role for chemotherapy in 2005 and beyond, and ongoing areas of clinical research.. Phase I and II studies have demonstrated biochemical and objective responses achieved with docetaxel-based chemotherapy in men with hormone-refractory prostate cancer. Two pivotal phase III clinical trials, TAX 327 and SWOG 9916 have demonstrated a survival advantage of docetaxel-based chemotherapy over mitoxantrone. Novel targeted therapies under investigation include calcitriol, growth factor-targeted agents, epothilones and others.. We now have a new standard of care for men with metastatic hormone-refractory prostate cancer. Further investigation of docetaxel-based regimens in earlier clinical states of disease is warranted and may demonstrate greater clinical benefit. Additional chemotherapy agents are being studied, and may also add to the future armamentarium available for prostate cancer. The enrolment of patients into these studies is critical to the ongoing evolution of prostate cancer management.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Calcitriol; Calcium Channel Agonists; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epothilones; Estramustine; Humans; Male; Mitoxantrone; Multicenter Studies as Topic; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Since the publication of the Southwest Oncology Group (SWOG) 99-16 and TAX 327 studies, which demonstrated a survival benefit for docetaxel-based therapy, clinicians for the first time have a therapy to offer men with metastatic prostate cancer that is not merely palliative in its effects. Phase 2 and phase 3 trials are now building on the findings of SWOG 99-16 and TAX 327 by evaluating the potential of combination taxane-based therapies, such as docetaxel plus high-dose calcitriol, docetaxel-estramustine-bevacizumab, and docetaxel-thalidomide. The optimal timing of docetaxel-based chemotherapy is still unknown, as there are no prospective clinical trial data to indicate whether earlier treatment (eg, at the time of prostate-specific antigen failure) is more or less effective than later treatment (eg, in metastatic and/or symptomatic disease).

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Paclitaxel; Prostatic Neoplasms; Taxoids

Until now, mitoxantrone was the standard drug for hormone resistant prostate cancer (HRPC). Docetaxel has shown more than 50% of biological response rate in HRPC in several phase II studies. Recently, two phase III studies comparing mitoxantrone and docetaxel were reported. In the view of the results of these studies, it is likely that we will change the usual treatment policy. First one , TAX 327, compared docetaxel 75 mg/m2 every 3 weeks, docetaxel 35 mg/m2 weekly and mitoxantrone 12 mg/m2 every 3 weeks. 1,006 patients were included, overall survival was better in the docetaxel arm than in the mitoxantrone arm (18.7 vs. 16.9 months; p = 0.009). The SWOG study compared docetaxel-estramustine and mitoxantrone-prednisone. 770 patients were included, the difference in overall survival was significantly in favor of the docetaxel arm (17.5 vs. 15.6 months; p = 0.02). These results shows that docetaxel is now the standard treatment of HRPC and the standard arm for future studies in this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Patients with metastatic hormone-refractory prostate cancer have a progressive disease with a median survival of approximately 11 months, and currently no treatment offers a survival advantage. The standard drug treatment is a corticosteroid and chemotherapy with mitoxantrone. In a comparison of docetaxel every 3 weeks and prednisone, versus mitoxantrone and prednisone, with a follow-up of approximately 21 months, there were less deaths in the docetaxel group than in the mitoxantrone group (166 of 335 patients and 201 of 337 patients, respectively). Docetaxel also prolonged the duration of survival compared with mitoxantrone (18.9 and 16.5 months, respectively). When given with prednisone, docetaxel was also shown to reduce pain and serum prostate specific antigen levels and improve quality of life compared with mitoxantrone/prednisone. In another trial in hormone-resistant prostate cancer patients, which compared docetaxel and estramustine with mitoxantrone and prednisone during a median follow-up of 32 months, there were fewer deaths with docetaxel/estramustine than with mitoxantrone/prednisone, which were 217 of 338 and 235 of 336 patients, respectively. Median survival was also longer in the docetaxel and estramustine group than in the mitoxantrone/prednisone group (17.5 and 15.6 months, respectively). In conclusion, two combinations (docetaxel/prednisone and docetaxel/estramustine) have been shown to be superior to mitoxantrone/prednisone in hormone-refractory prostate cancer and both should be considered for use. With the present information, there is little to distinguish between these combinations.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Prednisone; Prostatic Neoplasms; Taxoids

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

The rationale for evaluating the taxanes in hormone-refractory prostate cancer (HRPC) is strong. Preclinical data demonstrate that docetaxel is a potent inhibitor of bcl-2, an antiapoptotic gene implicated in the progression of HRPC and the development of chemotherapy resistance. The results of early clinical trials with docetaxel suggested that it could improve survival; trials in which docetaxel was combined with estramustine appeared even more promising. The Southwest Oncology Group intergroup trial (SWOG 9916) phase III was developed to compare the combination of docetaxel and estramustine to mitoxantrone-prednisone in men with HRPC. A total of 684 eligible patients were enrolled. Median survival was significantly improved with docetaxel-estramustine (17.5 months vs 15.6 months with mitoxantrone-prednisone, P = .02), and the relative risk of death was reduced by 20%. Progression-free survival was improved from 3.2 months with mitoxantrone-prednisone to 6.3 months with docetaxel-estramustine (P < .001). Significantly more patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50% compared with those treated with mitoxantrone-prednisone (50% vs 27%, P < .001). Toxicity was more common in the docetaxel-estramustine arm, likely due to estramustine. Other docetaxel-based regimens under investigation include combinations with calcitriol, thalidomide, or bevacizumab. With docetaxel/prednisone approved by the US Food and Drug Administration (FDA) as first-line treatment of HRPC, ongoing and future trials will build on its success by evaluating a number of docetaxel-based combinations in various prostate cancer settings. Other novel agents, including the oral platinum analog satraplatin, are being investigated as second-line treatment for HRPC.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Disease-Free Survival; Docetaxel; Estramustine; Forecasting; Humans; Male; Mitoxantrone; Organoplatinum Compounds; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Epothilones; Estramustine; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Of men with metastatic prostate cancer who undergo androgen ablation, 70-80% respond rapidly to therapy, as manifested by a reduction in prostate cancer-related symptoms and declines in serum prostate-specific antigen (PSA) level. Unfortunately, after a median of 18-24 months, nearly all patients with metastatic prostate cancer will progress to androgen independence. Until recently the standard of care for treating hormone-refractory prostate cancer (HRPCa) was the combination of mitoxantrone and prednisone, which palliated bone pain but did not extend survival. Two randomized trials with > 1700 patients showed for the first time a survival benefit for patients with HRPC treated with chemotherapy; when compared with mitoxantrone-based therapy, docetaxel based-therapy reduced the risk of death by 20-24%. Future trials in HRPC are attempting to improve the efficacy of docetaxel by incorporating new agents targeting angiogenesis, apoptosis, and signal transduction pathways; there is promising activity for these novel combinations in phase I and II studies. Concepts are also being refined about definitions of response and progressive disease, patient eligibility criteria, and the validity of surrogate markers of efficacy and survival, as shown by changes in PSA level.

Topics: Androgens; Antineoplastic Agents, Phytogenic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Survival Analysis; Taxoids

Prostate cancer is currently the most-frequency malignancy in men, and the second cause of death from cancer in the Western world. Once the disease has metastasized, palliative treatment is the rule. First-sine therapy consists in surgical or chemical castration, associated or not with anti-androgens. This treatment approach is active in 80% cases but failures occur within 12-18 months. When the disease becomes refractory to hormone therapy, few alternatives are available. The combination of mitoxantrone-steroids improves clinical symptoms, namely by reducing pain, but does not improve patient survival. Both docetaxel and estramustine act through microtubules and synergistic interactions have been shown between these two compounds. Recently, several studies have demonstrated the efficacy of a combination of estramustine and taxanes, and in particular docetaxel. Phase II trials using docetaxel monotherapy have demonstrated responses rates concerning PSA of 45 to 58% and objective response of 33% and 40%. Combination with estramustine increases the biochemical response rate from 45% and 74%. A randomized phase II trial revealed the superiority of this combination compared to mitoxantrone in terms of response rate and clinical benefit. The results of phase III trials are still not available, in particular as concerns survival, but the combination docetaxel-estramustine appears very promising, even though the ideal therapeutic protocol is still under evaluation.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomedical Research; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Prostatic Neoplasms; Taxoids

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

The scepticism dominating the chemotherapy of the hormone-refractory prostate cancer (HRPC) has been replaced by a wave of enthusiasm. Phase II studies with taxane-containing combination therapies could achieve high response rate in some cases, and HRPC can not longer be deemed resistant to chemotherapy. It remains to be seen whether the combinations offer a survival advantage. This will be tested in phase III studies. Palliative chemotherapy should be considered in patients with HRPC if the initial hormone therapy was effective for a short time only and after several hormone therapies have been completed. Since chemotherapy is not yet an established standard therapy of HRPC, patients should be, if possible, included in clinical studies.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Mitoxantrone; Neoplasm Staging; Palliative Care; Prednisone; Prostatic Neoplasms; Taxoids

Combinations of cytotoxic chemotherapy with estramustine phosphate (EMP), a nornitrogen mustard-estrogen conjugate, are used to treat patients with hormone-refractory prostate carcinoma (HRPC). However, thromboembolic events (TE), including deep venous thrombosis (DVT), pulmonary embolism, stroke, myocardial infarction, and arterial thrombosis, are significant toxicities of these regimens. The current study sought to establish the rate of TE and to determine risk factors for TE.. A MEDLINE-based search identified EMP-based clinical trials published in the English-language peer-reviewed literature after 1990 in which > or = 20 patients with HRPC were enrolled and TE were clearly documented. Patient characteristics and the dose of EMP given were analyzed to determine their association with the rate of TE.. Twenty-three studies, enrolling a total of 896 patients, were included in the analysis. The overall risk of TE was 0.07 (95% confidence interval [95% CI], 0.05-0.11). The risk of DVT was 0.06 (95% CI, 0.04-0.09). The risks of all other types of TE were <0.01. Using univariate logistic regression analysis, the dose of EMP administered, baseline patient age, and baseline prostate-specific antigen level were not found to be associated with the total risk of TE. The rates of total TE and DVT may be inflated because one of the analyzed studies initially had a very high rate of DVT (25%) when compared with the others.. The rate of TE in men with HRPC who are treated with EMP-based regimens is significant, but it does not appear to be related to the dose of EMP. Whether TE can be prevented with anticoagulant prophylaxis remains to be determined.

Topics: Antineoplastic Agents, Hormonal; Carcinoma; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Prostatic Neoplasms; Risk Factors; Thromboembolism; Venous Thrombosis

The role of chemotherapy in prostate cancer continues to evolve. In men with symptomatic androgen-independent prostate cancer, significant reduction in pain and analgesic requirements are achievable with mitoxantrone and glucocorticoid combinations compared with glucocorticoids alone. However, survival rates are not improved. Taxane-based combinations with estramustine phosphate or other new agents show promise. Prostate-specific antigen response rates with these combinations appear to be 1.5 to 2 times more frequent than with mitoxantrone-based combinations. Randomized trials of taxane versus mitoxantrone-based therapies are underway. New agents and applications of current agents in adjuvant settings should be explored if survival in men with prostate cancer is to be improved.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bridged-Ring Compounds; Calcitriol; Calcium Channel Agonists; Drug Therapy; Estramustine; Humans; Male; Mitoxantrone; Prostatic Neoplasms; Survival Rate; Taxoids

Treatment of hormone-resistance cancer prostate (HRCP) is undergoing evolution. Chemotherapy is now increasingly being utilized. The steps involved in the hormone management and the role for chemotherapy in the current time are being discussed. Hormonal management is carried out at different stages of hormonal sensitivity by sequential hormonal use. Once hormonal resistance is established, the combination of mitoxantrone and prednisone become a standard chemotherapeutic approach. New agents, such as docetaxel, are being tested in phase-III trials against mitoxantrone plus prednisone. HRCP is now regarded as a chemotherapy-sensitive tumor. The goals of chemotherapy in HRCP are to decrease PSA level and improve quality of life. New agents and combinations are needed to improve survival to meet this end.

Topics: Antineoplastic Agents, Hormonal; Docetaxel; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

Prostate cancer is the most common malignancy in men in the United States. With the long natural history of the disease, management of skeletal morbidity related to advanced prostate cancer becomes a major public health issue. The standard of care in advanced prostate cancer is androgen deprivation therapy. This may accelerate the development of osteoporosis and further exacerbate the risks of having adverse skeletal-related events develop. Recently, the use of bisphosphonates in men who have not responded to androgen deprivation therapy has been shown to reduce the incidence of skeletal-related events with time. Questions remain as to whether bisphosphonates should be broadly applied to earlier stages of the disease or tailored to men at higher risk of having bone-related morbidity. Work is ongoing to improve other approaches to the medical treatment of bone metastases in patients with advanced prostate cancer including the use of radiopharmaceuticals and combined chemotherapy.

Topics: Antineoplastic Agents, Hormonal; Bone Density; Bone Neoplasms; Diphosphonates; Disease Progression; Estramustine; Fractures, Spontaneous; Gonadotropin-Releasing Hormone; Humans; Hyperparathyroidism; Male; Prostatic Neoplasms

The recent literature is reviewed regarding the use of neoadjuvant and adjuvant chemotherapy, and promising new molecular targeted agents in patients with high risk localized prostate cancer.. A MEDLINE literature review was performed of studies evaluating chemotherapy and other systemic therapies for localized prostate cancer.. Patients with prostate cancer at high risk for recurrence despite local therapy include those with clinical stage T3 disease, biopsy Gleason scores of 8 to 10 or serum prostate specific antigen greater than 20 ng/ml. Although hormonal therapy has palliative benefit for the majority of patients with metastatic disease, randomized trials have not demonstrated a survival benefit from its administration before surgery for high risk localized disease. Recent trials have shown that cytotoxic chemotherapy has significant activity in hormone refractory prostate cancer, which has led to ongoing clinical trials that are investigating the use of chemotherapy in the neoadjuvant setting. Published and ongoing clinical trials in the use of systemic therapy for localized prostate cancer are reviewed.. Systemic therapy for advanced prostate cancer is improving. Efforts to use such therapies for managing localized disease are ongoing.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Docetaxel; Estramustine; Humans; Male; Neoadjuvant Therapy; Prostatic Neoplasms; Taxoids

Docetaxel (Taxotere) is a taxoid derived from the European yew tree, taxus baccata. In 4 phase-II studies docetaxel has important single agent activity with an overall prostate-specific antigen response rate of 42% in hormone refractory prostate cancer. Other phase-II studies suggest that the addition of estramustine to docetaxel results in a higher response rate but also in an increased toxicity. At present Docetaxel with and without estramustine is being evaluated in phase-III studies that will provide definitive information about its role in hormone refractory prostate cancer.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Docetaxel; Estramustine; Humans; Male; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

For >50 years, the standard treatment for advanced prostate cancer has been hormonal therapy. However, all such treated patients eventually develop disease refractory to androgen suppression as manifested by increasing prostate-specific antigen (PSA) levels, progressive disease on radiographic imaging, and ultimately, symptomatic deterioration. Historical perceptions that treatment of hormone-refractory prostate cancer was a largely futile venture have faded over the past decade with the advances in new therapeutic strategies. With the use of PSA values to follow the progress of patients after definitive therapy, physicians are seeing more patients who have failed hormonal therapy yet have no symptoms from their disease. There are standard therapies available for patients who require palliation for symptoms, but there is no consensus on treatment for asymptomatic patients. To date, there has been no definitive increase in survival with any therapy in this group of patients. In addition, several novel drugs have advanced through preclinical testing into early clinical trials. It is these drugs--alone or in combination--that are designed to target strategic tumor pathways in these patients. This article will review a selection of agents that may be potentially useful in this population.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Docetaxel; Estramustine; Forecasting; Genetic Therapy; Humans; Immunotherapy, Active; Male; Oligonucleotides, Antisense; Prostatic Neoplasms; Taxoids; Treatment Outcome

Seventeen patients were given lower dose and intermittent oral administration of estramustine phosphate (6 mg/kg/day) and etoposide (30 mg/m2/day) for 7 days. Then administration was discontinued for 7 days. This administration cycle was repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. Fifteen of the 17 patients were finally evaluated for PSA response. Overall, the pretreatment PSA levels were lowered at least 50% from baseline in 7 (47%) of the 15 patients. The median survival was 65 weeks. Five of the 17 patients complained of anorexia or nausea during the treatment, but none of them showed over grade 2 anorexia, none requiring transfusion or hospitalization. None of the patients showed edema, deep venous thrombosis, thrombocytopenia, anemia or myocardial infarction. Because of its rare and mild adverse effects, this intermittent administration of oral estramustine and oral etoposide may be a useful and secure regimen for hormone refractory prostate cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Etoposide; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Many chemotherapeutic regimens combined with estramustine phosphate (EMP) have been elaborated for the treatment of hormone-refractory prostate cancer over 30 years. However, older EMP-based combination chemotherapies with vinblastine, vinorelbine, doxorubicin or cyclophosphamide showed relatively low PSA response rate (25-58%) accompanied with high toxicities. On the other hand, newly developed EMP-based combination regimens with etoposide, pacitaxel, carboplatin or docetaxel demonstrated promising PSA response rate (43-77%) with moderate to severe toxicity in the rate of thromboembolic event (5-18%) and of neutropenia (9-41%). Treatment-related death was less in the latter combination group (5/615, 0.8%) than that in the former group (3/234, 1.3%). Of note, in the docetaxel combination with EMP, PSA response rate is as high as 77% with high rate (41%) of neutropenia but no treatment-related death was observed. Docetaxel combination with EMP seems to be the best regimen, though not completely justified by randomized trials, to be selected in the modern era, which will be followed by paclitaxel, carboplatin and EMP combination with PSA response rate of 71%. In addition, an interim report in 83 patients was presented. They were not consecutively enrolled but were treated on low-dose EMP monotherapy for previously untreated advanced prostate cancer in Department of Urology of Tokyo University and our 21 affiliated hospitals. Overall PSA response rate was as high as 93.4% out of 76 assessable patients. However, overall toxicity rate was abnormally high (39.5%) with drug discontinuation rate of 32.1%. The reason of low drug compliance may be attributed to gastrointestinal symptoms. To overcome the low drug compliance, appropriate patients for EMP administration should be selected by using gene analysis on the basis of sophisticated tailor-made medicine.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms

The development of hormone resistance is an unfortunate final common pathway in most patients with advanced prostate cancer, resulting in a narrowing of therapeutic options for the clinician, and limited median survival of 10-12 months for the patient. While cytotoxic chemotherapy has been utilized for many years, its efficacy has been disappointing. Quality of life assessments are increasingly used in assessing response in hormone-resistant prostate cancer (HRPC), and PSA has emerged as an important surrogate marker of response in both local and advanced disease. Estramustine and the taxanes have been investigated, as monotherapy and in combination, in the treatment of HRPC in phase 2 and 3 clinical trials, a number of which are ongoing. Substantial advances in the management of HRPC over the past decade have led to renewed optimism that improvement in survival can be achieved, and support the belief that chemotherapy plays a role in this pursuit. In tandem with the development of new agents, refined means of assessing response have been developed, and represent a key component of new research strategies in HRPC.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Estramustine; Humans; Male; Paclitaxel; Prostatic Neoplasms; Taxoids

While men with metastatic prostate cancer frequently show a good initial response to androgen ablation, few options have been available for progressive hormone-refractory prostate cancer, and survival following chemotherapy has not exceeded 9 to 12 months. The combination of prednisone and mitoxantrone has significant palliative effects on bone pain but does not extend survival. The combination of estramustine phosphate (EMP) with the taxanes paclitaxel or docetaxel produces greater than additive cytotoxicity in vivo, and phase I and II studies of taxane-based therapy demonstrate improved survival in hormone-refractory prostate cancer compared to historical controls. Docetaxel appears to have relatively high activity as a single agent and in combination with EMP. Further studies are needed to clarify the optimum dose of EMP, taking into account potential cardiovascular toxicity. Phase III studies of its combination with docetaxel are in progress.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Neoplasm Recurrence, Local; Paclitaxel; Palliative Care; Prostatic Neoplasms; Taxoids

Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Hormones; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Chemotherapy that targets microtubular trafficking induces responses in most patients with prostate cancer. One regimen under investigation is the combination of docetaxel and estramustine. We report on 2 patients with androgen-independent disease who received continuous weekly docetaxel and estramustine and who died of irreversible respiratory failure. The clinical, pathologic, and radiographic data support drug toxicity as the likely etiology. Inclusive of these patients, only 17 cases (10 fatal) of acute pulmonary toxicity using docetaxel have been reported, despite its wide use. We recommend that patients receiving weekly docetaxel, with or without estramustine, have frequent treatment breaks and be evaluated with computed tomography of the chest every 8 weeks.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Fatal Outcome; Humans; Male; Paclitaxel; Prostatic Neoplasms; Radiography; Respiratory Insufficiency; Taxoids

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Drug Administration Schedule; Drug Combinations; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Tegafur; Uracil

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Estramustine; Etoposide; Humans; Male; Paclitaxel; Prostatic Neoplasms; Taxoids; Vinblastine

Topics: Androgens; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Clodronic Acid; Cyclophosphamide; Dexamethasone; Docetaxel; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Strontium Radioisotopes; Taxoids; Tegafur; Treatment Outcome

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Androgen Antagonists; Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Paclitaxel; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Suramin; Taxoids; Testosterone; Treatment Outcome

Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.

Topics: Anthracyclines; Antineoplastic Agents; Estramustine; Humans; Male; Prognosis; Prostatic Neoplasms; Risk Factors; Suramin

Estramustine phosphate sodium (EMP) was first introduced in the early 1970s for the treatment of prostate cancer, when EMP was supposed to have the dual effect of estrogenic activity and cytotoxicity. For the following decades, it was used mainly in hormone-refractory cases, with a conventional dosage of 4-9 capsules/day, which showed a 30-35% objective response rate. However, a very limited number of cases have been reported that used EMP as a first-line monotherapy in the conventional dosage. One study showed a response rate of 82%, which is at least as effective as conventional estrogen (diethylstilbestrol; DES) monotherapy. Nevertheless, EMP was almost abandoned for the treatment of prostate cancer because of severe adverse side-effects, especially in the cardiovascular system and gastrointestinal tract. Recently, two facts have become evident. First, EMP interferes with cellular microtubule dynamics but does not show alkylating effects. Second, EMP is able to produce a complex with calcium when dairy products are taken concomitantly with EMP, resulting in a decrease in the absorption rate of EMP from the gut. Many clinical trials have been undertaken without warning against concomitant dairy product intake since the introduction of EMP. This fact will jeopardize almost all the clinical trials performed before 1990. It is considered that response rates have been underestimated and better results could have been obtained because side-effects decrease dose-dependently. Low-dose EMP monotherapy (2 capsules/day) has been performed infrequently in previously untreated advanced prostate cancer. The only large trial by the European Organization for Research and Treatment of Cancer in 1984 was biased in selecting patients. Nevertheless, the response rate of EMP is comparable to that of DES. In this study, the adverse side-effects of EMP were less than that of DES. Recently, a study was conducted at the University of Tokyo of 11 patients with advanced prostate cancer on low-dose EMP as first-line monotherapy. The study found that the mean serum prostate-specific antigen level decreased to within the normal range by day 50; mean serum testosterone, leutinizing hormone and follicle-stimulating hormone reduced to undetectable levels by day 20; and mean serum estradiol increased to a very high level within 1 week. These data implicate that low-dose EMP can suppress quickly and adequately the pituitary-gonadal axis, although the antitumor effect has not as yet been

Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Prostatic Neoplasms

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Chemotherapy, Adjuvant; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dexamethasone; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Enzyme Inhibitors; Estramustine; Etoposide; Genes, bcl-2; Humans; Hydrocortisone; Male; Microtubules; Mitosis; Mitoxantrone; Multicenter Studies as Topic; Neoplasm Proteins; Oligodeoxyribonucleotides, Antisense; Paclitaxel; Palliative Care; Prostatic Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Survival Analysis; Taxoids; Treatment Outcome; Tubulin

Hormone refractory prostate cancer (HRPC) is a difficult clinical problem. These patients are intolerant of aggressive cytotoxic therapies because of their age and poor performance status. Systemic chemotherapy, whether administered as single agents or in multidrug combinations, has not been shown to prolong survival. It is only recently that palliative endpoints, such as quality of life analyses, have been formally evaluated in the clinical trials of HRPC. As a result, mitoxantrone plus prednisone has been demonstrated to be a useful palliative therapy that provides improvements in pain and quality of life for approximately 40% of those treated. Other promising regimens, such as the estramustine combinations or docetaxel, are currently undergoing phase III trials designed to prove superiority to mitoxantrone plus prednisone. Suramin has been extensively studied, but due to its poor activity seen in recent randomized trials, as well as the toxicity and inconvenience, it will likely not be further developed in HRPC. In recent years, there has been a tremendous increase in the development of biological targets for cancer therapy and a number of these are in early trials for HRPC. Given the relative insensitivity of prostate cancer to cytotoxic agents, this area holds much potential.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Mitoxantrone; Pain; Palliative Care; Prednisone; Prostatic Neoplasms; Quality of Life; Suramin

Prostate cancer is perceived to be a disease of older men often diagnosed with widespread metastases that respond to hormonal ablation but for which there are few additional treatment options. Fortunately this perception is rapidly changing as newer combination chemotherapy trials demonstrate improved prostate-specific antigen and measurable response rates and enhanced quality of life. Still, treatment of prostate cancer lags behind treatment of other malignancies. Work remains in understanding the natural history of disease, refining our grouping of patients by stage into clinical trials, and adhering to new response criteria recently developed. Applying the newer active chemotherapy regimens to patients with earlier stage disease should lead to improvements in overall survival.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Neoplasm Staging; Paclitaxel; Prostatic Neoplasms; Quality of Life; Taxoids

Prostate cancer is the second leading cause of cancer mortality among men in Western countries. The initial treatment of advanced prostate cancer is suppression of testicular androgen production by medical or surgical castration, but nearly all men with metastases will develop disease progression. Patients with hormone refractory prostate cancer (HRPC) have a median survival of approximately 18 months and no therapy has yet demonstrated a definitive survival advantage. However, in the past several years, a number of promising new treatment strategies have emerged. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation. This approach is predicated on the recognition that HRPC is a heterogeneous disease and some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Until recently, cytotoxic chemotherapy was felt to be relatively ineffective in the treatment of HRPC. Combination regimens incorporating new active agents have demonstrated significant activity in this setting, renewing interest in the use of chemotherapy to treat HRPC. Recent advances in the understanding of prostate cancer biology have led to the development of drugs directed against precise molecular alterations in the prostate tumour cell. Biologic agents now in development include those capable of altering signal transduction, blocking angiogenesis, inhibiting cell cycle progression, and stimulating apoptosis. In addition, many types of immune therapies are showing promise. Evaluating these agents, and incorporating them into existing regimens, are major goals of ongoing clinical research in advanced prostate cancer.

Topics: Androgen Antagonists; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Drug Resistance, Neoplasm; Estramustine; Humans; Immunotherapy; Male; Mitoxantrone; Prostatic Neoplasms; Protease Inhibitors; Treatment Outcome; Vitamin D

Topics: Antineoplastic Agents; Cisplatin; Estramustine; Humans; Ifosfamide; Male; Peplomycin; Prostatic Neoplasms

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Drug Resistance; Drug Therapy, Combination; Estramustine; Humans; Male; Prostatic Neoplasms

In the past, the treatment options for patients with metastatic prostate cancer that progressed despite castrate levels of testosterone was limited, and no therapies provided an improvement in survival. The majority of these patients had extensive osseous disease, multiple comorbidities, and poor performance status. With the widespread use of prostate-specific antigen (PSA) to monitor their clinical course, patients have presented with less extensive disease and a better performance status. Clinical trial methodology has improved as well, through incorporation of post-therapy changes in PSA to evaluate novel agents. This approach allows more patients to enter clinical trials, and the results show that the majority of these patients will have significant reduction in pain, regression of measurable disease, and suppression of PSA. These data suggest that prostate cancer is not as resistant to chemotherapy as it was once thought to be.

Topics: Androgens; Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Endpoint Determination; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Angiogenesis is essential to prostate cancer progression. The first study of antiangiogenic therapy in patients with locally advanced prostate cancer at The University of Texas M. D. Anderson Cancer Center showed that preoperative treatment with a fumagillin analog was safe. Microvascular density correlated with Gleason score, but marked intertumoral and intratumoral changes were observed. Clinical experience with thalidomide (Thalomid), which inhibits angiogenesis induced by both vascular endothelial growth factor and basic fibroblast growth factor, has included observation of "clinical improvement" in patients with androgen-independent prostate cancer and anecdotal responses in patients with metastatic disease refractory to chemotherapy. In an effort to assess the in vivo effect of thalidomide in prostate carcinoma, we have initiated a study of neoadjuvant thalidomide treatment in patients with locally advanced prostate cancer that is to include serial ultrasonographic and pathologic evaluation, as well as serial collection of serum/urine markers that may prove useful surrogate markers of antiangiogenic activity. We have also initiated a phase I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) in patients with metastatic androgen-independent prostate cancer progressing after up to two courses of chemotherapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Estramustine; Humans; Male; Microcirculation; Paclitaxel; Prostatic Neoplasms

Hormone refractory prostate cancer is a disease that kills approximately 39,000 people per year. No single chemotherapeutic agent or regimen has been demonstrated to provide a survival advantage in this disease. Etoposide as a single agent, both in i.v. and oral formulations has not proven to be effective. In the 1990s, however, etoposide has been combined with several agents to create novel treatment regiments for patients with hormone refractory disease. Several of these regimens, all involving oral etoposide, have demonstrated promising results in Phase II trials and early results suggest that they may increase survival for hormone refractory patients, although this remains to be tested in a Phase III trial setting.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase II as Topic; Cyclophosphamide; Estramustine; Etoposide; Humans; Male; Prostatic Neoplasms

We describe the progress in oral anti-cancer drug therapy for urological cancer. Pure antiandrogen (e.g., flutamide) is widely used as a means of maximal androgen blockade (MAB) in the treatment of prostate cancer. However, all series reported in the past several years did not show positive effects on prolongation of the patient's survival. Evaluations by meta-analysis are in progress. As the mechanism of antiandrogen withdrawal syndrome has been recognized, it was widely accepted that antiandrogen should be discontinued when disease progression or PSA elevation becomes evident. Estramustine was recently clarified as an effective therapeutic agent in the treatment of hormone refractory prostate cancer in combination with oral etoposide. Oral etoposide therapy has been tried as a maintenance or a palliative chemotherapy for non-curative or high-risk germ cell tumor. UFT (a compound of tegafur and uracil) is said to be effective for bladder cancer. It has been also suggested that UFT was partly effective as a means of first-line endocrine chemotherapy for advanced prostate cancer and was a promising agent in the treatment of advanced renal cell carcinoma in combination with Interferon-alpha. Usually the age of the patient with urological malignancy, excluding testicular cancer, is high and complicated. For such patients, an aggressive intravenous chemotherapy can not always be used. Therefore, a less aggressive, less toxic chemotherapy with oral drug is often planned to maintain QOL.

Topics: Administration, Oral; Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Drug Combinations; Estramustine; Etoposide; Female; Flutamide; Humans; Kidney Neoplasms; Male; Prostatic Neoplasms; Tegafur; Uracil; Urinary Bladder Neoplasms

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. In 1997 it was estimated that more than 41,000 men died of this disease. Treatment of metastatic disease remains palliative, with androgen ablation used as first-line therapy. After failure of androgen ablation, chemotherapy can now be used to induce a remission in many men. Treatment regimens that include paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have been particularly successful in treating hormone-refractory prostate cancer in the phase II setting. We have conducted a trial of estramustine 280 mg orally three times per day for 14 days combined with etoposide 50 mg/m2/d (in general, one 50-mg tablet twice a day) for 14 days, with paclitaxel 135 mg/m2 over 1 hour on day 2. This regimen is repeated every 21 days for a maximum of six cycles. Patients responding to therapy are then given a break and re-treated at physician discretion. On preliminary analysis, 24 of 38 patients demonstrated a decline in pretreatment prostate-specific antigen of more than 50% (63%). The regimen was well-tolerated and only seven patients demonstrated grade 3 or 4 neutropenia. Further analysis is ongoing.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Estramustine; Etoposide; Humans; Male; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms

New combinations have been developed that show significant activity in therapy for hormone refractory prostate cancer. Several of these are designed to address specific cellular targets unique to prostate cancer. To date, the major benefits of these therapies have been palliative in nature, resulting in an improvement in quality of life, particularly with the combination of mitoxantrone and prednisone. None of these agents or regimens have been shown to affect survival significantly, and none can be considered to be standard therapy for this disease. Nonetheless, the success of these regimens in inducing response has challenged the skepticism concerning the appropriateness of chemotherapy for patients with advanced prostate cancer. The ability to slow and even reverse the growth of far advanced disease raises the possibility that the application of these regimens earlier in the course of the disease will have a more significant impact on the morbidity and, in the long run, on the mortality of prostate cancer. It is hoped that the enrollment of patients into properly designed clinical trials of new agents and combinations will result in the development of therapy with proven efficacy in the near future.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cyclophosphamide; Estramustine; Humans; Male; Prostatic Neoplasms; Suramin

Estramustine (EM), a conjugate of nornitrogen mustard and estradiol, is a antimicrotubule drug currently in use for the treatment of advanced prostatic carcinoma. Experimental data are accumulating concerning the antitumor effect of EM in other malignancies, and clinical studies in other malignancies are ongoing. This review summarizes the information available to date concerning the effects of EM and the development of drug resistance. EM depolymerizes microtubules by binding to microtubule-associated proteins (MAPs) as well as tubulin. Because of the radiosensitizing effect of this drug there has been a recent increase in interest concerning estramustine and its clinical use. Recently, it was proposed that EM induces an apoptotic cell death in glioma cells in vitro and in a rat model. EM resistance is distinct from MDR phenotype; it has been used in combination with antimitotic agents which are part of the MDR phenotype. Observations made with estramustine-resistant cell lines show the acquisition of estramustine resistance is a function of multiple adaptation by changes at tubulin expression pattern, and is also associated with changes in tau expression and phosphorylation.

Topics: Animals; Antineoplastic Agents, Hormonal; Drug Resistance, Neoplasm; Estramustine; Male; Microtubule-Associated Proteins; Prostatic Neoplasms; Rats; tau Proteins; Tubulin

In the United States, prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in men. Prostate cancer is a rare disease before age 40; however, the prevalence increases quickly to 80% by the age of 80, and with increasing life expectancy, hormone-refractory prostate cancer (HRPC) will soon represent the most common cancer in the male population in the United States and other Western countries. The evolution of early prostate cancer is variable and extends over many years; some tumors progress slowly or not at all, whereas others may progress more rapidly and be fatal after a few years. A widely held view is that chemotherapy has no role in HRPC because no single agent or combination has been shown to prolong survival in a randomized trial. This concept may be obsolete, as preliminary results for a number of approaches, mostly derived from laboratory observations, show that prostate cancers are not as resistant to chemotherapy as traditionally believed. The population of early "geriatric" HRPC patients is rapidly increasing, posing an even greater challenge to oncologists in coping with this difficult-to-manage patient population. In this article, we analyze the most novel chemotherapeutic combinations for the treatment of HRPC in otherwise healthy elderly men.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Doxorubicin; Estramustine; Humans; Liposomes; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Palliative Care; Prostatic Neoplasms; Suramin

As part of an extensive search of synergistic combinations of agents that demonstrate cytotoxic activity in tissue culture against prostate cancer cell lines, we have identified estramustine phosphate and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as active. Patients with hormone-refractory metastatic prostate cancer with good performance status were entered onto a phase I trial of this combination. Estramustine phosphate was given on a daily oral dosing schedule of 14 mg/kg; docetaxel was administered intravenously over 1 hour every 3 weeks. Prophylactic corticosteroids were administered to minimize taxane side effects. Four dose levels of docetaxel were studied: 40, 60, 70, and 80 mg/m2. Actual weight was used for dosing calculations. An intermittent docetaxel dose of 70 mg/m2 with estramustine phosphate at 12 mg/kg was determined to be a phase II dose and to allow repetitive dosing. Eight additional patients were entered at this dose level of docetaxel. In all patients, the limiting side effects were fatigue and leukopenia. Thromboembolic events also were seen in 16% of patients. In the first 17 patients treated in the phase I aspect of the study, the biochemical response rate was 82%, demonstrating greater than a 50% decline in prostate-specific antigen. Twenty-four percent had normalization of prostate-specific antigen. These early studies indicate that the combination of estramustine and docetaxel has activity in this population of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Docetaxel; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Taxoids

Treatment of hormone-refractory prostate cancer (HRPC) historically has shown limited efficacy. However, taxane-based chemotherapy regimens recently have demonstrated more promising results. Several groups have reported significant efficacy and minimal toxicity in patients with hormone-refractory disease receiving estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA). Others have demonstrated single-agent activity of platinum compounds in HRPC. Therefore, the combination of estramustine, docetaxel, and carboplatin is currently being tested in two separate trials of HRPC. The first is a Dana-Farber/Partners Cancer Care phase I study of estramustine, carboplatin, and escalating doses of weekly docetaxel. The second study is a Cancer and Leukemia Group B multicenter phase II study evaluating the combination of estramustine, docetaxel, carboplatin, and granulocyte colony-stimulating factor. The promise of taxane-based regimens in the treatment of hormone-refractory disease has led to consideration of treating patients at high risk for developing metastatic disease earlier in their clinical course. At Dana-Farber/ Partners Cancer Care, we are evaluating neoadjuvant weekly docetaxel alone followed by surgery in patients with high-risk localized prostate cancer using pathologic response as the primary end point. Adding carboplatin to the active combination of estramustine and docetaxel may improve the response rate in HRPC. Furthermore, the use of promising chemotherapy agents earlier in high-risk localized disease may improve clinical outcomes in these patients by decreasing their risk for systemic relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Docetaxel; Estramustine; Humans; Male; Neoadjuvant Therapy; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Taxoids

Historically, hormone-refractory prostate cancer has not been routinely treated with chemotherapy, based on perceptions that single agents were not all that active, this patient population was too fragile to receive such therapy, responses were virtually impossible to verify given the rarity of bidimensionally measurable disease, and, if seen, responses were not clinically meaningful. The "truths" of the 1970s and 1980s are the "myths" of the 1990s, but unfortunately many physicians continue to propagate these myths despite accumulating data to the contrary. Newer combination regimens produce objective response rates in measurable disease that rival those seen in other solid tumors that are uniformly labeled as "chemosensitive." The widespread use of the serum prostate-specific antigen level has allowed the detection of progressive disease at an earlier stage in patients with an excellent performance status. Although chemotherapy to date has not had an impact on patient survival, quality of life analyses have clearly demonstrated improved palliation in treated patients. Hopefully, as this knowledge is disseminated more widely, more patients will be offered cytotoxic therapy for this currently undertreated disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Mitoxantrone; Prostatic Neoplasms; Suramin

Long misclassified as an alkylating agent, estramustine phosphate is a stable conjugate of estradiol and nornitrogen mustard with antimitotic properties. Binding of the drug to microtubule-associated proteins, tubulin, and proteins of the nuclear matrix are presently considered to be the most likely mechanisms underlying the cytotoxicity of estramustine in androgen-independent prostatic carcinoma. Identification of these mechanisms of action has led to clinical reevaluation of estramustine phosphate (EMP) in several rationally designed drug combinations. Combination of EMP with either vinblastine, paclitaxel or etoposide has produced antitumor responses in 30% to 60% of patients with metastatic hormone-refractory prostate carcinoma as determined by reduction in bidimensionally measurable soft tissue disease, pain, and serum prostate-specific antigen. Whereas the antitumor activity of the combinations has been greater than additive for the single agents, the toxicities of treatment have not been greater than predicted for the individual drugs. The promising results of EMP-based chemotherapy encourage additional laboratory and clinical investigations to develop more effective therapy for hormone-refractory disease and for selected patients with earlier stages of prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Cyclophosphamide; Diethylstilbestrol; Doxorubicin; Estramustine; Humans; Male; Mitomycin; Neoplasm Recurrence, Local; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Rats; Survival Rate

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Diethylstilbestrol; Estramustine; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prognosis; Prostatic Neoplasms; Suramin; Vinblastine

The identification of active chemotherapeutic agents for use in the treatment of advanced hormone-refractory prostate cancer remains a priority of clinical research. An estimated 317,100 new cases will be diagnosed in 1996. This increased diagnosis of disease can be directly attributed to the widespread use of screening serum prostate-specific antigen. However, this has not been associated with a reduction in mortality; more than 41,000 men in the United States are expected to die of the disease this year. The natural history of hormone-resistant disease has remained unaltered, with patients having a median survival of only approximately 12 months. Use of surrogate endpoints, such as a reduction in prostate-specific antigen or improvement in pain, may be appropriate for the evaluation of novel agents or combinations. A number of promising new approaches have been recently tested and brought to trial, including combined antimicrotubular therapy, camptothecins, and matrix metalloproteinase inhibitors. It is only through the development of these and other novel compounds that we can hope to affect the natural course of prostate cancer.

Topics: Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Estramustine; Humans; Male; Metalloendopeptidases; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Vinblastine; Vinorelbine

In conclusion, there have been impressive efforts to identify new cellular targets for the treatment of hormone-refractory disease. It appears that in some cases, survival may be extended; however, further prospective trials are necessary to confirm these observations.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Estramustine; Humans; Ketoconazole; Male; Prostatic Neoplasms; Suramin; Treatment Outcome

Estramustine phosphate sodium (estramustine phosphate), a unique antitumour agent, is selectively taken up by prostate cells and exerts antineoplastic effects by interfering with microtubule of dynamics and by reducing plasma levels of testosterone. In noncomparative studies of estramustine phosphate in patients with hormone-refractory disease, objective response rates ranging from 19 to 69% have been reported. Preliminary clinical investigations indicate that combining estramustine phosphate with vinblastine, etoposide or paclitaxel improves objective response rates over single-agent treatment, although no survival benefit over single-agent treatment has been demonstrated to date. In comparative studies, estramustine phosphate produces similar objective response rates to conventional antineoplastic agents in patients with hormone-refractory prostate cancer. In previously untreated patients with advanced metastatic hormone-responsive prostate cancer, objective responses are achieved in approximately 80% of patients. Estramustine phosphate appears to be at least as effective as estrogen or flutamide therapy in these patients. Nausea and vomiting are the most frequently observed adverse effects of treatment with estramustine phosphate. While these symptoms are usually mild to moderate in nature, they may occasionally be more troublesome to the patient and necessitate withdrawal of treatment. Cardiovascular complications are a more serious, though less frequently encountered, adverse effect of the drug. However, these complications may be avoided by careful patient selection and prophylactic treatment measures. Unlike some other antineoplastic agents, estramustine phosphate is rarely associated with myelosuppression. In addition to producing similar objective response rates to other established agents, estramustine phosphate improves the subjective status of many patients and has been shown to reduce the intensity of pain and improve the performance status of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Absorption; Aging; Antineoplastic Agents; Clinical Trials as Topic; Drug Administration Routes; Estramustine; Humans; Male; Prostatic Neoplasms; Tissue Distribution

Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which during long term administration reduces circulating levels of gonadotrophins (luteinising hormone and follicle stimulating hormone) and sex hormones. Goserelin is administered subcutaneously as a biodegradable depot formulation incorporating 3.6mg of the drug, which is released continuously over 4 weeks. In men with untreated advanced prostate cancer, monthly goserelin 3.6mg has been confirmed as similar in efficacy to surgical castration and diethylstilbestrol (stilboestrol) 3mg daily taken orally. Goserelin is better tolerated than diethylstilbestrol and appears to have a more favourable effect on quality of life than surgical castration. Treatment of prostate cancer with a combination of goserelin and an antiandrogen remains controversial as a result of inconsistent findings, despite extended data from a large trial which indicated an advantage for the combined regimen over surgical castration with respect to duration of time to progression and survival. Combination therapy also minimises the initial increase in signs and symptoms (disease flare) that occurs in up to 4% of patients at the beginning of treatment with a GnRH analogue. Surgical castration remains the treatment of choice in patients at risk of metastatic compression of the spinal cord or ureteric obstruction. However, goserelin is an effective alternative to surgery, or estrogen therapy, in men with previously untreated advanced prostate cancer. Goserelin seems to be preferred to surgery by the majority of patients given a choice of treatment, and importantly in a palliative care situation where there are no survival advantages for treatment alternatives, it appears to have a more beneficial effect on the quality of life than surgery.

Topics: Absorption; Aged; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Estrogens; Flutamide; Gonadotropins; Goserelin; Humans; Male; Orchiectomy; Prostatic Neoplasms; Steroids

Topics: Estramustine; Etoposide; Humans; Male; Prostatic Neoplasms; Suramin; Vinblastine

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Male; Prostatic Neoplasms

Although the penis is highly vascularized, secondary penile tumors are rare and 28% of these metastasize from prostatic tumors. Urethral metastases are uncommon and may be caused by seeding following manipulation of the prostate with instruments or spread directly from the adjacent structures. This condition can be controlled and treated effectively with first or second line hormone therapy. Herein we describe a 65-year-old male with disseminated prostatic adenocarcinoma who presented multiple urethral metastases that were successfully treated with stramustine phosphate.

Topics: Adenocarcinoma; Aged; Biopsy; Bone Neoplasms; Estramustine; Humans; Male; Prostatic Neoplasms; Remission Induction; Urethra; Urethral Neoplasms

Three cases of prostatic carcinoma with palpable metastatic lymph nodes are presented. In case 1, the intrapelvic lymph node metastases were recognized as an abdominal mass. In case 2 and 3, non-regional superficial lymph node metastases were palpable. Orchiectomy and anti-androgen therapy were effective in all cases.

Topics: Adenocarcinoma; Aged; Combined Modality Therapy; Diethylstilbestrol; Estramustine; Humans; Lymphatic Metastasis; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

Hormonal treatment is effective for only a limited time in primary treatment of advanced prostate cancer, because of the development of hormone-resistant cells. It is unknown whether these cells were present in small numbers from the beginning or developed later by mutation of hormone-sensitive cells. Cytotoxic therapy has, up to now, mainly been used as second-line treatment when virtually all cells are hormone-resistant. Because 20% of all advanced prostate cancers do not respond to hormonal treatment even when given as primary therapy, hormone-resistant cells may have been present from the beginning. Trials using a combined hormonal and cytotoxic treatment as primary therapy would, therefore, be interesting. However, there is a lack of active compounds that do not show major toxicity. Estramustine phosphate (EMP) may be an exception. It is unusual because it combines hormonal and cytotoxic effects. Second-line treatment with chemotherapy has led to subjective improvement over a very short period of time only. EMP may be of benefit to patients who have had previous radiotherapy as it does not suppress the bone marrow. Although primary treatment of advanced prostate cancer with a combination of hormone and chemotherapy does not lead to a cure, it may extend time to progression, particularly in patients with poor prognostic factors at the onset. In future phase III studies, the role of prognostic factors must be further classified in order to obtain meaningful results.

Topics: Animals; Antineoplastic Agents; Estramustine; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms

Estramustine offers a mechanistically novel therapy for the treatment of prostatic cancer. The drug is composed of oestradiol coupled to nor-nitrogen mustard. The cytotoxic properties of estramustine act independently of its constituent molecules. In vivo and in vitro studies indicate that the drug binds microtubule associated proteins and inhibits microtubule regulated processes. We have lately shown that micromolar levels of estramustine inhibit selected processes in mitosis, suggesting that certain classes of microtubules and/or MAPs are differentially sensitive to the drug. New clinical trials using estramustine and vinblastine on patients with advanced hormone refractory disease suggest that the combination of two antimicrotubule agents acting by means of different target molecules may be important clinically.

Topics: Animals; Cell Division; Estramustine; Humans; Male; Microtubules; Prostatic Neoplasms; Rats

Prostatic carcinoma metastatic to the penis is a rare phenomenon. We report two cases of acute urinary retention due to penile metastases from a prostatic carcinoma. Patients may have a penile mass or diffuse swelling of the penis. Some patients develop priapism and urinary retention can be rarely observed. The most effective treatment seems to be local excision with wide resection and, if necessary, total penectomy. The prognosis remains poor regardless of the type of therapy employed.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Amputation, Surgical; Biopsy; Cystoscopy; Estramustine; Humans; Male; Middle Aged; Neoplasm Staging; Penile Neoplasms; Phlebography; Prognosis; Prostatic Neoplasms; Survival Rate; Urinary Retention

With estramustine phosphate the clinician has the possibility to ensure complete hormonal as well as cytotoxic control of advanced prostate cancer with a single drug. EMP is considered as a first choice for treatment of hormone refractory prostate cancer. It is at least as effective as conventional chemotherapy, yet less aggressive with regard to its toxicity profile. EMP is particularly useful in patients with limited bone marrow reserve, e.g. in case of prior or associated radiotherapy. As to the use of EMP in primary treatment, more information is required before we can define with certainty subgroups of patients who would benefit more from an early course of EMP than from other hormonal therapy. The existing data point in the direction of poorly differentiated tumors, patients with bone pain and poor prognosis. EMP treatment is associated with an increased risk of cardiovascular morbidity. This should be avoided as much as possible by proper selection of patients or by prophylaxis. Gastro-intestinal side effects, such as nausea, diarrhea and anorexia are dose-dependent. These adverse events tend to interfere with compliance at dosages over 560 mg/day. Dosage modifications or an anti-emetic may help. The intravenous administration of EMP offers the possibility for high loading doses at a substantially reduced risk for cardiovascular and gastrointestinal side effects.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Estramustine; Humans; Male; Prostatic Neoplasms

In a 44-year-old man with persistent back-pain for 3 months duration, radiological and echological investigations revealed prostatic mass lesion with multiple osteoblastic involvements. Transrectal biopsy to the prostate demonstrated pathohistologically poorly differentiated adenocarcinoma (Gleason's score 4-4:8). Serum ACP, ALP and IAP were elevated at the initial diagnosis pathologically. The clinical and pathological stage was D2, without metastasis to lung and liver. Combination chemo-endocrine therapy (methotrexate, adriamycin, pepleomycin, Estracyt and tegafur) with bilateral orchiectomies was performed exclusively as initial treatment. These consecutive treatments brought remarkable reduction of the prostatic mass lesion, decrease of tumor markers to normal range, rapid improvement of subjective symptoms and distinct decrease of abnormal activity in bone scintigram. More than 3 years survival was obtained, and normal performance-status was kept. Prostatic cancer in middle-aged adults is reviewed and discussed.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Doxorubicin; Estramustine; Humans; Male; Methotrexate; Nitrogen Mustard Compounds; Orchiectomy; Peplomycin; Prostatic Neoplasms; Remission Induction; Tegafur

The objective of this review is to explore different therapeutic options for metastatic adenocarcinoma of the prostate. Orchiectomy, estrogen therapy, synthetic LHRH analogs and possibly antiandrogens are equally effective frontline treatment modalities. Ketoconazole is indicated in emergency situations, but chronic use is prevented by serious idiosyncratic toxicity and by long term complications. Combined androgen blockade (CAB), with leuprolide (or tryptorelin) and flutamide is more effective than single modality treatment in patients capable of strict treatment compliance. Estramustine phosphate may be as effective as CAB and may be the frontline treatment of choice in sexually active patients. Institution of single modality treatment may be delayed until cancer becomes symptomatic. Controversy lingers over whether the institution of CAB at an earlier time may improve progression free survival (PFS) and survival. Research projects of immediate clinical relevance include: comparison of CAB and estramustine; determination of the optimal time for CAB; study of other forms of CAB; and phase II trials of new cytotoxic agents.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prostatic Neoplasms

Topics: Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Chemical Phenomena; Chemistry; Estramustine; Humans; In Vitro Techniques; Male; Microtubule-Associated Proteins; Microtubules; Nitrogen Mustard Compounds; Prostatic Neoplasms; Protein Binding

This review presents the most important hormonal, cytotoxic and pharmacokinetic properties of estramustine phosphate. Furthermore the results of randomized Phase III trials are described in patients with hormone refractory prostatic cancer with and without previous irradiation. Several randomized studies are reported with Estracyt also in the primary treatment of this disease.

Topics: Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Castration; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Prostatic Neoplasms

Tumor oriented anticancer agents with estrogen as a carrier have been extensively studied since 1950's. Only Estracyt and bestrabucil have been evaluated to be useful in clinical trials. Although the use of estrogen as a carrier for anticancer agents aimed at the development of the anticancer drug for the receptor mediated chemotherapy, these two drugs did not show any affinity to estrogen receptor. The history tells us that the development of anticancer agents for the estrogen receptor mediated chemotherapy is extremely difficult. Estracyt is reported to exert its anticancer effect on prostate cancer through the specific binding to the estramustine binding protein (EMBP) which is present only in the prostate gland and cancer. Bestrabucil shows the selective uptake by the various malignant cells and is indicated that bestrabucil exerts its anti-cancer effects on various malignant tumors including breast cancer and hematopoietic malignancy, through the affinity to malignant cells. The mechanism is unknown and to be elucidated.

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Chlorambucil; Drug Carriers; Estradiol; Estramustine; Estrogens; Humans; Male; Prostatic Neoplasms; Rats

Topics: Carrier Proteins; Clinical Trials as Topic; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms; Prostatic Secretory Proteins

Topics: Clinical Trials as Topic; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Dacarbazine; Diethylstilbestrol; Doxorubicin; Estramustine; Fluorouracil; Humans; Hydroxyurea; Male; Melphalan; Methotrexate; Mitomycin; Mitomycins; Prednisolone; Procarbazine; Prostatic Neoplasms; Streptozocin; Vincristine

Topics: Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms

Prostate cancer consists of epithelial and stromal elements that are heterogeneous with regard to androgen dependence. Nearly 80% of patients with symptomatic metastatic prostate cancer obtain prompt objective and subjective response to androgen deprivation. Surgical castration remains an effective form of therapy, has low morbidity, and obviates compliance problems with medical regimens. New LH-RH analogs offer complete medical androgen deprivation, appear as effective as estrogen therapy at 2-year follow-up, and have significantly lower cardiovascular side effects. Thus, LH-RH analogs may replace estrogen therapy for the medical management of metastatic prostate cancer. Androgen deprivation therapy has not been proved to prolong the survival of patients with prostate cancer. The optimal timing for initiation of endocrine therapy in these patients remains controversial. Techniques for predicting androgen dependence of prostate cancer are still evolving and are not yet applicable on a widespread clinical basis.

Topics: Adrenal Glands; Adrenalectomy; Androgens; Dihydrotestosterone; Estramustine; Estrogens; Gonadotropin-Releasing Hormone; Humans; Hypophysectomy; Hypothalamo-Hypophyseal System; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Testis

The national Prostatic Cancer Project has evaluated single and combination chemotherapeutic agents for the treatment of patients with advanced prostatic cancer that has been unresponsive to hormonal therapy. Although regression rates have been modest, a number of drugs have shown some efficacy and are now undergoing testing in combination. Current trials of the LH-RH agonists and the antiandrogen flutamide are in progress. These trials have demonstrated a role for chemotherapy in the treatment of the patient who has failed hormonal therapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carmustine; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Doxorubicin; Estramustine; Fluorouracil; Humans; Imidazoles; Lomustine; Male; Methotrexate; Mitomycin; Mitomycins; Prednimustine; Prednisone; Procarbazine; Prostatic Neoplasms; Random Allocation; Streptozocin; Vincristine

Estramustine phosphate is approved by the Food and Drug Administration for oral use in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a conjugate of 17 beta-estradiol and the carbamate of nitrogen mustard. Although its therapeutic efficacy has been demonstrated, it is not clear to what extent each constituent contributes to estramustine's effectiveness. Estramustine phosphate therapy achieves objective response rates of 60-90 percent in advanced stage D prostatic cancer patients with no prior hormonal therapy. These results are consistent with those obtained with conventional hormonal therapy in similar patient populations. Therapeutic efficacy does not appear to increase when estramustine is used concurrently with other cytotoxic chemotherapeutic agents. An objective response rate of 20-30 percent can be anticipated in patients refractory to conventional hormonal therapy. It is in this group, the estrogen-resistant patients, that estramustine shows the most promise. Adverse effects of estramustine are similar to those of diethylstilbestrol. Gastrointestinal and cardiovascular side effects appear to be the most important and may be severe enough to require discontinuation of therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular System; Clinical Trials as Topic; Costs and Cost Analysis; Digestive System; Estramustine; Female; Humans; Kinetics; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Adenocarcinoma; Animals; Bile; Biotransformation; Estradiol; Estramustine; Estrone; Half-Life; Humans; Hydrocortisone; Hydrolysis; Male; Nitrogen Mustard Compounds; Papio; Prostatic Neoplasms; Time Factors; Tissue Distribution; Transcortin

Topics: Animals; Carrier Proteins; Cytosol; Epithelium; Estradiol; Estramustine; Estrone; Humans; Male; Nitrogen Mustard Compounds; Organ Specificity; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Protein Binding; Rabbits; Rats

Topics: Absorption; Dose-Response Relationship, Drug; Estradiol; Estramustine; Estrone; Feces; Half-Life; Humans; Hydrolysis; Kinetics; Male; Metabolic Clearance Rate; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors; Tissue Distribution

Topics: Animals; Carrier Proteins; Estramustine; Estrogens; Free Radicals; Humans; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats

Topics: Administration, Oral; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Estramustine; Humans; Injections, Intravenous; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Topics: Acid Phosphatase; DNA, Neoplasm; Estramustine; Flow Cytometry; Gonadotropin-Releasing Hormone; Humans; Immunotherapy; Male; Methylation; Oncogenes; Prostatic Neoplasms

Topics: Animals; Antibody Formation; Diethylstilbestrol; Estramustine; Humans; Immune System; Immunity, Cellular; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Nitrogen Mustard Compounds; Prostatic Neoplasms; T-Lymphocytes

Topics: Acid Phosphatase; Antineoplastic Agents; Bromocriptine; Castration; Combined Modality Therapy; Cyproterone; Estramustine; Estrogens; Fluorouracil; Humans; Lisuride; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation

Topics: Antineoplastic Agents; Cisplatin; Cyclophosphamide; Doxorubicin; Estramustine; Humans; Male; Prostatic Neoplasms

Topics: Biopsy; Cell Nucleus; DNA, Neoplasm; Estramustine; Flow Cytometry; Humans; Male; Prognosis; Prostate; Prostatic Neoplasms

Topics: Animals; Cardiovascular System; Carrier Proteins; Castration; Clinical Trials as Topic; Diethylstilbestrol; DNA; Estramustine; Humans; In Vitro Techniques; Lymphocytes; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Time Factors; Tissue Distribution

Our studies on the application of hormone-polymer composites in urological field are discussed in this review. We first studied the modes of in vivo and in vitro release of testosterone from vinyl polymer-testosterone composites prepared by radiation-induced polymerization. It was ascertained by our group that in vivo and in vitro release of testosterone from biodegradable copolypeptide -testosterone composites as well as vinyl polymer composites was well controlled. Using this system, we were successful in preparing a testicular prosthesis, which was made of vinyl polymer-testosterone composites and was ascertained to release testosterone constantly for a long period in the dose range of clinical usage. We also applied this sustained release drug delivery system to the method of administration of an LH x RH agonist, which was one of the best therapeutic drugs for androgen dependent prostatic cancer. Sustained release of the LH x RH agonist in the dose range of clinical usage over a period of several months from copolymer-LH x RH agonist composites was confirmed in both male rats and in prostatic cancer patients. Prostatic cancer cells contain a major secretion protein (alpha-protein or estramustine-binding protein) and estramustine has a high affinity for alpha-protein. Therefore, we examined the effect of an estramustine-microsphere containing anticancer drugs, namely, the missile therapy for prostatic cancer. The missile therapy should open the way to specific and selective chemotherapy for prostatic cancer.

Topics: Animals; Artificial Organs; Delayed-Action Preparations; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Polymers; Prostatic Neoplasms; Rabbits; Rats; Testis; Testosterone

Topics: Biopsy; Cryosurgery; Estramustine; Estrogens; Humans; Male; Neoplasm Staging; Prostate; Prostatectomy; Prostatic Neoplasms; Seminal Vesicles

A number of chemotherapeutic agents show moderate promise for the palliative treatment of metastatic prostatic carcinoma. Although patterns of metastatic disease make classic response rates difficult to obtain and interpret, doxorubicin, cyclophosphamide, dacarbazine (DTIC), and cisplatin have activity in patients who have failed conventional hormonal treatment. In most studies, a survival advantage is seen for responders to these and other chemotherapeutic agents, but no survival advantage has been seen for the treatment cohorts when compared to groups not receiving chemotherapy. Therefore, estimates of the usefulness of these agents must be considered tentative. Multiple drug therapy has not yet shown definite superiority to single agent treatment. The uses and limitations of acid phosphatase as a tumor marker, as well as particular difficulties in measuring tumor response in the disease, are detailed herein.

Topics: Acid Phosphatase; Adenocarcinoma; Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Estramustine; Fluorouracil; Humans; Lomustine; Male; Prednimustine; Prostatic Neoplasms

Topics: Adenocarcinoma; Adrenalectomy; Aged; Animals; Castration; Cryosurgery; Estramustine; Estrogens; Growth Hormone; Hormones; Humans; Hypoglycemia; Hypophysectomy; Ketosteroids; Male; Middle Aged; Neoplasm Metastasis; Postoperative Complications; Prostatic Neoplasms; Recurrence; Remission, Spontaneous

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgens; Animals; Antineoplastic Agents; Arginase; Dihydrotestosterone; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Estradiol; Estramustine; Estriol; Estrogens; Flutamide; Haplorhini; Humans; Male; Mice; Neoplasms, Experimental; Prostate; Prostatic Neoplasms; Rats; Testosterone

Until the last few years very little information has been available regarding the potential of chemotherapy in prostatic cancer. Few drugs have been adequately tested to determine their efficacy, if any. Of the little conventional chemotherapy that has been documented, only diethylstilbestrol diphosphate (Stilphostrol, Honvan) has been safe, effective (at least in relieving bone pain) and available for repeat courses of treatment. The several well controlled clinical trials recently embarked upon and described in this article should reveal much about the effectiveness in prostatic cancer of agents already accepted in chemotherapy of other malignancies. Newer drugs will also require thorough testing. At this time no specific recommendations for chemotherpay other than the use of intravenous diethylstillbestrol diphospate can be made. Agents like estramustine phosphate (Estracyt) and flutamide (SCH-13521) with little to no bone marrow, liver, or renal toxicity are very promising. Studies of single-agent, sequential, and combined chemotherapy will necessarily lead to safe effective chemotherapy as adjuncts to surgery and/or radiotherapy for prostatic cancer in all stages.

Topics: Aged; Alkylating Agents; Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents; Bromocriptine; Cyproterone; Depression, Chemical; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Fluorouracil; Flutamide; Health Facilities; Hematologic Diseases; Humans; Kinetics; Male; Mitosis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established.. Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions.. The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events.. Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

Topics: Androgen Antagonists; Docetaxel; Estramustine; Humans; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects.. Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected.. Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms.. Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.

Topics: Androgen Antagonists; Androgens; Docetaxel; Estramustine; Humans; Male; Neoplasm Recurrence, Local; Orchiectomy; Prostatic Neoplasms

The optimal treatment for high-risk prostate cancer (PCa) remains to be established. We previously reported favorable, biochemical recurrence-free survival in high-risk PCa patients treated with a neoadjuvant gonadotropin-releasing hormone agonist or antagonist and estramustine phosphate (EMP) (chemohormonal therapy; CHT) followed by radical prostatectomy (RP). We conducted a retrospective study to elucidate the clinical benefit of neoadjuvant CHT for high-risk PCa patients.. We reviewed the clinical and pathological records of 1254 PCa patients who underwent RP and bilateral pelvic lymphadenectomy between July 1996 and April 2016 at Hirosaki University. According to the D'Amico risk classification, we focused on 613 patients in the high-risk group. The high-risk PCa patients were further divided into two groups based on whether the patients received neoadjuvant CHT before RP (EMP group) or not (non-EMP group). The endpoint was overall survival (OS) after surgery.. The 5- and 10-year OS rates were 98.5 and 92.6%, respectively. The 10-year OS rate in the EMP group was significantly higher compared to the non-EMP group (P = 0.021). In multivariate analysis, administration of neoadjuvant CHT, lymph node involvement, and castration-resistant PCa status were significantly associated with OS.. RP with neoadjuvant CHT using EMP for high-risk PCa patients provided excellent long-term OS.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Lymph Node Excision; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Rate

The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial.. Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS).. A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity.. This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Confidence Intervals; Disease-Free Survival; Docetaxel; Estramustine; Goserelin; Humans; Lymph Node Excision; Lymphatic Irradiation; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer.. In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only.. In all, 34 patients were enrolled and followed for a median of 13.1 years. Within 10 years most patients had biochemical recurrence (BCR-free probability 22%; 95% confidence interval [CI] 10-37%). However, the probability of disease-specific survival at 10 years was 84% (95% CI 66-93%) and overall survival was 78% (95% CI 60-89%). The CHT group had higher-risk features than the comparison group (123 patients), with an almost doubled risk of calculated preoperative 5-year BCR (69% vs 36%, P < 0.01). After adjusting for these imbalances the CHT group had trends toward improvement in BCR (hazard ratio [HR] 0.76, 95% CI 0.43-1.34; P = 0.3) and metastasis-free survival (HR 0.55, 95% CI 0.24-1.29; P = 0.2) although these were not statistically significant.. Neoadjuvant CHT followed by RP was associated with lower rates of BCR and metastasis compared with the RP-only group; however, these results were not statistically significant. Because this treatment strategy has known harms and unproven benefit, this strategy should only be instituted in the setting of a clinical trial.

Topics: Antineoplastic Agents; Carboplatin; Disease-Free Survival; Estramustine; Humans; Male; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.. We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.. We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.. Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.. Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Follow-Up Studies; France; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS).. Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05.. A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61).. NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease Progression; Early Termination of Clinical Trials; Estramustine; Etoposide; Humans; Male; Middle Aged; Neoplasm Grading; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

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

Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC.. Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed.. Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036).. Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carboplatin; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Prostatic Neoplasms; Taxoids; Treatment Outcome

To assess docetaxel-estramustine in patients with localised high-risk prostate cancer.. After staging pelvic lymph node dissection, patients with high-risk prostate cancer randomly received androgen deprivation therapy (ADT) (3 years)+DE (4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1-5) or ADT alone. Local therapy was administered at 3 months.. Four hundred and thirteen patients were accrued: T3-T4 (67%), Gleason score ~8 (42%), PSA >20 ng/mL (59%), pN+ (29%). In the chemotherapy arm, 94% of patients received the planned four cycles of docetaxel. Local treatment consisted of radiotherapy in 358 patients (87%) (median dose 74 Gy in both arms). ADT was given for 36 months in both arms. A PSA response (PSA ~0.2 ng/mL after 3 months of treatment) was obtained in 34% and 15% in the ADT+DE arm and in the ADT arm, respectively (p<0.0001). Febrile neutropenia occurred in only 2%. Moderate to severe hot flashes occurred less often in the ADT+DE arm (2% versus 22%; p<0.001). There was no toxicity-related death, no secondary leukaemia, and no excess second cancers. Chemotherapy had a negative impact on quality of life (global health status, p = 0.01; fatigue, p = 0.003; role functioning, p = 0.003; social functioning, p = 0.006) at 3 months but this effect disappeared at 1 year.. Docetaxel-estramustine can be combined safely with standard therapy in high-risk prostate cancer, with a promising PSA response rate and no negative impact on quality of life after 1 year. Long-term follow-up is required to assess the impact on relapse and survival.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Estramustine; Humans; Logistic Models; Male; Middle Aged; Prostatic Neoplasms; Quality of Life; Taxoids

Radical prostatectomy (RP) has limited cancer control potential for the patient with high-risk prostate cancer (Pca). We prospectively examined the efficacy and safety of neoadjuvant therapy with luteinizing hormone-releasing hormone (LHRH) agonist + low-dose estramustine phosphate (EMP) (LHRH+EMP) followed by RP.. High-risk Pca was defined by the D'Amico stratification system. A total of 142 patients with high-risk Pca were enrolled in this trial from September 2005 to March 2011. The LHRH+EMP therapy included administration of LHRH agonist and 280 mg day(-1) EMP for 6 months before RP. Pathological cancer-free (pT0) rate on the surgical specimen was the primary end point. Secondary end points were PSA-free survival and toxicity.. The average patient age was 67.4 years (interquartile range (IQR) 72, 65) and the median initial PSA level was 14.80 ng ml(-1) (IQR 26.22, 7.13). The median Gleason score was 9 (IQR 9, 7) and 97 patients (68.3%) had clinical stage T2c or T3. All patients completed 6 months of LHRH+EMP neoadjuvant therapy with no delays in RP. Seven patients (4.9%) achieved pT0. Surgical margins were negative in 125 patients (87.0%). At a median follow-up period of 34.9 months, PSA-free survival was 84.3%. No serious adverse events were reported during the study and there were no toxicity-related deaths.. Six months of LHRH+EMP neoadjuvant therapy followed by RP is safe and oncological outcomes are acceptable. Although this study was a single-arm trial with a relatively short follow-up, this treatment may have a potential to improve PSA-free survival in high-risk Pca patients. Further clinical trials are warranted.

Topics: Aged; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.. This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.. Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.. The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Castration; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Taxoids; Vascular Endothelial Growth Factor A

To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC).. In a phase I dose-escalation study, four peptides showing the highest levels of peptide-specific immunoglobulin G (IgG) to 14 vaccine candidates (ITK-1) were subcutaneously injected every week in three different dose settings (1, 3, and 5 mg per peptide) for 6 weeks with a low dose of EMP, and the patients were followed by maximum 2 years extension study either weekly or bi-weekly six times PPV as one course with a low dose of EMP.. Fifteen patients were enrolled in the phase I study. No serious treatment-related adverse events were observed. The most common adverse events were grade 2 skin reactions at the injection sites. The maximum acceptable dose of ITK-1 was 8.643 mg. There were no treatment-related systemic adverse events of grade 3 or more, and maximum tolerated dose could not be determined. Cytotoxic T lymphocyte responses measured by interferon-γ release assay were boosted in 10 of 15 (67%) patients, and IgG responses were boosted in 7 of 15 (47%) patients. Twelve patients proceeded to the extension study, and the median survival time was 23.8 months during a median follow-up of 23.8 months.. PPV treatment for HLA-A24 positive patients with CRPC could be recommended for further stages of clinical trials because of its safety and the higher frequency of boosting immune responses.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Cancer Vaccines; Combined Modality Therapy; Dose-Response Relationship, Immunologic; Estramustine; HLA-A Antigens; HLA-A24 Antigen; Humans; Immunoglobulin G; Interferon-gamma; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; T-Lymphocytes, Cytotoxic; Vaccines, Subunit

To assess the efficacy of a multiagent taxane-based chemotherapy combined with hormonal therapy in men with metastatic androgen-dependent prostate cancer in a multicenter, cooperative group, single-arm trial.. A total of 41 patients with newly diagnosed metastatic prostate cancer involving both the axial and the appendicular skeletons or viscera were enrolled. Of the 41 patients, 35 were treated with combined androgen blockade and ≤4 cycles of oral estramustine (280 mg orally 3 times daily) and etoposide (50 mg/m(2) daily) for 14 days of each 21-day cycle, with paclitaxel (135 mg/m(2) intravenously within 1 hour) on day 2 of each cycle. Chemotherapy was started within 30 days of the initiation of hormonal therapy. The patients were followed up to determine the progression-free survival.. The 35 patients received a total of 126 cycles of chemotherapy, with 30 receiving all 4 cycles. The median progression-free survival for the evaluable population was 13 months (95% confidence interval 10-16), with a median overall survival of 38 months (95% confidence interval 28-49). The main toxicities were myelosuppression, with 9 patients experiencing grade 3 or greater neutropenia and 1 developing grade 4 thrombocytopenia. One patient died of neutropenic infection. Thrombosis embolism occurred 4 times (3 of grade 4 and 1 of grade 3), with 1 episode of grade 4 cardiac ischemia.. The results of our study have shown that the administration of chemotherapy to this population is feasible, with moderate toxicity. Taxane-based chemotherapy did not demonstrate significant efficacy in this high-risk population of patients with a poor prognosis.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Estramustine; Etoposide; Humans; Injections, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Risk Factors

What's known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response.. • To assess quality of life (QoL) outcomes and pain changes in patients affected by castration-resistant prostate cancer enrolled in a phase II randomized trial of 3-week docetaxel (DOC)-based chemotherapy. • To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients' QoL.. • QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 questionnaire. • Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. • The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable.. • In all, 59 patients were evaluable. • Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non-responders. • There were no statistically significant changes in the QLQ-C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. • There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory.. • Our data confirm that QoL is generally maintained during chemotherapy. • There is a substantial reduction in pain. • Our results also suggest that baseline QoL may predict treatment response.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Chronic Disease; Docetaxel; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Pain; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Taxoids

The objective of this study is to assess the safety and efficacy of a treatment regimen comprising neoadjuvant conventional androgen deprivation therapy (ADT) plus estramustine phosphate (EMP) combined with three-dimensional conformal radiotherapy (3D-CRT) for patients with intermediate- to high-risk prostate cancer.. Thirty-nine patients with intermediate- to high-risk prostate cancer classified according to the NCCN practice guidelines recurrence risk group were randomly allocated into two groups: neoadjuvant LHRH agonist plus EMP for 6 months until completion of the 3D-CRT (EMP group, n = 20), or neoadjuvant LHRH agonist alone (LHRH group, n = 19). Both groups received 3D-CRT in daily fractions of 2 Gy for a total dose of 70 Gy. PSA relapse was defined according to the Phoenix definition.. The median duration of follow-up was 27.1 months. None of the patients died during the follow-up period, but three patients in the LHRH group developed distant metastasis. The 4-year PSA relapse-free survival outcomes for the EMP group and LHRH group were 61.2 and 49.4%, respectively (P = 0.04). Multivariate Cox regression model analyses of the pretreatment PSA level (>20 ng/ml n = 16 vs. < or =20 ng/ml n = 23), grade (G8 or more n = 11 vs. G7 or less n = 28) and modality (LHRH group n = 19 vs. EMP group n = 20) revealed these factors to be independent predictors of PSA relapse after treatment: pretreatment PSA had a relative risk of 3.84 (95% CI: 1.003-14.722), grade had a relative risk of 4.29 (95% CI: 1.093-16.824), and modality had a relative risk of 8.01 (95% CI: 1.867-34.361). No severe toxicities were observed in either group.. The present results indicate that the combination of neoadjuvant ADT plus EMP combined with 3D-CRT sustains freedom from PSA relapse in patients with intermediate- to high-risk prostate cancer. However, this regimen is insufficient for preventing biochemical failure, and an additional intervention such as adjuvant ADT, radiation dose escalation, or both, is required, especially for patients with a pretreatment PSA level of more than 20 ng/ml and high-grade cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Prostatic Neoplasms; Radiotherapy, Conformal; Risk Factors

To evaluate the efficacy and safety profile of vinorelbine and estramustine in combination with three-dimensional conformational radiotherapy (3D-CRT) in patients with localized high-risk prostate cancer.. Fifty patients received estramustine, 600 mg/m(2) daily, and vinorelbine, 25 mg/m(2), on days 1 and 8 of a 21-day cycle for three cycles in combination with 8 weeks of 3D-CRT (total dose of 70.2 gray [Gy] at 1.8-Gy fractions or 70 Gy at 2.0-Gy fractions). Additionally, patients received luteinizing hormone-releasing hormone analogs for 3 years.. All patients were evaluated for response and toxicity. Progression-free survival at 5 years was 72% (95% confidence interval [CI]: 52-86). All patients who relapsed had only biochemical relapse. The most frequent severe toxicities were cystitis (16% of patients), leucopenia (10% of patients), diarrhea (10% of patients), neutropenia (8% of patients), and proctitis (8% of patients). Six patients (12%) did not complete study treatment due to the patient's decision (n = 1) and to adverse events such as hepatotoxicity, proctitis, paralytic ileus, and acute myocardial infarction.. Vinorelbine and estramustine in combination with 3D-CRT is a safe and effective regimen for patients with localized high-risk prostate cancer. A randomized trial is needed to determine whether the results of this regimen are an improvement over the results obtained with radiotherapy and androgen ablation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cystitis; Diarrhea; Drug Administration Schedule; Estramustine; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Proctitis; Prospective Studies; Prostatic Neoplasms; Radiotherapy, Conformal; Remission Induction; Spain; Vinblastine; Vinorelbine

Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cross-Over Studies; Dose-Response Relationship, Drug; Estramustine; Follow-Up Studies; Humans; Lymphopenia; Male; Middle Aged; Nausea; Orchiectomy; Peptides; Prostatic Neoplasms; Skin Diseases; Survival Analysis; Treatment Outcome; Vomiting

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).. 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).. 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).. 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.. 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

Long-term androgen suppression plus radiotherapy (AS+RT) is standard treatment of high-risk prostate cancer. A randomized trial, Radiation Therapy Oncology Group trial 9902, was undertaken to determine whether adjuvant chemotherapy with paclitaxel, estramustine, and etoposide (TEE) plus AS+RT would improve disease outcomes with acceptable toxicity.. High-risk (prostate-specific antigen 20-100 ng/mL and Gleason score >or=7; or Stage T2 or greater, Gleason score 8, prostate-specific antigen level <100 ng/mL) nonmetastatic prostate cancer patients were randomized to AS+RT (Arm 1) vs. AS+RT plus four cycles of TEE (Arm 2). TEE was delivered 4 weeks after RT. AS continued for 2 years for both treatment arms. RT began after 8 weeks of AS began.. The Radiation Therapy Oncology Group 9902 trial opened January 11, 2000. Excess thromboembolic toxicity was noted, leading to study closure October 4, 2004. A total of 397 patients were accrued, and the data for 381 were analyzable. An acute and long-term toxicity analysis was performed. The worst overall toxicities during treatment were increased for Arm 2. Of the 192 patients, 136 (71%) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 (37%) of 189 patients on Arm 1. Statistically significant increases in hematologic toxicity (p < 0.0001) and gastrointestinal toxicity (p = 0.017) but not genitourinary toxicity (p = 0.07) were noted during treatment. Two Grade 5 complications related to neutropenic infection occurred in Arm 2. Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2. At 2 and 3 years after therapy completion, excess long-term toxicity was not observed in Arm 2.. TEE was associated with significantly increased toxicity during treatment. The toxicity profiles did not differ at 2 and 3 years after therapy. Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Drug Administration Schedule; Estramustine; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Paclitaxel; Prostatic Neoplasms; Thromboembolism

Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Bone and Bones; Bone Density Conservation Agents; Bone Remodeling; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Interleukin-6; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Zoledronic Acid

This paper applies the Dynamically Modified Outcomes (DYNAMO) model to a clinical trial of two chemotherapeutic regimens on global health-related quality of life (GHRQL) in hormone-refractory prostate cancer.. DYNAMO identifies the causal influences operating in a clinical trial and their mediation, moderation, and modulation by uncontrolled variables. The Southwest Oncology Group trial S9916 randomized assignment to mitoxantrone plus prednisone (M + P) versus docetaxel plus estramustine (D + E) treatments. In this application, we examine baseline-adjusted impacts of worst pain (McGill Pain Questionnaire) on GHRQL (EORTC Quality of Life Questionnaire-C30) at 10 weeks.. The average treatment levels of pain did not differ, hence, the average mediated effect of treatment on GHRQL was zero. Nonetheless, M + P reduced the impact (the relational outcome) of pain on GHRQL by 54% relative to D + E. Individual variation in the relational outcome (modulation) was of the same magnitude as the average difference between the groups. Performance status moderated the direct effects of treatment, with D + E being more effective in good, but not poor, performance strata.. The DYNAMO approach comprehensively accounted for treatment effects. Rather than a single average effect, there were three distinct treatment effects: one direct effect for each performance status level and a direct effect on the relationship between pain and GHRQL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Models, Statistical; Neoplasms, Hormone-Dependent; Pain; Pain Measurement; Prednisone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC.. Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1-21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostate-specific antigen (PSA) levels and lesion assessment.. From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week-43 months); median survival was 23 months (range 3 weeks-64+ months).. Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC).. 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.. 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.. 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

Until today, docetaxel is the only EMEA and FDA approved active agent in hormone refractory prostate cancer (HRPC). In the absence of other effective and approved drugs we evaluated the toxicity and efficacy of intermittent-docetaxel-chemotherapy in patients whose cancers progressed after successful first-line docetaxel therapy.. 46, 18, and 5 patients with HRPC received 1, 2, or 3 cycles of docetaxel based chemotherapy. Toxicity, PSA response and general condition were evaluated systematically. SPSS 15.0 was applied for statistic analysis.. 26 (56 %) patients achieved a PSA response of > 50 %, another 10 (22 %) patients of up to 50 %; 10 (22 %) patients were progressive under docetaxel. The median overall survival of the whole cohort calculated from the first docetaxel application was 16 (3-60 +) months. Tolerance, toxicity and general condition were crucial for the administration of a second cycle (n = 18); in contrast, age or the degree of the PSA decline in cycle 1 did not seem to be of importance. The -median overall survival of all patients who -received at least two blocks was 35 months; more-over, 13 / 18 patients achieved a biochemical response in cycle 2. Toxicity did not rise significantly. Five patients were given a third docetaxel cycle, three of whom responded. Higher frequencies of -grade 3 / 4 stomatitis, skin toxicity and leukocytopaenia were observed.. Intermittent docetaxel therapy is well tolerated and shows high response rates in the sec-ond and third sequences of treatment in select-ed HRPC patients who presented with low docetaxel toxicity, good clinical condition and responded to prior docetaxel-based treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Neoplasm Staging; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Retreatment; Survival Rate; Taxoids

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 investigate the feasibility and efficacy of docetaxel-based chemotherapy in patients with hormone-refractory prostate cancer (HRPC).. Forty-six consecutive HRPC patients treated between January 2003 and March 2008 were included in this analysis. Docetaxel was given at a dose of 35 mg/m(2) twice every 3 weeks and oral estramustine concurrently for three consecutive days during weeks 1 and 2 of each cycle. During each treatment week, the dose of estramustine was 1260 mg on the first day, 980 mg on the second day and 840 mg on the third day. Patients were premedicated with 4 mg twice a day of oral dexamethasone for three consecutive days. Treatment was continued until evidence of disease progression or unacceptable toxicity. Prostate-specific antigen (PSA) levels were evaluated at least once every 4 weeks.. Patients received a median of three cycles of chemotherapy. Of the evaluable 46 patients, 25 (54%) had a >or=50% PSA decline and 12 (26%) had a >or=75% PSA decline. Median time to PSA progression and overall survival time were 10.1 and 27.0 months, respectively. Median follow-up was 15.0 months. Major severe toxicities were grade 3 or 4 leukopenia in five (11%) patients. Mild toxicities included grade 1 or 2 nausea in eight (17%) patients. Two patients could not continue the treatment because of interstitial pneumonitis and a gastric hemorrhage, respectively.. Docetaxel plus estramustine chemotherapy represents an active and well tolerated treatment for Japanese HRPC patients.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Docetaxel; Drug Therapy, Combination; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Taxoids; Treatment Failure

To investigate the safety and efficacy in terms of PSA response of a low-dose oral combination of estramustine phosphate (EMP) and etoposide (VP16) in hormone- refractory prostate cancer (HRPC) patients. Well-tolerated outpatient chemotherapy regimens for patients unfit and/or unwilling to be admitted to hospital are needed.. Fifty-six HRPC patients with metastatic disease (median age 75 years) were randomized between arm A (daily oral EMP 10 mg/kg, in 3 doses) and arm B (28-day cycle with low-dose EMP 3 mg/kg once daily plus VP16 25 mg/m(2) once daily on days 1 through 14). Baseline characteristics between the two groups were similar. LHRH therapy was maintained. Anti- androgen was stopped 1 month before entry.. The low-dose combination was better tolerated, with a significant advantage in terms of time to treatment interruption for any reason (p = 0.01) or toxicity (6 vs. 12 months, p = 0.02). A trend in favour of arm B was evident in terms of PSA reduction (41.4 vs. 15%), performance status and pain improvement. Hospital admission due to toxicity was never required for arm B patients and there were no treatment-related deaths.. Low-dose oral combination of EMP and VP16 might represent a treatment option for patients unfit for i.v. chemotherapy. This regimen requires minimal toxicity monitoring when administered at home for prolonged periods.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Estramustine; Etoposide; Hospitalization; Humans; Male; Middle Aged; Patient Compliance; Prostatic Neoplasms

To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer.. One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%.. The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04).. The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Belgium; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Time Factors; Treatment Outcome

Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug.. Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily).. Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a > or = 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months).. The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Sulindac; Survival Analysis; Taxoids; Thromboembolism

A multicenter phase 2 trial was conducted to evaluate the safety and feasibility of radiotherapy after paclitaxel, estramustine phosphate, and carboplatin (TEC) plus androgen deprivation therapy in previously untreated unfavorable-risk localized prostate cancer patients.. Patients with localized high-risk prostate cancer were treated with 4 cycles (16 weeks) of continuous weekly paclitaxel at 80 mg/m(2) intravenously with estramustine at 280 mg orally 3 times a day for 5 days a week and carboplatin (area under the curve of 6) on Day 1 of every cycle followed by 3-dimensional conformal or intensity-modulated radiotherapy (total dose of 77.4 gray [Gy] in 1.8-Gy fractions). All patients received androgen deprivation therapy with either goserelin acetate at 3.6 mg subcutaneously or leuprolide acetate at 7.5 mg intramuscularly monthly for 6 months starting at Day 1 of therapy. Patients were evaluated for acute and late toxicities along with progression-free survival and time to prostate-specific antigen (PSA) failure associated with the multimodality therapy.. Twenty-seven of 34 patients completed therapy and were evaluable for safety and feasibility. There was 1 patient with grade 3 nausea during chemotherapy. No other grade 3 or 4 gastrointestinal, cardiovascular, or genitourinary acute or late toxicities were reported. The most common grade 1 to 2 late toxicities were proctitis (11%), dysuria (11%), and urinary frequency/urgency (33%). Two deaths due to prostate cancer were observed. Median follow-up was 38 months among 24 surviving patients; median PSA progression-free survival was 12.1 months (95% confidence interval, 13.3-25.9).. Neoadjuvant chemohormonal therapy with TEC followed by high-dose radiation therapy is safe and feasible in a multicenter setting.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Estramustine; Feasibility Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms

We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease.. Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy.. Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events.. There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Estramustine; Humans; Ketoconazole; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Vinblastine

Bone-targeted therapy that combines strontium-89 (Sr-89) with alternating weekly chemohormonal therapy may improve clinical outcomes in patients with metastatic hormone-refractory prostate cancer. This phase II study investigated the addition of Sr-89 to an alternating weekly regimen of doxorubicin and ketoconazole with paclitaxel and estramustine in patients with progressive prostate cancer and bone involvement.. Twenty-nine patients with progressive adenocarcinoma of the prostate and osteoblastic bone metastases who failed conventional hormonal therapy were registered for the study. Of those, 27 were treated with Sr-89 on day 1 of week 1. On weeks 1, 3, and 5, patients received doxorubicin (20 mg/m on day 1) and oral ketoconazole (400 mg 3 times a day for 7 days). On weeks 2, 4, and 6, patients received paclitaxel (100 mg/m(2)) and oral estramustine (280 mg 3 times a day for 7 days). No treatment was given during weeks 7 and 8. Cycles were repeated every 8 weeks.. A > or =50% reduction in prostate-specific antigen level was maintained for at least 8 weeks in 77.7% of the patients (21 patients) at 16 weeks and in 66.6% (18 patients) at 32 weeks. The median progression-free survival was 11.27 months (range, 1.83-29.53), and the median overall survival was 22.67 months (1.83-57.73+). Two patients died during study because of disease progression. Overall, the chemotherapy combined with Sr-89 was well tolerated.. Our results demonstrate that the combination of alternating weekly chemohormonal therapies with Sr-89 demonstrates a prolonged progression-free and overall survival with acceptable toxicity. Further investigation of combination therapies with Sr-89 is warranted.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Doxorubicin; Estramustine; Humans; Ketoconazole; Male; Middle Aged; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Strontium Radioisotopes; Survival Rate; Treatment Outcome

Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate (estramustine) has been reported to be effective for HRPC. Low-dose estramustine suppresses the pituitary-gonadal axis. Docetaxel plus 5-fluoro-5'-deoxyuridine (5'-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5'-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine.. All of the HRPC patients were treated with estramustine 140 mg orally twice 5'-dFUrd 200 mg orally four times daily on days 1-21, and docetaxel 60 mg/m(2) was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL).. Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially.. This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Estramustine; Floxuridine; Granulocyte Colony-Stimulating Factor; Humans; Japan; Male; Middle Aged; Neutropenia; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Survival Rate; Taxoids

Treatment options for patients with hormone refractory prostate cancer (HRPC) showed unsatisfactory outcomes. Docetaxel-based combinations could offer more promising and tolerated results. A phase II trial was conducted with the combination of zoledronic acid, docetaxel and estramustine. Eligibility consisted of metastatic prostate adenocarcinoma with objective progression or rising prostate specific antigen levels (PSA) despite androgen deprivation therapy. Zoledronic acid was given at a dose of 4 mg on day 1, docetaxel (25 mg/m2) on days 1, 8 and 15, and estramustine orally at 140 mg two times daily on days 1 to 21 of a 28-day cycle. Twenty-seven patients were enrolled between October 2002 and November 2004. Median age was 68 years (53-83 years). A total of 124 cycles were administered with a median of 4.6 cycles per patient (1-8 cycles). The major toxicities were grades 1 to 3 anemia (55%), fatigue (15%), alopecia (11%) and hypocalcemia (11%). Two patients presented with deep venous thrombosis and died from pulmonary embolism. Another third patient died from Stevens-Johnson syndrome and grade 4 hepatic toxicity. Out of the 25 patients assessed for efficacy, 13 (52%) had a biologic response (>50% PSA decline). Three (21%) patients among the 14 with measurable disease had objective response: 1 complete response (CR) and 2 partial responses (PR). Response duration was 2 months for PR and 4 months for CR. A total of 12 patients (48%) experienced clinical benefit with pain reduction. This combination seemed effective; however toxic deaths especially from venous thrombosis counterbalanced the advantage of this regimen.

Topics: Administration, Oral; Aged; Aged, 80 and over; Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Diphosphonates; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Fatigue; Humans; Hypocalcemia; Imidazoles; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Thrombocytopenia; Time Factors; Treatment Outcome; Zoledronic Acid

The aim is to evaluate the efficacy and toxicity of weekly docetaxel and estramustine for Japanese men with hormone refractory prostate cancer who were treated at a single institution. Twenty eligible patients had histologically proven adenocarcinoma of the prostate with metastases that were progressing despite complete androgen blockade and antiandrogen withdrawal. All of the patients received docetaxel 30 mg/m(2) weekly (days 1, 8, 15, 22, 29, and 36). After a two week break, the treatment schedule was repeated. Patients were scheduled to receive daily oral estramustine 560 mg/day throughout the protocol. In the serum prostate specific antigen (PSA) response, three (15%) patients achieved a complete response, and 8 (40%) acheived a partial response. Overall survival and time to progression were 13.4 months and 6.4 months, respectively, however sixty-seven percent of the patients had to discontinue treatment because of toxicity. The high toxicity of this protocol suggests that the regimen and/or the timing should be altered for Japanese patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Estramustine; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

To determine the feasibility and toxicity of adjuvant paclitaxel plus estramustine in prostate cancer patients at high risk of a 2-year PSA failure after prostatectomy.. Patients with prostate adenocarcinoma who underwent radical prostatectomy with at least a 50% probability of PSA failure at 2 years postprostatectomy received 4 cycles of paclitaxel 90 mg/m(2) by 1-hour infusion, weekly for 3 weeks, followed by a 1-week treatment rest. Patients received estramustine phosphate 140 mg orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received warfarin 1 mg daily to prevent thromboembolism. Serum PSA was measured monthly during adjuvant therapy, then every 3 months for a minimum of 2 years.. Between December 2001 and September 2004, 17 patients underwent radical prostatectomy and received protocol treatment at the University of Pennsylvania. The median risk of a 2-year PSA failure was 70%. Five (30%) patients had PSA failure develop after radical prostatectomy. The median time to PSA failure was 19 months. A statistically significant difference (P = 0.001) was noted between the expected rate of PSA failure (0.70) and the actual rate of PSA failure (0.30). Grade 3 to 4 toxicities were uncommon and included thromboembolism (6%) and neutropenia (6%). All patients completed 4 cycles of therapy and there were no treatment related deaths.. The adjuvant use of paclitaxel and estramustine in resected high-risk prostate cancer patients is feasible and well tolerated. Adjuvant cytotoxic chemotherapy deserves further investigation with randomized studies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Estramustine; Feasibility Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Pilot Projects; Prostatectomy; Prostatic Neoplasms; Risk Factors

To conduct a trial of neoadjuvant chemohormonal therapy and radical prostatectomy for patients with poor-prognosis localized prostate cancer (prostate-specific antigen [PSA] value 20 ng/mL or greater, Gleason score 8 or higher, and clinical stage T2c or greater), who are at high risk for local and systemic relapse.. Complete androgen blockage and four cycles of docetaxel (70 mg/m2) on day 2 and estramustine (280 mg three times daily) on days 1 to 5 every 21 days were given to 22 patients before radical prostatectomy and nerve preservation.. Patient characteristics, as median (range), were as follows: age 61 (49 to 70) years, PSA value 21.2 (3.2 to 71.6) ng/mL, and Gleason sum 7 (6 to 9). Clinical stage was T3a-c in 14 patients (64%), T2c in 4 (18%), T2b in 3 (14%), and T1c in 1 (4%). Presurgery characteristics after chemohormonal therapy were as follows: PSA value 0.21 (0.05 to 0.6) ng/mL, clinical stage T1c in 14 patients (63.7%), T2a in 6 (27.3%), and T3a in 2 (9%). The pathologic specimens revealed viable disease in all patients, organ-confined disease in 14 (63.6%), specimen-confined disease in 16 (72.7%), seminal vesicle disease in 9 (40.9%), and lymph node involvement in 4 (18.1%). To date, at a median follow-up of 23.6 (12.1 to 54.7) months, 10 patients (45.4%) relapsed, with PSA doubling time of 1.5 (0.4 to 34.3) months. Of the relapsed patients, 8 (89%) had organ/specimen involvement.. The neoadjuvant chemohormonal approach with nerve-preservation surgery is feasible in patients with poor-prognosis localized prostate cancer. It leads to clinical tumor downstaging. The pattern of relapse suggests that local therapy, with radiotherapy for patients with surgical or capsular involvement, and additional systemic therapy should be integrated.

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoadjuvant Therapy; Preoperative Care; Prognosis; Prostatectomy; Prostatic Neoplasms; Risk Factors; Taxoids

To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone-refractory prostate cancer (HRPC).. Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m(2) on day 1 (arm A), or docetaxel 70 mg/m(2) on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1-5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate-specific antigen (PSA) level.. Forty-five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by > or =50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time.. These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

To determine the safety and efficacy of combination chemotherapy with docetaxel (DTX), estramustine phosphate (EMP), and carboplatin (CBDCA) in patients with hormone-refractory prostate cancer (HRPC).. This study included a total of 40 HRPC patients. We evaluated the activity of the following schedule: weekly DTX 30 mg/m(2) iv, daily EMP 10mg/kg po, and CBDCA AUC=6 iv on day 1 of a every 4-wk cycle. Treatment was continued until disease progression or excessive toxicity.. All patients were assessable for response. A median of six consecutive cycles was administered per patient. Levels of prostate-specific antigen decreased by more than 50% in 95.0% of the patients. Consumption of medication for cancer-induced pain was reduced in 84.6%. Partial response was attained in 66.7% of measurable lesions. Of patients with bone metastasis, 8.3% demonstrated partial response. With a median follow-up of 11.4 mo, the median time to progression was 12.0 mo, and the median overall survival time was 26.6 mo. The predominant toxicities were grade-3 or -4 anemia in 32.5% of the patients, leukopenia in 20.0%, and thrombocytopenia in 17.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. There were no therapy-related deaths.. Combination chemotherapy with DTX/EMP/CBDCA was found to have significant clinical activity with an acceptable toxicity profile in HRPC patients. More suitable selection of patients may be beneficial in terms of improved overall survival in the future.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

To assess the feasibility and activity of a neoadjuvant treatment combining a luteinizing hormone-releasing hormone (LHRH)-analogue, estramustine and docetaxel before radical retropubic prostatectomy (RRP) in patients with high-risk prostate cancer.. High-risk patients were defined as clinical stage > or =T3 and/or a prostate-specific antigen (PSA) level of > or =15 ng/mL, and/or biopsy a Gleason sum of > or =8. Patients received LHRH analogue treatment until the PSA nadir (a stable PSA level for two consecutive determinations) and then, continuing hormone therapy, a combined regimen of estramustine and docetaxel. Patients had RRP within a month of completing the neoadjuvant regimen. All patients were assessed for toxicity and surgical complications. A clinical response was defined as complete (CR, the disappearance of all palpable and radiological abnormalities and a decline in PSA level of > or =90%) or partial (PR, a decline in PSA level of half or more with stable or improved palpable and/or radiological abnormalities). A pathological response was defined as 'complete' (undetectable cancer), 'substantial' (residual cancer in < or =10% of the surgical specimen) or 'minimal' (residual cancer in >10% of the surgical specimen). The biomarkers p53, bcl-2, MIB1, erbB2 and factor VIII were also evaluated.. Of 22 patients enrolled between March 1999 and January 2002, 21 (mean age 63 years; mean PSA level 61 ng/mL; median biopsy Gleason sum 8) completed the neoadjuvant therapy. The clinical stage was organ-confined in three patients (15%); five (25%) had pelvic lymphadenopathy on computed tomography. The neoadjuvant treatment was well tolerated, with only one grade 2 toxicity (Eastern Cooperative Oncology Group grading). All PSA values decreased by >90% from baseline after hormonal therapy only, and the mean reduction from before to after chemotherapy was statistically significant (P = 0.001). Three patients (15%) had a CR, 16 (80%) had a PR and one (5%), with sarcomatoid tumour, had progression; 19 had non-nerve-sparing RRP and there were no major complications during or after RRP. The pathological assessment showed that one patient (5%) had no tumour (pT0) and six (32%) had a 'substantial' response. The overall rate of organ-confined disease was 58%, vs a mean 8% predicted likelihood from the Kattan nomogram. Five patients (26%) had positive surgical margins and four (21%) had positive lymph nodes. At a median follow-up of 53 months, eight patients (42%) were disease-free. Organ-confined disease (P = 0.022), residual cancer at pathology in < or =10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease-free survival.. A neoadjuvant chemohormonal regimen before RRP is feasible and active in patients with high-risk prostate cancer. The rate of pathological organ-confined disease was higher than expected and responding patients had an 85% disease-free survival rate at 5 years.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Feasibility Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk Factors; Survival Rate; Taxoids; Treatment Outcome; Triptorelin Pamoate

Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC.. Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE).. Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups.. Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Patient Selection; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Quality of Life; Survival Analysis; Taxoids

To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC.. In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days.. In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013).. Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.

Topics: Aged; Androgens; Animals; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System; Docetaxel; Estramustine; Genotype; Humans; Male; Mice; Mice, Nude; Middle Aged; Prostatic Neoplasms; Survival Analysis; Taxoids; Thalidomide; Treatment Outcome

The aim of this study was to investigate prognostic factors of patients with metastatic hormone refractory prostate cancer (HRPC) under combined administration of personalized peptide vaccination and low-dose estramustine phosphate (EMP). From February 2001 to July 2004, 58 men with metastatic HRPC received the combination therapy of personalized peptide vaccination and low-dose EMP. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and survival times were also evaluated. The combination therapy was well tolerated with no major adverse effects. Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 29 of 37 (78%) patients and in 36 of 41 (88%) patients tested, respectively. A prostate-specific antigen decline of at least 50% occurred in 24% of patients. The median survival time was 17 months (95% confidence interval, 12-25 months). Cox proportional hazards analysis showed that a low number of lymphocytes (p = 0.0075, odds ratio 2.700), a negative immunological activity response after the vaccination (p = 0.0185, odds ratio 2.658), and poor performance status (p = 0.0347, odds ratio 2.569) were independent predictors of disease death. These encouraging results show the need for further evaluation of the combination of personalized peptide vaccination and low dose of EMP for metastatic HRPC patients.

Topics: Aged; Aged, 80 and over; Amino Acid Sequence; Antibody Formation; Cancer Vaccines; Combined Modality Therapy; Epitopes, T-Lymphocyte; Estramustine; Humans; Immunity, Cellular; Immunoglobulin G; Immunotherapy, Active; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Peptides; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; T-Lymphocytes, Cytotoxic; Treatment Outcome

The objective was to define the toxicity and activity of weekly docetaxel administered with a short course of estramustine and enoxaparine in patients with hormone-resistant prostate cancer (HRPC).. Twenty-four patients were treated with the next regimen: weekly docetaxel 36 mg/m(2) iv for three consecutive weeks every 28 days, and estramustine 280 mg three times a day for three consecutive days beginning the day before docetaxel (days 1-3, 8-10 and 15-17). In order to prevent thromboembolic events, 40 mg of subcutaneous enoxaparine was administered daily sc on the same days as estramustine. Primary endpoints were: toxicity, especially the presence of thromboembolic events, PSA response rate and response in measurable disease. Secondary endpoints were: time to PSA progression and overall survival.. Nineteen of 24 patients (79.1%, 95% CI 71-87%) had a PSA response = or >50%. Four of the eleven patients with measurable disease had a partial response. The median time to PSA progression was 7 months (CI 95%: 6.5-9) and the median survival was 19 months (IC 95%: 11-24). Toxicity was manageable with no treatment- related mortality. Only two patients had grade 4 neutropenia. Two patients had thrombotic events, one deep venous thrombosis and one stroke. The main grade 3 non-haematologic toxicity was diarrhoea and asthenia, both in 25% of patients.. Weekly docetaxel with a short course of estramustine and enoxaparine is active and tolerable in HRPC patients. The observed incidence of thrombosis was lower than previously reported but the association of enoxaparine was not enough to completely prevent the thromboembolic events.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Enoxaparin; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Taxoids; Time Factors; Treatment Outcome

Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.. A phase I trial of docetaxel/estramustine/ imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m2 to 60 mg/m2 to 70 mg/m2. Thirteen patients were treated.. On dose level 3 (docetaxel 70 mg/m2 and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m2 and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.. The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Estramustine; Humans; Imatinib Mesylate; Male; Middle Aged; Piperazines; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrimidines; Survival Rate; Taxoids; Treatment Outcome

The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy.. Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a > or = 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m2 orally on days 1-14, and paclitaxel 135 mg/m2 intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF).. Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively.. The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Estramustine; Etoposide; Feasibility Studies; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Treatment Outcome

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m(-2) of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1-3, 8-10, 15-17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1-9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44-72) and median duration of PSA response was 8.0 months (95% CI: 6.9-9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Celecoxib; Disease Progression; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prospective Studies; Prostatic Neoplasms; Pyrazoles; Soft Tissue Neoplasms; Sulfonamides; Survival Rate; Taxoids

Physicians typically switch therapies unless clinically relevant thresholds of response are observed, and treatments that produce high-quality responses and that are active in the salvage setting are generally felt to be promising. With the goal of efficiently selecting promising regimens for more advanced trials, we conducted a randomized selection trial of four regimens to identify promising treatments for androgen-independent prostate cancer.. Patients without prior exposure to cytotoxic therapy were randomly assigned to one of four regimens (i.e., cyclophosphamide, vincristine, and dexamethasone [CVD]; ketoconazole plus doxorubicin alternating with vinblastine plus estramustine [KA/VE]; weekly paclitaxel, estramustine, and carboplatin [TEC]; paclitaxel, estramustine, and etoposide [TEE]). Patients were evaluated every 8 weeks to assess response and adverse events. Patients who responded continued with the same treatment; those who did not were randomly assigned to one of the other three treatments. Response was assessed by considering tumor-specific symptoms, tumor regression, and prostate-specific antigen (PSA) changes. Treatment was continued until two consecutive courses induced a response (i.e., overall success, the major criterion for which was 80% PSA reduction) or until patients were given two different regimens that failed to induce such a response.. Median overall survival from registration among all 150 patients was 22 months (95% confidence interval [CI] = 19 to 26 months). Estimated survival at 3 and 5 years, respectively, was 26% (95% CI = 20% to 35%) and 10% (95% CI = 5% to 16%). Overall success was achieved in 35 patients with the initial treatment (i.e., four treated with CVD, seven with KA/VE, 14 with TEC, and 10 with TEE) and in nine more patients with a second-line regimen (i.e., two with CVD, five with KA/VE, and two with TEC). For all 44 (29%, 95% CI = 23% to 37%) patients with overall success, median survival was 30 months (95% CI = 26 to 40 months); for the other 106 patients, it was 19 months (95% CI = 17 to 22 months). TEC produced the greatest number and proportion of successful courses of treatment, and TEC followed by KA/VE was the most promising two-stage strategy.. Some patients responded to particular treatments, and responses to second-line treatments were not rare. We propose that TEC be considered for phase III evaluation.

Topics: Aged; Algorithms; Androgens; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Confidence Intervals; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Estramustine; Etoposide; Humans; Ketoconazole; Logistic Models; Male; Middle Aged; Paclitaxel; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Research Design; Survival Analysis; Treatment Outcome; Vinblastine; Vincristine

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m(-2) intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m(-2) i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3-4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63-82%) obtained a >/=50% PSA decline with 15 patients (37.5%; 95% CI 20-50%) that demonstrated a >/=90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8-8.2 months) and 19.2 months (95% CI 13.9-24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Prednisone; Prostatic Neoplasms; Survival Rate; Taxoids

We evaluated the efficiency and toxicity of estramustine phosphate (ECT), ifosfamide (IFM) and cisplatin (CDDP) combination chemotherapy in twenty-one patients with hormone-refractory prostate cancer (HRPC), for which there is currently no effective treatment. Patients received a daily dose of 560 mg ECT in combination with 1.2 g/m2 IFM on days 1 to 5 and 70 mg/m2 CDDP on day 1. This combination therapy was given every 3 to 4 weeks. An objective response of more than 50% reduction in prostate-specific antigen was observed in 9 of 18 patients (50%), and a more than 50% reduction in bi-dimensionally measurable soft-tissue lesions was observed in 2 of 7 patients (29%). The median duration of response among the cases showing partial response was 40 weeks, while the median duration of response of overall partial-response plus stable cases was 30 weeks. The median survival duration of all cases was 47 weeks. Toxicity was modest and acceptable. In conclusion, the ECT, IFM and CDDP combination chemotherapy regimen is a viable treatment option for HRPC. However, in comparison with our previous chemotherapy regimen of IFM and CDDP, no additional long-lasting effects resulting from the inclusion of ECT could be affirmed.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Estramustine; Humans; Ifosfamide; Male; Middle Aged; Prostatic Neoplasms; Survival Rate; Treatment Outcome

Gefitinib, which is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated activity against hormone-refractory prostate cancer (HRPC) in preclinical studies. In this pilot Phase I trial, the authors evaluated the tolerability, efficacy, and pharmacokinetics of gefitinib combined with estramustine and docetaxel in patients with HRPC.. Patients received gefitinib (at a dose of 250 mg/day or 500 mg/day) on each day of a 21-day treatment cycle. Docetaxel (at a dose of 60 mg/m(2)) was administered on Day 1, and estramustine (at a dose of 280 mg) was administered 3 times daily on Days 1 through 5.. Fifteen patients were recruited at each gefitinib dose level. The most common adverse events observed were consistent with the known profiles of gefitinib, docetaxel, and estramustine. No dose-limiting toxicity was observed. Adverse events considered to be gefitinib related included diarrhea (n = 23 patients), rash (n = 8 patients), nausea (n = 7 patients), dry skin (n = 6 patients), and emesis (n = 6 patients). Overall, 9 of 22 evaluable patients (40.9%) experienced a pain response. and 9 of 30 patients (30%) had a prostate-specific antigen response. A partial objective tumor response was demonstrated in 1 of 13 evaluable patients (7.7%) in each dose group; the median time to progression for both doses combined was 185 days (range, 28-233 days). Data comparisons within individual patients suggested that docetaxel and estramustine had no effect on gefitinib steady-state levels. Gefitinib had no effect on docetaxel exposure at the 250-mg dose but decreased exposure at the 500-mg dose. However, gefitinib may increase exposure to estramustine, particularly at the 500 mg/day dose.. The results of the current study demonstrated that gefitinib combined with estramustine and docetaxel had acceptable and predictable tolerability. However, it is unclear whether gefitinib provides an additional clinical benefit over docetaxel and estramustine alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Docetaxel; Estramustine; Gefitinib; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Quinazolines; Taxoids

The primary objective of the current study was to identify the tolerable dose level of oral vinorelbine when given in combination with estramustine to men with hormone-refractory prostate cancer (HRPC). The secondary objectives were to describe the toxicities of the combined regimen in patients with HRPC and to estimate the efficacy of oral vinorelbine in combination with estramustine based on the prostate-specific antigen (PSA) response.. Thirty-three patients with HRPC were treated on a 28-day cycle with estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 50 mg/m2 and was escalated to 70 mg/m2 using the time-to-event continual reassessment method.. Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m2 dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a dose of 60 mg/m2 and no dose-limitig toxicities were reported at the 50 mg/m2 dose. The overall response rate by > or = 50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%).. Oral vinorelbine at doses of 70 mg/m2 may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Confidence Intervals; Disease Progression; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Therapy, Combination; Estramustine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Vinblastine; Vinorelbine

Docetaxel alone or in combination with estramustine prolongs survival in patients with metastatic hormone-refractory prostate cancer. The role of chemotherapy is undefined in the treatment of patients who develop an increasing serum prostate-specific antigen (PSA) level after primary therapy but have no detectable metastases. This phase II study was performed as a preliminary evaluation of the feasibility and efficacy of weekly docetaxel/estramustine in patients with prostate cancer and increasing serum PSA levels.. Between March 2001 and September 2003, 34 patients entered this phase II trial. All patients had biopsy-proven adenocarcinoma of the prostate and had increasing PSA levels but no clinically or radiographically detected metastases after primary therapy. All patients received docetaxel 35 mg/m(2) intravenously on days 1, 8, and 15 and estramustine phosphate 140 mg 3 times daily for 7 doses, beginning the evening before each dose of docetaxel. Treatment courses were repeated at 28-day intervals, and responding patients received a total of 6 courses.. Thirty-one patients (91%) completed 6 courses of treatment. Thirty-two of 33 evaluable patients (97%) had a decrease in serum PSA level of > 50% during treatment, and 27 patients (82%) had normalization of serum PSA level. The median progression-free survival was 28 months, with 33% of patients progression free at 3 years. This treatment regimen was well tolerated with no myelosuppression-related complications or uncommon grade 3 nonhematologic toxicity.. Treatment with weekly docetaxel and estramustine is feasible and active in patients with prostate cancer and increasing serum PSA levels. However, the benefit of early treatment versus treatment when clinical metastases are detected requires demonstration in a randomized phase III trial.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Retreatment; Taxoids; Treatment Outcome

Palliation of bone pain can be achieved in men with androgen-independent prostate cancer treated with docetaxel and estramustine (DE) or mitoxantrone and prednisone (MP). While Southwest Oncology Group trial 99-16 demonstrated a survival improvement of DE over MP, the study also was designed to compare the palliation of disease-related symptoms.. Pain palliation and global quality of life (QOL) were the two primary patient-reported outcomes. Pain was measured with the Present Pain Intensity scale of the McGill Pain Questionnaire-Short Form. The European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (QLQ-C30) and its Prostate Cancer Module (PR25) measured QOL and symptom status. Pain and analgesic use were measured at random assignment, every cycle for eight cycles, and 1 year from random assignment; the QLQ-C30 and the PR25 were administered at random assignment, before cycle four (week 10) and cycle eight (month 6) and at 1 year. In addition to the primary intent-to-treat, missing at random analysis, sensitivity analyses were performed to assess robustness of global QOL conclusions under alternative informative missing data assumptions.. Six hundred seventy four eligible patients received DE (n = 338) or MP (n = 336). In an intention-to-treat analysis, median overall survival was 17.5 months for the DE arm and 15.6 months for the MP arm (P = .02). There were no statistically significant differences in pain palliation between the treatment arms. The sensitivity analyses showed a consistent lack of statistically significant global QOL differences for the two arms.. DE had superior clinical efficacy (overall survival, time-to-progression, and prostate-specific antigen declines) with similar global QOL and pain palliation in the MP arm.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Pain; Pain Measurement; Palliative Care; Prednisone; Prostatic Neoplasms; Quality of Life; Survival Analysis; Taxoids

To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival.. In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity.. Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation.. In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Analysis of Variance; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Docetaxel; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

We investigated the clinical efficacy and the prolongation of survival with combination therapy of estramustine phosphate (EMP) and endocrine therapy in untreated patients with progressive prostate cancer.. We randomly divided 57 patients with untreated stage D prostate cancer into two groups, an endocrine monotherapy group and a group receiving combination treatment, consisting of endocrine therapy plus EMP. Treatment was continued until deterioration.. There were no significant differences in the improvement rating for subjective/objective symptoms or in progression-free survival between the two groups. However, overall survival was significantly prolonged in the combination therapy group (log-rank test, P = 0.0394; generalized Wilcoxon's test, P = 0.0145). In particular, overall survival was significantly prolonged, compared to that in the endocrine monotherapy group, in patients in the combination therapy group who were less than 74 years old, those with a performance status (PS) of 1 to 3, a pretreatment prostate-specific antigen (PSA) level of more than 20 ng/ml, moderately or poorly differentiated carcinoma, or a partial response (PR) based on the PSA level 12 weeks after the start of treatment. There was no significant difference in the incidence of side effects between the combination therapy and the endocrine monotherapy groups.. A combination of EMP with endocrine therapy may be useful for initial treatment in younger patients (aged 73 or younger) and in patients at high risk of progressive prostate cancer.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Disease-Free Survival; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prostatic Neoplasms; Survival Analysis

The objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle.. Eighty-four patients were registered into the trial. Paclitaxel 80 mg/m2 and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy.. Intent-to-treat analysis revealed a > or = 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade > or = 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%).. Paclitaxel/estramustine/carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Survival Rate; Treatment Outcome

This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy.. Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m2 over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days.. Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily.. The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Disease Progression; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Thalidomide; Time Factors; Treatment Outcome

To determine the safety and efficacy of two docetaxel doublets in hormone-refractory prostate cancer (HRPC) patients and to examine the prognostic role of polymorphisms in host genes important to docetaxel metabolism and transport.. Sixty-four chemotherapy-naive patients with HRPC were randomized to docetaxel and vinorelbine (D, 20 mg/m2 i.v. days 1 and 8; V, 25 mg/m2 i.v. days 1 and 8) or docetaxel and estramustine phosphate (D, 60-70 mg/m2 i.v. day 1; E, 280 mg oral thrice daily days 1-5) administered q21d. Primary end point was clinically significant toxicity. A pharmacogenetic analysis of host genes was done in patients who received at least one cycle of docetaxel therapy.. Grade 3/4 toxicity occurred in 15.6% of DV patients and in 28.6% DE patients. Neither arm exceeded the threshold of clinically significant toxicity. In the DV arm, objective response rate was 33%, prostate-specific antigen response rate was 20%, and median survival was 16.2 months. In the DE arm, objective response rate was 67%, prostate-specific antigen response rate was 43%, and median survival was 19.7 months. Pharmacogenetic analyses showed a significant association between survival beyond 15 months and the ABCG2 421 C > A (Q141K) polymorphism compared with the wild-type (C/C) genotype (66% versus 27%; P = 0.05).. DV and DE doublets are active with a tolerable toxicity profile in patients with HRPC; however, efficacy does not seem superior to standard single-agent docetaxel. The ABCG2 421 C > A (Q141K) polymorphism may be an important predictor of response and survival in HRPC patients treated with docetaxel-based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Patient Selection; Prostatic Neoplasms; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

Androgen-deprivation therapy (ADT) is effective for relapsed prostate cancer, but is rarely curative. The purpose of this trial was to determine the feasibility, toxicity, and prostate-specific antigen (PSA) response of chemotherapy and limited ADT for men with PSA relapse.. Eligible men had an increasing PSA and no metastases after prostatectomy and/or radiation for localized disease. Treatment consisted of four cycles of docetaxel (70 mg/m2) every 21 days and estramustine 280 mg tid on days 1 through 5. After chemotherapy, goserelin acetate and bicalutamide were prescribed for 15 months.. Sixty-two patients were enrolled. A complete PSA response (CR) was defined as PSA at or below the assay-specific lower limit. The proportion of patients with CR after chemotherapy, after ADT, and at 1 year after completion of ADT was 53%, 63%, and 36%, respectively. Testosterone was more than 100 ng/dL (median, 250 ng/dL) 1 year after completion of ADT in 97% of patients. Patients with a PSA less than 3.0 ng/mL at enrollment had a significantly longer time to progression (TTP; P = .0004). Of 56 patients who were observed at least 1 year after completion of ADT, 23 (41%) have not experienced progression as of their last follow-up. The median TTP is 34 months from treatment initiation (maximum, 74 months free from progression).. Chemotherapy plus ADT was feasible for early prostate cancer relapse. Forty-one percent of men who are at least 1 year after completion of ADT with recovered testosterone have not experienced progression. This approach is being tested in a randomized trial with investigation of predictors of response.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Estramustine; Humans; Male; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Remission Induction; Salvage Therapy; Taxoids

Chemotherapy is often poorly tolerated in elderly patients or patients with poor performance status. This trial was designed to determine whether low-dose weekly docetaxel/estramustine was efficacious with acceptable toxicity.. Dexamethasone was administered as premedication. Subjects received docetaxel 25 mg/m2 intravenously on days 2, 9, and 16 and estramustine 140 mg orally twice daily on days 1-3, 8-10, and 15-17. Cycles were 28 days. Participants received < or = 6 cycles unless progression or intolerable toxicity occurred.. Fifty-eight subjects were enrolled at 31 sites in the US Oncology Network. Median age was 78 years (range, 64-92 years); performance status scores (0, 1, 2, and 3) were 36%, 38%, 24%, and 2%, respectively; 55 subjects received > or = 1 cycle of treatment; and 4 participants were nonevaluable because they completed < 2 cycles. Among the 56 treated subjects, 38 (68%) had a decreased prostate-specific antigen level (> or = 50% compared with baseline level and maintained for 4 weeks). There were 40 subjects with measurable tumor(s). Responses, assessed using Response Evaluation Criteria in Solid Tumors, were 1 complete response (2.5%), 7 partial responses (17.5%), 26 stable diseases (65%), and 6 progressive diseases (15%). At 1 year, 17% of participants were progression free; median progression-free survival was 5.3 months (range, 1-14.5 months); estimated 1-year survival was 65%. There were no grade 4 treatment-related events. Grade 3 treatment-related events included fatigue/asthenia (11%) and arrhythmia, dehydration, cerebral ischemia, thrombocytopenia, and dyspnea (4% each). There was 1 treatment-related death (acute respiratory distress syndrome).. These findings suggest that elderly men with advanced-stage prostate cancer tolerate this regimen, with significant responses and prolonged progression-free survival. These patients should not be excluded from chemotherapeutic interventions based on age alone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Taxoids; Treatment Outcome

The safety, toxicity, and immunological response of individualized peptide vaccination or human leukocyte antigen (HLA)-A24+ hormone refractory prostate cancer (HRPC) patients in combination with a low dose of estramustine were evaluated.. Sixteen patients with HLA-A24+ HRPC were enrolled in the phase I/II study. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and quality of life (QOL) outcomes using a self-reported patient questionnaire were also evaluated.. Vaccinations were well tolerated, but all patients developed grade 1 or 2 local redness and swelling at the injection site. There was no significant immunosuppression in most cases when the peptide and a half dose (280 mg/day) of estramustine were administrated. Augmentation of peptide-specific CTL precursors or peptide-specific IgG was observed in 10 of 14 or 7 of 14 patients at 12 weeks (peptide vaccination alone), and in 6 of 8 or 10 of 12 patients at 24 weeks (during the combination therapy), respectively. All 13 patients treated, with the combination therapy, showed a decrease of serum prostate-specific antigen (PSA) level from the baseline, including six patients with a serum PSA level decrease of >or=50%. QOL outcomes were not deteriorated during the treatment.. These results might encourage the further evaluation of the combination of peptide vaccination and a low dose of estramustine phosphate for HLA-A24+ HRPC patients.

Topics: Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Estramustine; Follow-Up Studies; HLA-A Antigens; HLA-A24 Antigen; Humans; Immunotherapy; Male; Middle Aged; Prostatic Neoplasms; Quality of Life; Treatment Outcome; Vaccines, Subunit

Mitoxantrone/prednisone ameliorates symptoms in hormone refractory prostate cancer (HRPC) but has no effect on survival. Docetaxel (Taxotere)/estramustine improves response but with significant toxicity. We reasoned that a sequential administration of the two regimens could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity.. Thirty HRPC patients were treated with mitoxantrone 10 mg/m(2), day 1, every 3 weeks, plus prednisone 5 mg twice daily, for three cycles, followed by estramustine phosphate, 280 mg three times daily, days 1 to 5, plus docetaxel 75 mg/m(2), day 2, every 3 weeks for a maximum of 10 cycles.. All patients were assessable for response and toxicity. After mitoxantrone/prednisone treatment, the prostate-specific antigen (PSA) response rate was 23%, which increased to 63% after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine treatment (12 partial and 7 complete responses). With a median follow-up of 18 months, median survival for all patients was 18 months, and median progression-free survival was 10 months. The mitoxantrone/prednisone regimen was well tolerated, and the only grade 3-4 toxicity was grade 3 neutropenia in four (13%) patients. Twenty-nine patients received a total of 173 cycles of docetaxel/estramustine (median, 6 cycles/patient). Six (20%) patients had grade 3-4 neutropenia and two (6%) patients had febrile neutropenia episodes. The most frequent non-hematological toxic effects were asthenia, nausea and vomiting, edemas and onycholysis. Two (6%) patients had deep venous thrombosis.. Mitoxantrone/prednisone followed by docetaxel/estramustine is a well-tolerated and active regimen in HRPC. Sequential therapy is feasible and can be used to integrate novel, more active regimens.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids

To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC).. Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2].. Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months.. Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Docetaxel; Dose-Response Relationship, Drug; Estramustine; Humans; Ketoconazole; Male; Maximum Tolerated Dose; Middle Aged; Mitoxantrone; Prostatic Neoplasms; Taxoids; Time Factors; Treatment Outcome

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Epothilones; Estramustine; Fatigue; Humans; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Prostatic Neoplasms; Thrombosis

Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP).. One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily).. One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic.. The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mitoxantrone; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prednisone; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Taxoids; Treatment Outcome

Recent phase III studies in hormone refractory prostate cancer (HRPC) showed an improvement in terms of overall survival (OS), objective response (OR) and biochemical response (BR); however, chemotherapy is usually accompanied by negative side effects that determines poor quality of life (QoL) and only marginally improves individual clinical response (ICR) in terms of pain relief and performance status. Ellagic acid is a polyphenol that is found in many species of flowering plants. It is an antioxidant that determines apoptosis, down regulation of IGF-II, activates p21 (waf1/Cip1), mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells.. The aim of this study was to assess the effects of ellagic acid support therapy on toxicity, OR, ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine.. Patients with HRPC were randomly distributed in two study groups: a control group (group A) who underwent chemotherapy with vinorelbine and estramustine phosphate, and an experimental group (group B) where chemotherapy regimen was associated with ellagic acid.. The mean number of chemotherapy cycles/patient was 4 (range 3-8 cycles) and 6.5 (range 5-11) in group A and B patients, respectively. A reduction in systemic toxicity, statistically significant for neutropenia, associated with better results in term of OR rate, ICR, and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups.. our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity, in particular neutropenia, in HRCP patients; however, further studies are required to confirm our results.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ellagic Acid; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Treatment Failure; Vinblastine; Vinorelbine

Prostate cancer is a dynamic disease. Androgen ablation is palliative, and does not cure advanced prostate cancer. The hormone-sensitive cells die, and the hormone-resistant cells come into excess; the disease then progresses, which results in a deterioration of the condition of the patient. The theoretical basis of the curing strategy is the fact that the prostate tumour itself changes during the progression; the molecular determinants of the resistance are present in the varying stages of the disease. The treatment of advanced prostate cancer remains unsolved; it is a well-known fact that a hormone-resistant state develops after the primary treatment forms (androgen withdrawal). The drug of choice for the secondary treatment is estramustine. This can be utilized as monotherapy or in combination.. In the present study, the results of estramustine treatment of 79 patients with advanced prostate cancer were evaluated. The preparation, known and clinically applied for more than 20 years, was studied in 12 centres.. The mean prostate-specific antigen level improved for 6 months, but rose from the 9th month on. The improvement in the subjective condition of the patients paralleled the change in the prostate-specific antigen level. The shortness of the improvement was a consequence of the very high prostate-specific antigen level and the poor general condition.. Estramustine administration is recommended when the prostate-specific antigen level becomes more than doubled following the primary treatment. At a starting prostate-specific antigen level of >100 ng/ml, the treatment leads to total androgen blockade. If the prostate-specific antigen level has not decreased after treatment for 3 months, the secondary strategy is to apply chemotherapy.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Treatment Outcome

This phase II study was designed to evaluate the efficacy of vinorelbine in combination with estramustine in patients with chemotherapy-naïve hormone-refractory prostate cancer.. Patients received vinorelbine (i.v. 25 mg/m2) on days 1 and 8 every 3 weeks and estramustine (oral, 600 mg/m2) daily. Eligible patients were required to have progressive metastatic disease following the first hormonal manipulation.. Of the 51 patients enrolled (median age = 69 years), 84% presented bone involvement and 75% had at least two organs involved at the time of study entry and 47 were evaluable for treatment efficacy. Prostate specific antigen (PSA) response (> or =50% decrease) which was the primary efficacy criterion was reported in 21 patients (41.2%) in the intent-to-treat (ITT) population and in 20 patients (48.8%) in the per protocol (PP) population. Of the 7 patients with measurable disease, 2 achieved partial response. Median progression-free survival and overall survival were 4.7 months (range: 1.9-8.6) and 14.3 months (range: 4.2-21.2), respectively. Grade 3-4 neutropenia was reported in 6.1% of patients and in 1% of cycles. The incidence of complicated neutropenia (febrile neutropenia reported in 1 patient and septic shock with severe neutropenia reported in 2 patients) was 5.8%. The most frequent grade 3-4 non-haematological events (% of patients > or =5%) included anorexia (10%), thrombosis/embolism (8%), vomiting and hypotension (6% each). There were 3 toxic deaths (5.9 %) resulting from pulmonary embolism, angina pectoris, and septic shock. The impact of combined chemotherapy on the quality-of-life (QL) of the patients was assessed between baseline and the first evaluation scheduled at 6 weeks indicated a marked reduction in pain while the rest of the symptoms remained stable. Overall, health status improved slightly over the treatment period.. This study confirmed that the combination of vinorelbine and estramustine is an active regimen in patients with hormone-resistant prostate cancer who had not been treated previously with chemotherapy. Main toxicities included complicated neutropenia even though the incidence of severe neutropenia was low. We observed a higher incidence of toxic deaths which could have been related to the regimen of estramustine used in the study.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Vinblastine; Vinorelbine

We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer.. Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients.. A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria.. High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Calcitriol; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

To evaluate the safety profile and therapeutic value of the combination of estramustine, mitoxantrone, and vinorelbine in the treatment of hormone-refractory prostate cancer.. Fifty-two patients with hormone-refractory prostate cancer were included in the study. Median age was 70 years (range, 49 to 100 years), World Health Organization performance status ranged from 0 to 2. The treatment schedule consisted of estramustine capsules (140 mg 3 times daily on days 1 to 3 and days 8 to 10 per os), intravenous mitoxantrone (12 mg/m2 on day 2), and intravenous vinorelbine (25 mg/m2 on day 2 and day 9), given in a 3-week cycle.. Thirty-one percent of patients with measurable soft-tissue disease demonstrated an objective response, which included six complete and ten partial responses in all involved organs (bone responses not included). Twenty-nine patients (56%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 6.9 months, and the median survival for all patients was 14.5 months.. The combination of estramustine, vinorelbine, and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Feasibility Studies; Hormones; Humans; Male; Middle Aged; Mitoxantrone; Prostatic Neoplasms; Survival Rate; Vinblastine; Vinorelbine

We aimed to determine the safety and efficacy of monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer (HRPC).. Patients with prostate cancer that was progressing despite androgen ablation therapy were treated with i.v. paclitaxel, 175 mg/m2, over 3 h, followed by carboplatin (area under the curve, 5) on day 1, with oral estramustine phosphate, 280 mg twice daily, for a 28-day treatment cycle. Estramustine phosphate was precluded in those patients who had experienced adverse effects during prior chemotherapies. Patients were evaluated for response every cycle, and the treatment was continued until the cancer progressed.. Twenty-one patients with progressive hormone-refractory disease were treated for a median of 4 cycles (range, 1 to 11 cycles). Estramustine phosphate was precluded in seven patients. Post-therapy decreases in serum prostate-specific antigen levels of 50% and 75%, respectively, were seen in 43% and 19% of the patients (95% confidence intervals, 22% to 64% and 2% to 36%). Of the nine patients with measurable disease, 1 (11%) had a complete response and 2 (22%) had a partial response. The overall median time to progression was 4 months, and the median survival time for all patients was 11 months. Major grade 3 or 4 adverse effects were anemia (29%), neutropenia (48%), and thrombocytopenia (24%). Mild peripheral neuropathy and myalgia/arthralgia were observed in 11 (52%) and 9 (43%) patients, respectively.. Monthly paclitaxel and carboplatin with oral estramustine phosphate has significant antitumor activity and is well tolerated in patients with progressive HRPC.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Rate

Docetaxel based chemotherapy not only reduces pain and improves quality of life in advanced hormone refractory prostate cancer (HRPC), but it also improves survival. We investigated the combination of docetaxel and estramustine in patients with HRPC regarding efficacy and prognostic parameters.. We conducted a phase-II trial, administering docetaxel (70 mg/m(2) i.v., day 2, every 3 weeks) and estramustine (280 mg 3 times daily p.o., 1 day prior to docetaxel, on 5 consecutive days) to patients with HRPC. Patients were monitored for PSA (prostate-specific antigen) response and toxicity.. 62 patients were treated. The median age was 67.5 years, the median PSA was 177.9 ng/ml. The median number of cycles was 6. The median time to progression (TTP) and median survival time were 14 (+/-2) and 24 (+/-5) months, respectively. A = 50% decrease in PSA levels from baseline occurred in 38 (61.3%) patients of whom 25 (40.3%) had a = 75% PSA decrease. The main grade 3-4 hematologic toxicities were neutropenia 34% and anemia 18%.. The combination of docetaxel and estramustine exerts substantial activity in HRPC suggesting an overall survival benefit with manageable toxicity. This trial also demonstrated a survival advantage for patients with early chemotherapeutic intervention. We identified PSA relapse, baseline PSA and hemoglobin as valuable prognostic factors in this setting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Germany; Humans; Male; Middle Aged; Prevalence; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Assessment; Risk Factors; Severity of Illness Index; Survival Analysis; Survival Rate; Taxoids; Treatment Failure; Treatment Outcome

Topics: Adenocarcinoma; Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Infusions, Intravenous; Male; Mitoxantrone; Prednisone; Prospective Studies; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer.. A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis.. Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group.. Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Estramustine; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Probability; Prognosis; Prostatic Neoplasms; Survival Analysis; Treatment Outcome

Based on the results of combined data from three North American Phase II studies, a randomised Phase II study in the same patient population was performed, using combination chemotherapy with estramustine phosphate (EMP) and vinblastine (VBL) in hormone refractory prostate cancer patients. In all, 92 patients were randomised into a Phase II study of oral EMP (10 mg kg day continuously) or oral EMP in combination with intravenous VBL (4 mg m(2) week for 6 weeks, followed by 2 weeks rest). The end points were toxicity and PSA response in both groups, with the option to continue the trial as a Phase III study with time to progression and survival as end points, if sufficient responses were observed. Toxicity was unexpectedly high in both treatment arms and led to treatment withdrawal or refusal in 49% of all patients, predominantly already during the first treatment cycle. The mean treatment duration was 10 and 14 weeks, median time to PSA progression was 27.2 and 30.8 weeks, median survival time was 44 and 50.9 weeks, and PSA response rate was only 24.6 and 28.9% in the EMP/VBL and EMP arms, respectively. There was no correlation between PSA response and survival. While the PSA response in the patients tested was less than half that recorded in the North American studies, the toxicity of EMP monotherapy or in combination with VBL was much higher than expected. Further research on more effective and less toxic treatment strategies for hormone refractory prostate cancer is mandatory.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Resistance, Neoplasm; Estramustine; Humans; Infusions, Intravenous; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Vinblastine

To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC.. Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups.. The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant).. The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Dexamethasone; Diabetes Mellitus; Disease-Free Survival; Estramustine; Etoposide; Gastrointestinal Diseases; Gonadotropin-Releasing Hormone; Hematologic Diseases; Humans; Life Tables; Male; Middle Aged; Orchiectomy; Peptides, Cyclic; Prostatic Neoplasms; Somatostatin; Survival Analysis; Treatment Outcome; Triptorelin Pamoate

The current study determined the efficacy and toxicity of weekly paclitaxel in combination with estramustine phosphate (EMP) in patients with androgen-independent prostate carcinoma (AIPC).. Patients with progressive AIPC received 90 mg/m2 paclitaxel by 1-hour intravenous infusion weekly for 3 weeks, followed by a 1-week treatment rest. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received 1 mg warfarin daily to prevent thromboembolism.. Sixty-six patients with progressive AIPC received treatment at 29 centers. Forty-two percent of patients had a 50% decline in prostate-specific antigen (PSA; 95% confidence interval [CI], 30-54%). For 26 patients with bidimensionally measurable disease, the objective response rate was 15% (95% CI, 1-30%). The median time to disease progression was 6.3 months, and the median time to PSA progression was 11.4 months. The median survival period was 15.6 months. Grade 3-4 toxicities were uncommon and included thromboembolism (8%), anemia (3%), neutropenia (3%), and peripheral neuropathy (2%). There was one treatment-related death.. This regimen of EMP plus weekly paclitaxel was an active and well tolerated treatment for patients with AIPC.

Topics: Aged; Aged, 80 and over; Androgens; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Analysis; Treatment Outcome

Additive antitumor effects could be achieved by combination of immunotherapy and cytotoxic agents with no or minimum suppression.. Thirteen patients positive for human leukocyte antigen (HLA)-A24 or -A2 with metastatic hormone refractory prostate cancer (HRPC) who had failed to respond to the prior-peptide vaccination were entered in the combined peptide vaccination and estramustine phosphate. Conducted immune monitoring on those 13 patients were mainly peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by IFN-gamma productions and peptide-reactive IgG by an enzyme-linked immunosorbent assay (ELISA).. Grade 3 arrhythmia or cerebral infarction was observed in two cases, and Grade 1 or 2 dermatologic reaction at the vaccination sites was observed in all 13 cases. Eleven patients who received more than one cycle of treatment were eligible for immunological and clinical evaluation. There was no significant immunosuppression in most cases when the peptide and a half dose (280 mg/day) of estramustine were administrated, whereas severe immunosuppression was observed in the first two patients who received both the peptide and a full dose (560 mg/day) estramustine. Augmentation of peptide-specific CTL precursors or peptide-specific IgG was observed in 6 of 11 or 10 of 11 cases, respectively. Ten of 11 patients showed serum prostate-specific antigen (PSA) level decrease from the baseline including 8 patients with a serum PSA level decrease of > or =50%.. These results encouraged the further evaluation of the combination of peptide vaccination and low-dose estramustine phosphate for metastatic HRPC patients.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Estramustine; Humans; Immunoglobulin G; Immunosuppression Therapy; Interferon-gamma; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Vaccines, Subunit

To describe the 5-year outcomes of patients with high-risk localized prostate cancer treated with neoadjuvant estramustine and vinblastine followed by concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT).. A total of 23 patients completed therapy consisting of two 8-week cycles of vinblastine, weekly as 4 mg/m2, followed by 8 weeks of concomitant chemotherapy and 3D-CRT. Estramustine was given daily at 10 mg/kg in three divided doses. 3D-CRT consisted of a total dose of 7560 cGy.. Assessable patients include 9 with Stage T3 or greater tumors and 5 with lymph node metastasis at diagnosis. All patients had a Gleason score 7 or greater. The median follow-up was 60 months. Of the 23 assessable patients, 15 (65%) experienced biochemical relapse by American Society for Therapeutic Radiology Oncology criteria. The median time to prostate-specific antigen relapse was 12 months (range 7 to 16). Five patients (22%) developed metastases. The median time to metastasis had not been reached by last follow-up. Of the 23 assessable patients, 11 (48%) received no additional therapy and had noncastrate testosterone levels. Six patients had no evidence of disease and 9 patients were receiving androgen blockade. Three patients died (one of prostate cancer and two of other diseases).. A substantial proportion of patients with unfavorable-risk localized prostate cancer achieved long-term disease control with estramustine and vinblastine and concurrent 3D-CRT, no significant long-term toxicities were seen and 48% underwent no further therapy after RT. These long-term findings support the continued study of chemotherapy combined with RT as a potential alternative to prolonged androgen deprivation.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Disease-Free Survival; Estramustine; Feasibility Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Risk; Survival Analysis; Testosterone; Treatment Outcome; Vinblastine

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.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Mitoxantrone; Palliative Care; Prednisone; Prostatic Neoplasms; Quality of Life; Survival Analysis; Taxoids

Six patients with hormone refractory prostate cancer were orally administered 560 mg of Estramustine daily in 2 equally divided doses for four or five days. In addition 70 mg/m2 of Docetaxel was infused through intravenous drip from day 1, decreasing to 40-60 mg/m2 if any side effects such as bone marrow depression were observed. One cycle was three weeks in hospital and one month after discharge. Patients were treated until progression or the development of treatment-limiting toxicity. In five of the six patients (83.3%), serum prostate specific antigen (PSA) was decreased by more than 50%. Currently, this therapy is ongoing in four outpatients. A side effect of leucopenia (grade 2 or 3) was observed in all patients. Granulocyte-colony stimulating factor (G-CSF) formulation was given as treatment. One case was withdrawn due to loss of appetite after one cycle. This therapy is considered to be effective against hormone refractory prostate cancer. However, further examination is needed about dosage and dosing regimen of Estramustine and Docetaxel.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Prostatic Neoplasms; Taxoids

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15-17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a > oe = 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/ estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/ estramustine are recommended.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Humans; Logistic Models; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Paclitaxel; Probability; Prognosis; Prostatic Neoplasms; Reference Values; Risk Assessment; Survival Analysis; Treatment Outcome

Early chemohormonal therapy in metastatic prostate cancer may offer an advantage by simultaneously targeting androgen-dependent and -independent clones. Hence, a phase II trial was conducted to evaluate the efficacy and toxicity of estramustine and etoposide in hormone-sensitive metastatic prostate cancer.. Eligibility consisted of untreated metastatic prostate cancer, adequate organ function, and a performance status of 0 to 2 by Zubrod criteria. A 21-day schedule of oral estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) was administered every 28 days. Hormonal therapy was allowed at the end of the protocol therapy. Toxicity was assessed weekly, PSA levels were assessed with each cycle, and objective response was evaluated every 3 cycles.. Twenty-one patients were enrolled (10 white, 11 black) with a median age of 59.5 years (range, 42-79 years), a median PSA of 338 ng/mL (range, 0.9-20,000 ng/mL), and a median Gleason score of 8 points. Ten patients had bone-only metastases, 11 had measurable disease, of whom 4 had visceral metastases. A total of 128 cycles were administered (median, 6 cycles). No dose reductions were required. Nineteen patients were able to be evaluated for response. Severe toxicities included thromboembolic events and anemia in 2 patients each and fatigue in 1 patient. There were no episodes of febrile neutropenia. Response was observed in 8 of 11 patients (73%) with measurable disease. Median PSA nadir after therapy was 0.45 ng/mL, and undetectable PSA (<0.1 ng/mL) was achieved in 4 patients. Median time to PSA progression was 16.65 months. At a median follow-up of 34 months, 18 patients were alive. The 1-, 2-, and 3-year overall survival rates were 90%, 82%, and 72% respectively. Median survival has not yet been reached.. The combination of estramustine and etoposide is well tolerated, and has promising activity in newly diagnosed metastatic prostate cancer.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Rate

In designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial.. A historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult.. In the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%).. A hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials, Phase III as Topic; Cohort Studies; Decision Support Techniques; Estramustine; Humans; Male; Paclitaxel; Probability; Prostatic Neoplasms; Research Design; Retrospective Studies; Survival Analysis; Treatment Outcome

Several multicomponent regimens have been reported to be useful in advanced androgen-independent prostate cancer. We used a randomized phase II design to evaluate and compare two such regimens. Patients were accrued primarily in the community setting.. Patients with progressive, androgen-independent prostate cancer were randomly assigned to one of two treatments: either ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time.. A total of 75 patients were registered; 71 are included in the analysis. By the criterion of an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months) for patients treated with KA/VE. Many patients (24%) failed to complete at least 6 weeks of therapy, including five (8%) treatment-related early deaths.. Each of these regimens produced clinically significant responses, and the observed median survival (18.9 months for all 71 patients) compares favorably with previously published results, especially in the community setting. Nonetheless, it is apparent that these first-generation regimens must be applied judiciously, and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Resistance, Neoplasm; Estramustine; Etoposide; Humans; Ketoconazole; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Survival Rate; Treatment Outcome

To evaluate the efficacy and safety of neoadjuvant docetaxel and estramustine in patients with high-risk, newly diagnosed, prostate cancer.. Eligible patients had prostate cancer with one or more of the following criteria: clinical Stage T2b or greater, prostate-specific antigen (PSA) of 15 ng/mL or greater, and/or Gleason score of 8 to 10. Chemotherapy consisted of docetaxel (70 mg/m(2)) on day 1 and estramustine (280 mg three times daily) on days 1 to 3 every 21 days for three to six courses. This was followed by local therapy, as deemed appropriate.. Twenty-one patients with a median age of 60 years, median PSA level of 16.1 ng/mL (range 2.4 to 175), and median baseline testosterone of 3.4 ng/mL were enrolled. Seven patients met one of the inclusion criteria, 10 met two, and 4 met three. The Gleason score was 8 or greater in 14 patients. A median of five cycles of chemotherapy was delivered. The most frequent high-grade toxicities were grade 3 (8 patients) and 4 (1 patient) neutropenia and deep venous thrombosis (grade 3 in 2 patients) before institution of low-dose warfarin. All patients responded as determined by protocol-defined criteria. Ten patients underwent radical prostatectomy, with negative surgical margins in 7 patients, and 11 received radiotherapy with negative preradiotherapy biopsies in 2.. Induction docetaxel and estramustine is well tolerated and feasible in patients with newly diagnosed, high-risk prostate cancer. This combination is active; however, its efficacy relative to hormonal therapy will require a controlled randomized trial.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Docetaxel; Estramustine; Feasibility Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Testosterone; Treatment Outcome

The purpose is to determine a safe weekly dose of i.v. estramustine phosphate (EMP) to combine with weekly paclitaxel and monthly carboplatin in patients with advanced prostate cancer.. Patients with advanced prostate cancer (castrate and noncastrate) were administered escalating doses of weekly 1-h infusion of i.v. EMP (500-1000-1500 mg/m(2)) in combination with weekly paclitaxel (100 mg/m(2) over 1 h) and i.v. carboplatin (area under the curve 6 mg/ml-min every 4 weeks). Four weeks of therapy were considered one cycle. In the first three cohorts, EMP was given i.v. 3 h before paclitaxel. Cohorts 4 and 5 reversed the administration order: EMP (doses 1000-1500 mg/m(2)) was given immediately after the end of paclitaxel infusion. Plasma levels of EMP and its metabolites, estramustine and estromustine, were monitored at time 0, at 120 min, and approximately at 20, 21, and 168 h from the start of EMP infusion. Paclitaxel concentrations were determined at basal (0), 30, 60, 90, and 120 min and 18 h after the start of paclitaxel infusion, and a concentration-time curve was estimated. Pharmacokinetic evaluation was performed in cycles 1 and 2 during the first week of therapy.. Nineteen patients were entered on the initial three dose levels (cohorts 1-3). Dose-limiting transient hepatic toxicity was encountered in cohort 3 (EMP = 1500 mg/m(2)). An additional 13 patients were treated with paclitaxel (100 mg/m(2)) first, followed by i.v. EMP at 1000 mg/m(2) (cohort 4), and 1500 mg/m(2) (cohort 5). No dose-limiting toxicities were seen, and cohort 5 was determined safe for Phase II studies. Thromboembolic events were observed in 9% of patients (no prophylactic coumadin was used). Plasma concentrations of EMP and metabolites increased proportionally with dose. In all cohorts, there was a slight decrease in EMP and estramustine plasma concentrations between cycles 1 and 2. Although not significant, higher levels of estromustine at cycle 2 were observed in comparison to cycle 1. Decreased clearance of paclitaxel leading to higher than expected paclitaxel plasma concentrations was observed during the first cycle of therapy. Paclitaxel plasma concentrations were lower during cycle 2. In 17 patients with androgen-independent disease, 59% had >/=50% posttherapy decline in PSA and 22% showed measurable disease regression.. The regimen of weekly i.v. EMP in combination with paclitaxel and carboplatin can be safely administered with hepatic toxicity being transient and reversible. Pharmacokinetic results suggest that EMP competitively inhibits the biotransformation of paclitaxel after the first administration. This effect is counterbalanced, after repeated administrations, by a possible induction of the metabolic system caused by EMP. Phase II testing is ongoing to evaluate the efficacy of this combination.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Estramustine; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Treatment Outcome

To consider the safety profile and therapeutic value of the combination of estramustine and mitoxantrone in a bimonthly schedule to treat hormone-refractory prostate cancer. The survival of patients with prostate cancer who relapse after androgen ablation is limited and the therapeutic options are restricted.. Twenty-nine patients with relapse after previous treatment were included in the study; however, 3 patients who refused to start treatment were not included in the analysis, leaving 26 eligible patients. The median age was 64 years (range 44 to 82), the World Health Organization performance status ranged from 1 to 3, and the mean prostate-specific antigen level was 103 ng/mL (range 1 to 620). The Gleason score ranged from 2 to 9. The patients received a total of 208 therapeutic cycles (mean 8, range 3 to 24). Every cycle consisted of oral estramustine 140 mg, 3 times a day continuously, and intravenous mitoxantrone 20 mg (total dose). The regimen was repeated every 2 weeks.. Twenty-seven percent of patients with measurable soft-tissue disease demonstrated an objective response, which included one complete and six partial responses. Thirteen patients (50%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 9.2 months, and the median survival for all patients was 15 months. The most common side effects were neutropenia and thrombocytopenia.. The combination of estramustine and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. More patients are needed to partake in Phase III studies to establish the survival benefit that this combination may offer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Estramustine; Feasibility Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms

Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone-refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three-drug combination of paclitaxel, estramustine, and etoposide (TEE).. Twenty patients with carcinoma of the prostate that was progressing despite hormone therapy were enrolled on this Phase II trial. Patients were treated with oral estramustine, 280 mg three times daily, and oral etoposide, 50 mg/m2, once daily on Days 1-7, with i.v. paclitaxel, 135 mg/m2, over 1 hour followed by carboplatin (area under the curve, 5) on Day 2 of each 21-day treatment cycle. Patients were evaluated for response after three cycles, and three additional cycles were given to responding or stable patients.. Nineteen patients were evaluable for response, and 12 patients had measurable disease at baseline. The measurable response rate was 58% (7 of 12 patients; 95% confidence interval [95% CI], 28-85%), and all of those were partial responses. Eleven patients had decreases >50% from their baseline prostate specific antigen levels during therapy, for a response rate of 58% (95% CI, 34-80%) by this criterion. The median time to disease progression was 5.5 months, with a median survival of 14.2 months. Major toxicities included Grade (according to version 2 of the National Cancer Institute Common Toxicity Criteria) 4 neutropenia in 4 patients, Grade 4 thrombocytopenia in 4 patients, and anemia > or = Grade 3 in 4 patients. One patient had a deep vein thrombosis.. The combination of TEEC was active in patients with hormone-refractory prostate carcinoma. The regimen was tolerable, with primarily hematologic toxicity. The addition of carboplatin to TEE did not appear to add to the efficacy of the three-drug combination of antimicrotubule agents.

Topics: Adenocarcinoma; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease Progression; Estramustine; Etoposide; Humans; Male; Middle Aged; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Survival Rate; Treatment Outcome

Paclitaxel used in combination with estramustine has been shown to exert synergistic cytotoxicity in patients with hormone-refractory prostate cancer (HRPC). There have been few reports of this therapy in an Asian male population.. Nine patients with progressive metastatic HRPC completed at least one cycle of combination therapy employing weekly paclitaxel plus estramustine. Paclitaxel was given weekly for 3 weeks as a 2-h intravenous infusion at a dose of 100 mg/infusion. The cycle was repeated every 4 weeks. A dose of 280 mg of oral estramustine was administrated twice daily for 21 days from the first day of each cycle. Both efficacy and toxicity were recorded.. Grade 1 sensory neuropathy was seen in three patients (33%) and grade 4 thrombopenia/anemia was seen in one patient (11%). Performance status improved in three of seven patients (43%), while six patients (67%) showed a 50% or greater decline in prostate-specific antigen levels. Two of these patients experienced significant improvement in bone pain. One patient died of cardiac infarction during this trial and another died of disseminated intravascular coagulopathy subsequent to gastrointestinal bleeding. An additional patient suffered non-fatal pulmonary infarction. The one-year median survival rate was 22.2% and the overall survival period was 36 weeks.. Although weekly paclitaxel plus estramustine may pose a significant risk, this combination may have a beneficial effect on the quality of life HRPC patients. A well-designed phase I-II trial in an Asian male population is highly recommended.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Lymphatic Metastasis; Male; Middle Aged; Paclitaxel; Pain; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer.. Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks.. Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%).. The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bone Neoplasms; Castration; Dose-Response Relationship, Drug; Epothilones; Estramustine; Humans; Male; Maximum Tolerated Dose; Microtubules; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

The combination of paclitaxel, oral estramustine phosphate (EMP), and carboplatin (TEC) has shown antitumor activity in patients with castrate, metastatic prostate carcinoma. To improve the therapeutic efficacy and reduce the toxicity of TEC, the authors substituted intravenous (i.v.) EMP for oral EMP based on single-agent studies demonstrating an improved safety profile with i.v. EMP.. Patients with progressive, castrate, metastatic prostate carcinoma were treated with up to 6 4-week cycles of i.v. EMP (500-1500 mg/m(2) per week), paclitaxel (100 mg/m(2) per week), and carboplatin (target area under the curve = 6 mg/mL every 4 weeks).. Thirty patients were treated in 6 dose cohorts. Deep venous thrombosis occurred in 5 of 30 patients (17%). Other common Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria) toxicities included hepatic toxicity (23%) and leukopenia (24%). Posttherapy prostate specific antigen declines > 50% were seen in 18 of 30 patients (60%), and declines > 80% were seen in 15 of 30 patients (50%). Eleven of 17 patients (65%) with measurable soft tissue disease achieved a partial response. Four of 27 patients (15%) with osseous metastases demonstrated improvement on bone scan.. Intravenous EMP was administered safely with paclitaxel and carboplatin and produced clinical outcomes similar to the outcomes achieved with the TEC regimen. Substitution of i.v. EMP for the oral formulation was found to result in a lower incidence of severe nausea but increased hepatic toxicity.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carboplatin; Disease-Free Survival; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

The objective of the current study was to evaluate the efficacy and toxicity of weekly paclitaxel, oral etoposide, and estramustine phosphate in the treatment of patients with advanced, hormone-refractory prostate carcinoma.. Patients with hormone-refractory prostate carcinoma who had received no more than one previous chemotherapy regimen were eligible for this trial. Forty-two patients were treated between February 1998 and March 2000. Toxicity was excessive in the first 3 patients treated (Grade 3-4 leukopenia, 3 patients; death due to sepsis, 1 patient); the remaining 39 patients received lower doses of etoposide and estramustine phosphate (paclitaxel 50 mg/m(2) as a 1-hour, intravenous infusion on Days 1, 8, 15; etoposide 50 mg orally twice daily on Days 1-10; and estramustine phosphate 280 mg orally 3 times daily on Days 1-10). Courses were repeated every 28 days. Patients were evaluated for objective and/or serologic response after two courses of treatment; responding patients continued treatment for six courses.. Fourteen of 40 evaluable patients (35%) had either an objective response or a serologic response to treatment. The median survival for the entire group was 9.5 months, with 1-year, 2-year, and 3-year survival rates of 38%, 12%, and 10%, respectively. Neutropenia was the most common Grade 3-4 toxicity and occurred in 38% of patients (11% of courses). Thirteen patients (33%) had severe fatigue, and 2 patients had treatment-related deaths due to sepsis.. Although the three-drug combination had activity in patients with hormone-refractory prostate carcinoma, the results did not appear any better than the results achieved with less toxic taxane/estramustine phosphate combinations. Further development of this three-drug regimen is not recommended.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Estramustine; Etoposide; Fatigue; Humans; Infusions, Intravenous; Male; Middle Aged; Neutropenia; Paclitaxel; Prostatic Neoplasms; Sepsis; Survival Analysis; Treatment Outcome

The authors determined the safety and efficacy of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor (G-CSF) support in patients with hormone-refractory prostate carcinoma.. In the current multicenter, cooperative group study, patients with advanced prostate carcinoma whose disease progressed despite androgen deprivation therapy were treated with a combination of oral estramustine(240 mg three times per day for 5 days), 70 mg/m2 of docetaxel, and carboplatin at a dose of (area under the curve) 5. G-CSF was used to minimize the neutropenia associated with this regimen. Each cycle was repeated every 21 days.. Forty patients were treated with a median of 7 cycles of therapy. Of the 34 evaluable patients with elevated pretreatment prostate-specific antigen (PSA) levels, 23 (68%) had a > or = 50% decline in PSA and 20 (59%) had a > or = 75% decline. Twenty-one patients had measurable disease, with 1 complete response (5%) and 10 partial responses (47%), for an overall measurable response rate of 52% (95% confidence interval [95% CI], 30-74%). The most common Grade 3 or Grade 4 toxicities (according to the National Cancer Institute Common Toxicity Criteria) included neutropenia in 23% of patients, thrombocytopenia in 13%, and fatigue in 13%. Febrile neutropenia occurred in 1 patient (3%). The overall median time to disease progression was 8.1 months (95% CI, 6-10 months) and the overall survival period was 19 months (95% CI, 13-26 months).. The combination of estramustine, docetaxel, and carboplatin with G-CSF support was found to have significant clinical activity with an acceptable toxicity profile in patients with progressive hormone-refractory prostate carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease Progression; Docetaxel; Estramustine; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids

The purpose of The Cancer and Leukemia Group B (CALGB) 90203 trial is to determine which of 2 treatment strategies is superior in treating men with high-risk, clinically localized adenocarcinoma of the prostate (stage T1 to T3a NX M0), defined as a predicted probability < or =60% of remaining free from disease recurrence for 5 years after surgery. Patients with a > or =10-year life expectancy will be randomized to either radical prostatectomy (RP) alone versus estramustine and docetaxel before RP. Participants will be excluded if they have received prior therapy for prostate cancer (except transurethral resection of the prostate) or are judged not to be appropriate candidates for RP. Eligible patients will be stratified according to their predicted probability of remaining free from disease recurrence at 5 years after surgery (0% to 20%, 21% to 40%, and 41% to 60%) and randomized. Neoadjuvant chemotherapy will be 6 cycles (1 cycle = 21 days) of estramustine (280 mg tid, days 1 to 5) and docetaxel (70 mg/m2 on day 2). Warfarin (2 mg/day orally) will be given for prophylaxis against deep venous thrombosis. Bilateral pelvic lymph node dissection and RP will be performed within 60 days of registration/randomization for men randomized to the surgery-alone arm. For men randomized to receive preoperative chemotherapy, the surgical procedure will be performed within 60 days of completion of chemotherapy. Patients will be monitored with history review, physical examination, and serum prostate-specific antigen (PSA) levels every 3 months for the first 3 years after surgery, every 6 months for the next 3 years, and annually thereafter. Biochemical disease recurrence will be defined as a serum PSA level >0.4 ng/mL on 2 consecutive occasions > or =3 months apart after RP. The time of biochemical failure is measured from the date of randomization to the time of the first PSA level <0.4 ng/mL that is confirmed on the second serial PSA. The primary study end point is to determine if early systemic treatment with neoadjuvant estramustine and docetaxel before RP in patients with high-risk prostate cancer will decrease 5-year recurrence rates when compared with RP alone. Secondary outcomes will include (1) the safety and tolerability of neoadjuvant estramustine and docetaxel before RP; (2) the impact of this neoadjuvant strategy on pathologic tumor stage, including lymph node and surgical margin status; (3) time to clinically apparent disease recurrence; and (4) overall sur

Topics: Adenocarcinoma; Anticoagulants; Clinical Trials, Phase III as Topic; Disease-Free Survival; Docetaxel; Estramustine; Feasibility Studies; Humans; Lymph Node Excision; Male; Multicenter Studies as Topic; Neoadjuvant Therapy; Patient Selection; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk; Taxoids; Thromboembolism; Treatment Outcome; Warfarin

Estramustine 600 mg/m2 can be administered safely with 225 mg/m2 of paclitaxel if administered as a 3-hr infusion for the treatment of hormone refractory prostate cancer. Significant anti-tumor activity has been reconfirmed despite the change in schedule of administration of the paclitaxel.. This phase I study was conducted to identify the maximum tolerated dosage of paclitaxel administered as a 3-hr infusion combined with a stable dosage of estramustine capsules daily in men with hormone refractory prostate cancer. A secondary endpoint was to assess anti-tumor efficacy in this targeted patient population.. Twenty-six male patients, all with hormone refractory prostate cancer were enrolled in this trial. Estramustine was administered at a dosage of 600 mg/m2 daily, and paclitaxel was dose-escalated in cohorts from 125 to 250 mg/m2 administered as an infusion over 3 hr every 21 days. Patients were treated until maximum response was achieved, or toxicity or progressive disease precluded further treatment. Toxicity to determine maximum tolerated dose was assessed only during the first 3-week cycle.. The maximum tolerated dose of paclitaxel on this schedule was 225 mg/m2 based on unacceptable dose-limiting fatigue observed at the next higher dosage level. Other grade 3 or 4 events included myelosuppression, left ventricular dysfunction, elevated liver function tests, deep venous thrombosis, vomiting, and development of depression. Using a response criteria of prostate specific antigen decline of > 50% persisting for a minimum of 6 weeks, eight of 26 patients responded (30.8%). Two of seven patients with documented soft-tissue disease experienced > 50% reductions in size of lesions or number of sites. The median response duration was 6 months, and the median survival time was 16 months.. The recommended phase II dose of paclitaxel is 225 mg/m2 when administered over 3 hr in combination with estramustine. This regimen has an acceptable toxicity profile, is a convenient schedule, and results in significant antitumor activity even in a heavily pre-treated population of patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Analysis

The activity of estramustine phosphate is synergistic with paclitaxel against hormone refractory prostate cancer. Moreover, the single agent activity of carboplatin has demonstrated a 17% response rate in measurable disease. Therefore, we conducted a prospective trial to establish more effective chemotherapy consisting of paclitaxel, estramustine phosphate and carboplatin for hormone refractory prostate cancer.. The study included 32 patients with hormone refractory prostate cancer. Prior chemotherapy was accepted. Patients were treated with 100 mg./m.2 paclitaxel intravenously weekly, 10 mg./kg. estramustine phosphate orally daily and carboplatin intravenously to an area under the curve of 6 on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity.. Of the 32 patients 30 were assessable for response. A median of 7 consecutive cycles was administered per patient. Ten patients had received prior cytotoxic chemotherapy. Levels of prostate specific antigen decreased by greater than 50% in 100% of patients and by greater than 90% in 56.7%. Partial response was obtained in 61.1% of measurable lesions. Consumption of medication for cancer induced pain was reduced in 89.5% of patients. Tumor volume reduction and/or antitumor therapeutic effects were exhibited in 81.0% of patients with positive biopsy. At a median followup of 48 weeks median time to progression was 48 weeks and median overall survival was 95 weeks. Two patients suffered myocardial infarction and hepatic insufficiency, respectively, and discontinued treatment during the first cycle. Major toxicities were grade 3 or 4 anemia in 59.4% of patients, leukopenia in 37.5%, thrombocytopenia in 28.1% and neuropathy in 12.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents.. Paclitaxel, estramustine phosphate and carboplatin chemotherapy was extremely effective for hormone refractory prostate cancer. Although hematological and neurotoxicity were modest, this therapy may be more manageable with lower doses.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Estramustine; Humans; Male; Middle Aged; Multivariate Analysis; Paclitaxel; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms

The efficacy of weekly high-dose paclitaxel in androgen-independent prostate carcinoma and its cytotoxic synergy with estramustine led to the evaluation of a weekly schedule of paclitaxel and estramustine in this Phase II trial.. Patients were eligible if they had metastatic prostate adenocarcinoma with objective progression or rising prostate-specific antigen (PSA) levels despite androgen deprivation therapy and antiandrogen withdrawal. Prior radiation and/or one prior chemotherapy regimen was permitted. A Zubrod performance status of 2 or less and adequate bone marrow and hepatic and renal function were required. Estramustine was administered orally at a dose of 280 mg three times daily on days 1 to 3, 8 to 10, and 15 to 17. Paclitaxel (150 mg/m2) was administered as a 1-hour intravenous infusion on days 2, 9, and 16. Therapy was repeated every 28 days (one cycle).. Twenty-eight patients were enrolled (median age 71.5 years). Fifteen patients had measurable disease (nine nodal and seven visceral) and 13 had bone-only metastases. A total of 116 cycles of therapy were delivered (median 4 cycles per patient, range 1 to 12). Nine patients required dose reduction. The predominant toxicities consisted of grade 3 neuropathy in 6 patients and grade 3 and 4 neutropenia in 4 patients, with one hospitalization for febrile neutropenia. Three patients had thrombotic manifestations: one deep venous thrombosis and two non-Q wave myocardial infarctions. Of the 28 patients, 26 were assessable for response. Of 13 patients with measurable disease, 5 demonstrated a partial response (1 in the liver and 4 in the lymph nodes), and 8 of 13 patients with bone-only metastases had a 50% or greater decrease in PSA level. Three patients had a 90% or greater decline in PSA. The overall PSA response rate was 61.53% (95% confidence interval 38.1% to 74.2%). The median time to progression was 4.64 months, and the median survival was 13 months.. The combination of weekly estramustine and paclitaxel is active in metastatic androgen-independent prostate cancer.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Analysis

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Drug Administration Schedule; Drug Combinations; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Tegafur; Uracil

To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP).. A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment.. The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2).. High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Fatigue; Humans; Hypotension; Infusions, Intravenous; Liver; Male; Middle Aged; Nausea; Pain; Prostatic Neoplasms; Thrombosis; Vomiting

Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion.. From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy.. Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen.. Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

Estramustine phosphate (EMP) and vinblastine have radiosensitizing properties and significant activity against hormone refractory prostate carcinoma. Strontium-89 is a palliative agent that acts as a selective radiation source for bone metastasis. The combination of EMP, vinblastine, and strontium-89 was developed to exploit the potential for radiosynergy. PATIENTS AND METHODS Forty-four patients at the Brown Oncology Group affiliated hospitals were treated with oral EMP 600 mg/m2 daily on Weeks 1-4 and 7-10, vinblastine 4 mg/m2 intravenously once each week on Weeks 1-4 and 7-10, and strontium-89 2.2 MBq/kg on Day 1. Courses were repeated every 12 weeks. Response assessment was based on a change in the serum prostate specific antigen (PSA) levels, correlated with change in measurable disease and bone scan appearance.. A greater than or equal to 50% decline in PSA for at least 6 weeks was observed in 21 patients (48%, 95% confidence interval, 33-62%). Median duration of response was 23 weeks (range, 6-70.8 weeks). The median survival was 13 months with 1- and 2-year survival rates of 55% and 25%, respectively. After completion of protocol therapy, a retrospective review showed that only nine patients received subsequent palliative external beam radiation after progression.. The addition of strontium-89 to the regimen of EMP and vinblastine can be delivered safely and in repeated doses, provides effective palliation, and may decrease the need for future radiation therapy. A randomized trial is necessary to quantify these effects.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Carcinoma; Combined Modality Therapy; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Strontium Radioisotopes; Treatment Outcome; Vinblastine

The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer.. Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week.. From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50-83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0-802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75-10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%).. Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Rate; Treatment Outcome; Vinblastine; Vinorelbine

To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer.. In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease.. Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed.. TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate

To evaluate the clinical usefulness of an oral combination of cyclophosphamide, uracil plus tegafur (UFT) and estramustine in the treatment of patients with hormone-refractory prostate cancer (HRPC).. Twenty-one patients were treated with oral administration of cyclophosphamide (100 mg/day), UFT (400 mg/day) and estramustine phosphate (560 mg/day). The median age of the patients was 70 years. Twelve patients had symptomatic bone metastasis, 6 had asymptomatic bone metastasis, 5 had lymph node metastasis, while 2 had only biochemical progression evaluated by prostate-specific antigen (PSA).. Twelve (57%) out of 21 patients showed a PSA decline of 50% or greater. The median response duration was 7 months (range 2-15 months). Among the 20 patients assessable for bone pain, 2 (10%) improved, 12 (60%) remained stable and 6 (30%) progressed. Among the 10 patients assessable for bone metastasis, 1 (10%) improved, 5 (50%) were stable and 4 (40%) progressed on bone scan. Among 3 patients assessable for measurable disease (lymph node metastasis), 2 (67%) showed partial response and 1 (33%) progression. Most toxicities were mild.. The combination of cyclophosphamide, UFT and estramustine is an active and well-tolerated regimen for HRPC. To evaluate the survival benefit, further randomized studies are required.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cyclophosphamide; Estramustine; Humans; Lymphatic Metastasis; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Tegafur; Treatment Outcome; Uracil; Urination

To report the results of a Phase II trial of neoadjuvant estramustine and etoposide before radical prostatectomy in patients with locally advanced disease.. Treatment consisted of three cycles of estramustine (10 mg/kg/day) and etoposide (50 mg/m(2)/day) orally on days 1 through 21, repeated every 28 days, followed by radical prostatectomy. The eligibility criteria included locally advanced prostate cancer (clinical Stage T2b/c or T3, prostate-specific antigen [PSA] level of 15 ng/mL or greater, or Gleason score of 8 or higher) without evidence of metastatic disease. The median PSA level was 14 ng/mL (range 5.3 to 50), the median Gleason score was 7 (range 6 to 9), and 44% had Stage T2b/c or T3 disease. The primary endpoint was feasibility of neoadjuvant therapy and radical prostatectomy, including drug and surgery-related toxicities. Secondary endpoints included the pre-prostatectomy PSA level, local response, pathologic outcomes, and time to PSA failure.. Eighteen patients were entered and completed all three cycles of therapy, and 16 (89%) underwent radical prostatectomy. A local response occurred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA reached undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two with deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. The median operative time was 125 minutes, the mean blood loss was 665 mL, and the mean length of stay was 2.5 nights. Five minor surgical complications occurred in 4 patients. The pathologic analysis demonstrated residual carcinoma with squamous metaplasia and androgen deprivation effect in all patients. Five patients (31%) had organ-confined disease and 9 patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively and at a median follow-up of 14 months (range 5 to 20) and without additional therapy, all 14 patients with negative lymph nodes were disease free.. This trial confirms the feasibility of radical prostatectomy with acceptable surgical morbidity after neoadjuvant therapy with estramustine and etoposide in patients with locally advanced prostate cancer. However, this regimen is associated with estramustine-induced thromboembolic toxicity. The results of the pathologic analysis suggest a higher than expected rate of organ-confined and specimen-confined disease, but little histologic evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm with other drug regimens is warranted.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Estramustine; Etoposide; Follow-Up Studies; Humans; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

There are limited data available regarding the cost of care in patients with androgen independent prostate carcinoma (AIPC), and there are no data on the impact of direct nonmedical and indirect costs (DNM/IC). This lack of data, along with the feasibility of collecting DNM/IC, was examined in patients with AIPC who took part in a randomized trial using a newly developed questionnaire, the Collection of Indirect and Nonmedical Direct Costs (COIN) form.. Patients with AIPC were randomized to one of three treatment arms: 1) strontium only (strontium 4 Mci in Week 1 and Week 12) (STRONT); 2) vinblastine 4 mg/m(2) per week for 3 weeks then 1 week off and estramustine, 10 mg/kg per day (CHEMO); or 3) a combination of treatments outlined in the arms for CHEMO and STRONT (CHEMO/STRONT). Direct medical costs were collected through the hospital billing system. DNM/IC data were obtained prospectively using the COIN form. Cost data were analyzed for a period of 6 months.. Twenty-nine patients were randomized, after which the protocol was closed because of poor accrual. The median survival of the patients was 22.3 months. The mean and median total costs for the 20 of 29 patients with complete cost information were $12,647 and $11,257 over 6 months, respectively. DNM/IC represented 11% of the total cost (range, from < 1% to 42%); in 20% of participating individuals, these costs accounted for 35-42% of total costs. Failure to collect complete cost information was due to early death, administrative difficulties, and loss to follow-up.. In this pilot project, the collection of these cost data using the COIN form was feasible and practical and was limited primarily by logistic, not form specific, issues. DNM/IC were found to be a significant proportion of total costs (up to 42%) in selected patients, and this information proved to be a useful addition to the cost analysis. Approximately 98 patients would be required to detect a 20% difference in total costs between arms in a properly powered, randomized trial. Considering the potentially significant impact on total costs, DNM/IC data should be included in future cost-analysis studies of patients with AIPC and other diseases.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Bone Neoplasms; Cost of Illness; Drug Costs; Estramustine; Health Care Costs; Health Expenditures; Hospital Costs; Humans; Male; Middle Aged; Pain; Pilot Projects; Prostatic Neoplasms; Strontium; Vinblastine

The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting.. Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy.. Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values.. This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Etoposide; Humans; Male; Middle Aged; Nausea; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Venous Thrombosis

To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC).. Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy.. Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease.. This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Hydrocortisone; Male; Paclitaxel; Prostatic Neoplasms; Survival Rate; Taxoids

The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma.. Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13.. Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease.. The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Dose-Response Relationship, Drug; Estramustine; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Prostatic Neoplasms; Treatment Outcome

A Phase II study was initiated to evaluate the effectiveness of an oral regimen of etoposide and estramustine in patients with early recurrent prostate carcinoma.. Patients with early recurrent prostate carcinoma as indicated by an increasing prostate specific antigen (PSA) level and without any evidence of metastatic disease were treated with oral etoposide 50 mg/m2/day and estramustine 15 mg/kg/day in divided doses for 21 days, followed by a 7-day rest period. Patients received a maximum of four cycles.. Eighteen patients were entered in this study. The median serum PSA was 3.1 (range, 0.3-30.3) at the time of entry into the trial. Sixteen patients were assessable for response. Serum PSA declined to undetectable levels in 13 patients with 2 additional patients meeting the criteria for partial response; the median duration of response was 8.5 months (range, 1-18 months). Most patients developed gastrointestinal, cardiac, or hematologic complications. Grade 3 toxicities included neutropenia (one patient), deep venous thrombosis (three patients), and chest pain (one patient). One patient developed acute myelogenous leukemia (French-American-British, acute myelogenous leukemia M5) 23 months after initiating the chemotherapy.. The combination of oral etoposide and oral estramustine resulted in a high rate but only a short duration of response in patients with early recurrent prostate carcinoma. The regimen was poorly tolerated, and the toxicity was significant. This regimen should not be considered standard therapy for the treatment of early recurrent prostate carcinoma, but further exploration of treatment in this setting is warranted.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Disease-Free Survival; Estramustine; Etoposide; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

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 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.. 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).. 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

To exploit the favorable dose intensity and safety profile of weekly paclitaxel, we conducted a Phase I trial of paclitaxel by 3-hour infusion in combination with estramustine phosphate (EM) in men with hormone-refractory prostate cancer (HRPC). The antimicrotubule drug combination of paclitaxel by 96-hour infusion plus EM is active in HRPC.. Twenty-four patients with metastatic HRPC and progressive tumor after antiandrogen withdrawal were enrolled in this study. Oral EM was taken at a dose of 600 mg/m(2) daily for the initial 21 patients and on a reduced schedule of 280 mg twice daily for the final 3 patients. Paclitaxel was escalated from 60 to 118 mg/m(2).. The major toxicities were gastrointestinal and thromboembolic complications related to daily oral dosing of EM. Of the first 21 patients, one third (n = 7) discontinued therapy within 4 weeks because of protracted nausea and/or thrombotic complications. Dose-limiting toxicities at 118 mg/m(2) paclitaxel were fatigue and hepatotoxicity. Of 13 patients with measurable soft-tissue lesions, 6 had objective partial regressions, and 9 (37.5%) of 24 patients (95% confidence interval 19.1% to 59.1%) with elevated prostate-specific antigen levels had a 50% or greater decline of at least 4 weeks' duration.. Weekly paclitaxel at doses of 60 to 107 mg/m(2) were feasible in combination with oral EM, but daily oral EM produced unacceptable toxicity. On the basis of these results, a Phase II trial of weekly paclitaxel with the reduced dose and schedule of EM was initiated by the Eastern Cooperative Oncology Group to assess further the benefits and risks of this treatment in men with metastatic HRPC.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Anaphylaxis; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Edema; Estramustine; Gonadotropin-Releasing Hormone; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Paclitaxel; Prostatic Neoplasms; Thrombophlebitis; Treatment Outcome

The combination of docetaxel and estramustine has exhibited synergistic activity both in prostate cancer cell lines and in patients with hormone-refractory prostate cancer (HRPC). Based on these promising preclinical and phase I/II data, we conducted a study of weekly docetaxel and estramustine in patients with metastatic HRPC and a poor performance status. A total of 30 patients received (1) a 3-day course of oral estramustine during weeks 1 and 2 of each 3-week cycle plus (2) docetaxel, 35 mg/m(2) intravenously on day 2 of weeks 1 and 2. The median number of cycles per patient was 5, ranging from 1 to 22. The median patient age was 74 years (range, 61 to 90 years), and the median baseline Karnofsky performance status was 60% (range, 50% to 80%). Twenty-three patients (76%) had a > or =50% decrease in serum prostate-specific antigen (PSA); 17 (56%) of these patients had a > or =75% decrease in PSA. Pain scores and performance status likewise improved in 70% of patients. Three complete responses and four partial responses were observed among 12 patients with measurable disease. Toxicities were primarily nonhematologic in nature, with the most common being grade 1 through 3 nausea, asthenia, diarrhea, and edema. Given the activity and tolerability of weekly docetaxel and estramustine in this study, this regimen appears to be more suitable than previously studied docetaxel/estramustine administration schedules for treating metastatic HRPC in elderly patients with a poor performance status.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Analysis; Taxoids

Over the past 10 years, men with prostate cancer have received earlier diagnoses and are undergoing prostatectomy and/or radiation therapy with curative intent; however, many men have increasing prostate-specific antigen (PSA) levels without evidence of local progression or metastatic disease during the first 2 years after definitive local therapy. Optimal treatment of men with PSA-only recurrent prostate cancer has not been established. This ongoing phase II trial is evaluating docetaxel (70 mg/m(2) administered intravenously over 1 hour on day 2 every 21 days for four cycles) and estramustine (10 mg/kg/d orally on days 1 to 5 every 21 days for four cycles) followed by bicalutamide and goserelin acetate in men with increasing PSA levels after prostatectomy and/or radiation therapy. Patients received pretreatment with dexamethasone, and after the third patient enrolled, patients received warfarin for prophylaxis against thrombosis. Colony-stimulating factor support was allowed. In preliminary results, 11 of 15 patients completed protocol chemotherapy; 12 of 15 patients achieved complete response (ie, normalization of PSA) after four cycles of chemotherapy. In addition, testosterone levels were reduced to the castrate range in all patients after chemotherapy. The regimen was generally well tolerated, and toxicities were mostly hematologic, with grade (3/4) neutropenia reported in approximately half of patients. Preliminary results of this phase II trial are encouraging, and enrollment is ongoing.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

The incidence of human epidermal growth factor receptor 2 (HER2) protein overexpression and its prognostic value are not well characterized in patients with prostate cancer. A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC). HER2 positivity was not required because safety was the primary endpoint. Patients received oral estramustine 280 mg three times daily (days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2 mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease progressed or toxicity became unacceptable. This regimen was well tolerated among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of administered cycles. There were two episodes of febrile neutropenia and two thrombembolic events. Of the 13 patients evaluable for prostate-specific antigen (PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two (33%) of six patients with measurable disease had objective responses, and one complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab appears to be a safe combination when used in the treatment of metastatic AIPC. The response data are too preliminary for speculation about the relative benefits of this 3-drug regimen compared with the combination of only docetaxel and estramustine in this clinical setting.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Genes, erbB-2; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Taxoids; Trastuzumab

Twenty-two institutes have organized Keio University Prostate Cancer Study Group to study clinical efficacy and safety of Leuprolide acetate (Leuplin) for the treatment of advanced prostate cancer (clinical stage D1 and D2). Cotreatment of Leuplin and Estramustine phosphate disodium (Estracyt) has been performed to investigate its clinical efficacy.. One hundred and two cases of advanced prostate cancer were treated either with Leuplin alone (group I), Leuplin and Estracyt (group II) or Estracyt alone (group III). After 12 weeks treatment, clinical effects against subjective symptoms (pain, voiding difficulty, performance status and body weight), serum testosterone level, tumor size and serum PSA level were examined to investigate short-term effect of each treatment. The treatment had been continued for 24 months and the treatment effects including progression free survival and overall survival were analyzed.. Clinical efficacy after 12 weeks treatment were examined among 97 cases (group I; 35 cases, group II; 36 cases, group III; 26 cases). The background of those patients in each group was statistically equal. Treatment effects against subjective symptoms and serum testosterone level statistically revealed no significant difference among 3 groups. Treatment effects against primary tumor, bone metastatic lesion, lymphnode metastatic lesion and serum PSA level were investigated and anti-tumor effect was characterized by total efficacy rate (complete remission rate plus partial remission rate) of each treatment group. Treatment efficacy rates for each lesion and PSA demonstrated no statistical difference among 3 treatment groups. Total efficacy rate of group I, II and III were 88.2%, 84.0% and 78.3%, respectively, which statistically revealed no significant difference. Total efficacy rate of each group after completing 24 months treatment was; group I 80.0%, group II 55.6% and group III 83.3%, which statistically showed no significant difference among 3 treatment groups. The median day for progression free survival of group I, II and III were 661, 731 and 517, respectively. The overall survival rate of group I, II and III after completing 24 months treatment were 77.5%, 83.0% and 72.4%, respectively. Both progression free survival rates and overall survival rates revealed no significant difference among 3 groups. Side effects during 24 months treatment were seen in 8.6% of group I, 47.2% of group II and 26.9% of group III, and these occurrence rates were significantly different among the groups (p = 0.0013).. Although number of the cases had not been able to continue the treatment for their side effects, the statistical characterization demonstrated that cotreatment of Leuplin and Estracyt had no greater treatment effect than monotreatment of each drug.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer.. A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given.. None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378).. Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Dexamethasone; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

We assessed the feasibility and efficacy of integrating chemotherapy and androgen ablation with radical prostatectomy in patients with locally advanced prostate cancer. The neoadjuvant approach was adopted because it allows an in situ assessment of antitumoral activity.. Thirty-three patients were enrolled who met the clinical criteria of stage T1-2, Gleason score of >/= 8 or T2b-T2c, Gleason score of 7 and prostate-specific antigen (PSA) level greater than 10 ng/mL (n = 15), or clinical stage T3 (n = 18). Therapy consisted of 12 weeks of ketoconazole and doxorubicin alternating with vinblastine, estramustine, and androgen ablation followed by prostatectomy. The ability of neoadjuvant chemotherapy and hormonal therapy to induce a 20% rate of pT0 in the prostatectomy specimen as well as surgical feasibility were assessed.. Chemotherapy complications were comparable to those reported with this regimen previously. No major intraoperative complications occurred. Postoperative complications occurred in 10 (33%) of 30 patients. One patient died at home after discharge (postoperative day 17; no autopsy was performed). Ten (33%) of the 30 patients had organ-confined disease, and 20 (70%) of 30 had extraprostatic extension; 11 (37%) of the 30 had positive lymph nodes. Only five (17%) of 30 exhibited positive surgical margins. All patients achieved an undetectable PSA level postoperatively, and 20 of the surviving 29 patients remain without disease recurrence with a median follow-up of 13 months (range, 9 to 18 months).. Chemotherapy and androgen ablation followed by radical prostatectomy was feasible in patients with locally advanced prostate cancer. Although the goal of achieving a 20% rate for pT0 status was not achieved, we believe this type of integrated therapeutic strategy should be investigated further for its ability to alter the course of regionally advanced prostate cancer.

Topics: Adult; Aged; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Doxorubicin; Estramustine; Feasibility Studies; Follow-Up Studies; Humans; Ketoconazole; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Ultrasonography; Vinblastine

Nearly all cases of metastatic prostate carcinoma progress, after hormonal ablation, to a hormone refractory status. To the authors' knowledge no standard chemotherapy for patients with hormone refractory prostate carcinoma (HRPC) exists. In a prospective study, the efficacy and toxicity of an oral combination of estramustine and cyclophosphamide were evaluated.. Between March 1996 and April 1998, 32 consecutive patients (median age 74 years; range, 53-84 years) with metastatic HRPC were treated with oral estramustine (10 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 14 days every 28 days. Inclusion criteria were previous complete androgen blockade, antiandrogen withdrawal evaluation, and clinical or biochemical disease progression. Response assessment was based on a decrease > or =50% in the prostate specific antigen (PSA) level associated with improvement (or no worsening) in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and relief of bone pain (if present).. All patients were evaluable for efficacy and toxicity. PSA levels decreased by at least 50% in 14 patients (43.7%) (95% confidence interval, 26.5-60.9), remained stable in 12 patients (37.5%), and rose in 6 patients (18.8%). ECOG PS was 0 in 5 of 14 patients, improved from 1 to 0 in 7 patients, and remained unchanged in 2 patients. Bone pain, present in 8 of 14 patients, disappeared in 7 and was partially relieved in 1. The median duration of response was 30 weeks (range, 8-88+ weeks). An objective partial response was obtained in two cases. Toxicity was mild and mainly gastrointestinal (World Health Organization [WHO] Grade 1). No cases of WHO Grade 3-4 hematologic toxicity occurred.. The oral combination of estramustine and cyclophosphamide appears to be safe and effective in patients with HRPC. In responding patients its use shows a clinical benefit in terms of improvement of ECOG PS and pain control.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Chi-Square Distribution; Confidence Intervals; Cyclophosphamide; Disease Progression; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Pain; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Safety

To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer.. Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score > or =8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months).. Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed.. Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Estramustine; Etoposide; Gastrointestinal Diseases; Humans; Injections, Intravenous; Male; Male Urogenital Diseases; Neoadjuvant Therapy; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Risk Factors; Treatment Outcome; Vinblastine; Vindesine

The purpose of the present study was to evaluate the antitumor activity and toxicity of oral estramustine phosphate (EMP) in combination with oral etoposide in patients with hormone-refractory prostate cancer.. Twenty patients with adenocarcinoma of the prostate that progressed after one or more regimens of androgen-deprivation therapy were enrolled into this trial. Oral EMP was administered twice daily, for a total daily dose of 560 mg, and oral etoposide (50 mg/bodyweight per day) was given on days 1-21 and was stopped on days 22-35. Treatment was continued until evidence of disease progression appeared or two consecutive rises in the prostate-specific antigen (PSA) value were observed.. Ten of 20 patients showed a decrease of 50% or greater in the PSA value from initially elevated PSA levels after therapy. The median progression-free duration and 2 year cause-specific survival rate of these 10 patients were 208 days (range 71-693 days) and 67.5%, respectively. There were no significant differences in age, pretreatment PSA value, duration from initial treatment to relapse, prior therapy or survival between patients who had a decrease of 50% or greater in PSA values after this combination therapy and those who did not. The main toxicities (> or =grade 2) were anemia, leukocytopenia, thrombocytopenia, gastrointestinal and hepatic disorders, which occurred in 40, 15, 10, 15 and 5% of patients, respectively.. The combination of oral EMP and etoposide is considered to be a well-tolerated outpatient treatment regimen for patients with hormone-refractory prostate cancer and the therapy deserves further investigation.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Middle Aged; Prostatic Neoplasms

Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer.. From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2).. A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months.. The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate; Vinblastine

We evaluated the efficacy of the combination of estramustine phosphate and vinblastine in 13 patients with hormone-refractory prostate cancer. Of 12 patients with an elevated prostate specific antigen (PSA) level at the start of treatment, 5 (42%) had a greater than 50% decrease in PSA level. In a patient with cervical and mediastinal lymph node metastases, about a 57% decrease was observed in bidimensional measurement. Side effects were mild and manageable. The survival rate was not significantly different between patients who showed a greater than 50% decrease in PSA levels or regression of lymph node metastases versus the other patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Estramustine; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Vinblastine

The aim of this study was to determine the safety and activity of vinorelbine in combination with estramustine in men with androgen-independent metastatic prostate cancer.. Twenty-five men with androgen-independent metastatic prostate cancer were treated with the combination of vinorelbine and estramustine. Vinorelbine 25 mg/m(2) was administered by intravenous bolus on Days 1 and 8. Estramustine 140 mg was administered three times a day by mouth on Days 1 through 14. Treatment was repeated every 21 days.. A total of 132 cycles of treatment were administered. The median number of cycles per patient was 5 (range: 1-16). Mild Grade 1 or 2 gastrointestinal toxicity and fatigue were the most common adverse effects. Hematologic toxicity was minimal. Treatment resulted in a sustained > 50% decrease in serum prostate-specific antigen (PSA) in 6 of 25 patients (24% of patients; 95% confidence interval (CI) 9-45%). The median duration of PSA response was 10 weeks (range: 3-39 weeks). Of the five men with bidimensionally measurable disease, none achieved a complete or partial response. There were no documented improvements in post-treatment bone scans. Median overall survival time was 14.1 months.. The combination of vinorelbine and estramustine is a well-tolerated and modestly active regimen in men with androgen-independent metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Survival Analysis; Vinblastine; Vinorelbine

Twenty-nine patients with progressive hormone-refractory metastatic adenocarcinoma of the prostate were treated with daily estramustine phosphate at 10 mg/kg, and I.V. doxorubicin 50 mg/m2 every 3 weeks. Twenty-six patients were evaluable. Four of seven patients with nonosseous measurable disease had partial responses lasting 3 to 10 months. Eleven of 19 patients with osseous metastases had stable disease or improvement on bone scan, 6 of these for 7 months or longer. Median time to progression was 20 weeks, and the median survival was 43 weeks.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Pilot Projects; Prostatic Neoplasms; Survival Analysis

To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer.. Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days.. Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a > or = 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values.. The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.

Topics: Aged; Aged, 80 and over; Androgens; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Dose-Response Relationship, Drug; Estramustine; Gastrointestinal Diseases; Hematologic Diseases; Humans; Male; Middle Aged; Paclitaxel; Pain; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids

To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials.. Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status < or = 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static; docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m2. Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks.. Five patients were entered at a docetaxel dose of 40 mg/m2, three at 60 mg/m2, six at 70 mg/m2, and three at 80 mg/m2. Only one patient had received prior chemotherapy. Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m2. The phase II dose was defined at 70 mg/m2 with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m2): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA < or = 4 ng/ml). One patient had a partial response with measurable lung and liver lesions.. EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Prognosis; Prostatic Neoplasms; Survival Rate; Taxoids; Treatment Outcome

To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC).. A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m(2) by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m(2) PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V.. Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P =.08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P <. 001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with >/= 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P <.0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P <.0001); however, grade 2 or worse nausea (26% v 7%, respectively; P =.0002) and extremity edema (22% v 8%, respectively; P =.005) were more frequent for EM-V.. Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Estramustine; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Treatment Outcome; Vinblastine

To evaluate the combination of intravenous (IV) paclitaxel, oral estramustine, and oral etoposide in patients with advanced hormone-refractory prostate cancer.. Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled onto this phase II trial. Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days, with paclitaxel 135 mg/m(2) IV over 1 hour on day 2 of each 21-day treatment cycle. Patients received a maximum of six cycles of therapy.. Thirty-seven patients were assessable for response. Twenty-two had measurable disease at baseline; response was not assessable in six of these patients. Overall response was 45% (10 of 22 patients; 95% confidence interval [CI], 24% to 68%), and response was 63% (10 of 16) in assessable patients. Twenty-six patients had a > or = 50% decrease from their baseline prostate-specific antigen levels during therapy, for a response rate of 65% (95% CI, 48% to 79%) by this criterion. Median duration of response was 3.2 months, with an estimated median survival of 12.8 months. Major toxicities of therapy were leukopenia (eight patients had > or = grade 4 leukopenia) and anemia. Hematologic toxicity seemed to be associated with liver metastases. Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) showed no significant change in quality of life (QOL) as a result of therapy.. The combination of IV paclitaxel, oral estramustine, and oral etoposide is active in patients with advanced prostate cancer. The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; Estramustine; Etoposide; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Quality of Life; Soft Tissue Neoplasms; Survival Rate; Treatment Outcome

Evaluation of the combined regimen of estramustine and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) in men with hormone-refractory prostate cancer is in its early stages. While this combination is promising in terms of efficacy, adverse events associated with estramustine are a concern. Estramustine has been associated with side effects such as nausea, vomiting, edema, and serious vascular events. Reported here are the results of phase I and phase II trials in which 280 mg estramustine was given three times daily on days I to 5 in 21-day treatment cycles with docetaxel at varying doses. Data from patients evaluable thus far support the efficacy of this combination, both in chemotherapeutically naive patients and in those who have had prior therapy. A survival benefit from this combination appears achievable from these early studies. As significant antitumor activity can be achieved with docetaxel alone, future studies need to define the minimal dose of estramustine for this combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids

Combinations of estramustine with other antimitotic agents, such as docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), are synergistic in vitro and show significant clinical activity in hormone-refractory prostate cancer (HRPC). We have studied intravenous docetaxel 70 mg/m2, oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. Of the 47 men who were enrolled, 40 are evaluable for response and/or toxicity. One patient (3%) has had a complete response and eight (20%) have had a partial response, yielding a total objective response rate of 23%. Of 39 patients with elevated pretreatment prostate-specific antigen levels who have had at least one posttreatment prostate-specific antigen measurement, 27 (69%) have had > or =50% decreases and 21 (54%) have had > or =75% decreases in prostate-specific antigen levels. Toxicity is modest but manageable. This therapy is efficacious and well tolerated in HRPC and should be compared in phase III trials with other drugs active in HRPC, such as mitoxantrone and hydrocortisone.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Hydrocortisone; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids

Preclinical data suggest that small quantities of estramustine phosphate are synergistic with taxanes and may be useful in the treatment of hormone-refractory prostate cancer. The current trial was designed to reduce the duration of exposure to estramustine phosphate, which carries with it the risk of anorexia and gastrointestinal, cardiovascular, and thromboembolic toxicity during long-term treatment. Patients with histologically confirmed adenocarcinoma of the prostate showing evidence of progressing disease 4 to 6 weeks after antiandrogen withdrawal were enrolled into the study. Patients may have received up to two prior chemotherapy regimens. Patients received estramustine phosphate 280 mg orally every 6 hours for a total of five doses (24-hour exposure), docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) 70 mg/m2 intravenously over 1 hour, coumadin 2 mg orally every day, and dexamethasone as premedication for docetaxel. Cycles were repeated every 21 days, up to a maximum of 6. Of the 18 evaluable patients, seven showed more than 50% declines in prostate-specific antigen for a duration > or =4 weeks; two of eight patients had soft tissue partial responses. Nine of 11 had improvement in pain and/or urinary symptoms. In a total of 98 cycles, grade 3 toxicities observed included leukopenia (N = 7), neutropenia (N = 6), fatigue (N = 13), headache (N = 1), local skin reactions after extravasation (N = 2), nail changes (N = 1), diarrhea (N = 2), and hyperglycemia (N = 3); grade 4 toxicities included neutropenia/fever requiring admission (N = 2), leukopenia (N = 2), and neutropenia (N = 6). No thromboembolic complications were seen. All toxicities were reversible within 1 week after occurrence. Thus, preliminary evidence suggests that in this heavily pretreated patient population 1-day treatment with an estramustine/docetaxel combination is active and has acceptable toxicity.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Taxoids

Prostate-specific antigen (PSA) has been used as a marker of advanced prostate cancer but remains controversial. To evaluate PSA as a predictor of survival, we analyzed data from sequential phase II trials of estramustine and etoposide.. A landmark analysis that used data from 62 men with PSA levels at baseline and 8 weeks was conducted. The best PSA measure (of six evaluated) was incorporated into a multiple regression model with performance status (PS); relative change in PSA level; and pretreatment PSA, alkaline phosphatase, and hemoglobin values.. A decrease in PSA of 50% or greater at 8 weeks was associated with a significantly increased survival (P=.0005, two-sided log-rank test). Median survival from the landmark was 91 weeks in patients with a 50% or greater decrease at 8 weeks versus 38 weeks in those without this decrease. Modeling showed that PS, pretreatment hemoglobin level, and relative change in PSA level were significant prognostic factors, with a significant interaction between PS and pretreatment hemoglobin level. In the final model, a relative change in PSA level at 8 weeks of less than 50% had an adjusted relative risk of 2.20 (95% confidence interval, 1.21 to 4.00). A decrease in PSA level of 50% or greater at any time during therapy was associated with a response in measurable disease (P=.0369, two-sided Fisher's exact test).. The PSA value after 8 weeks of this cytotoxic regimen does predict survival. A decrease in PSA level is associated with both survival and response in soft tissue lesions and should be incorporated into the response criteria and reporting of trials of cytotoxic agents in prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Hemoglobins; Humans; Male; Middle Aged; Multivariate Analysis; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Regression Analysis; Survival Rate

The antiemetic effect of prednisolone on nausea/vomiting was investigated in 67 patients with advanced prostatic cancer and a performance status of < or = 2. The study was a double-blind, placebo-controlled, randomized trial with a parallel group design. The objective was to compare the incidence and severity of nausea/vomiting between the two groups. Prednisolone or placebo was given twice daily for 3 weeks with the dose decreased during the third week from 15 mg/day to 10 mg for 3 days and finally to 5 mg/day during the last 4 days. EMP was given as two 140 mg capsules daily for 3 days at the beginning, then as four capsules for 4 days followed by six capsules for 21 days. Areas under curves (AUCs) for nausea and for nausea/vomiting scores were calculated based on the patient's diary notes: nausea (0-3), vomiting (0-6), nausea/vomiting (0-9). Control of emesis in terms of complete, moderate or poor control was registered. Pretreatment characteristics were evenly balanced. The results indicated that no statistical differences between the two groups of patients were present in AUCs for weeks 1-3 or weeks 1-4. We conclude that it was not possible to demonstrate a significant antiemetic efficacy of prednisolone. However, in all but one case the patients in the prednisolone group could be treated for at least 3 weeks without any major incidents of nausea/vomiting.

Topics: Aged; Antiemetics; Antineoplastic Agents, Alkylating; Area Under Curve; Double-Blind Method; Estramustine; Humans; Male; Nausea; Prednisolone; Prostatic Neoplasms; Treatment Outcome; Vomiting

The Genito-Urinary Tract Cancer Cooperative Group (GU Group) is one of the 18 European Organization for Research and Treatment of Cancer (EORTC) cooperative groups. It was established as a nonprofit organization in 1976 with the aim of conducting phase II and phase III clinical trials. Its membership includes urologists, oncologists, radiotherapists, and endocrinologists that work in close collaboration with its five data managers and one statistician in the EORTC Data Center. Eight subcommittees meet independently to plan and to monitor urological trials and to design programs on quality of life and quality control. In the past 20 years, 3,500 prostate cancer patients have been recruited in 16 phase III trials in untreated and advanced disease and in seven phase II trials in hormone-refractory, metastatic disease. This vast experience led the EORTC GU Group to be involved in the development of response and progression criteria, as well as the validation of prognostic factors, quality of life questionnaires, and basic expertise on the design and analysis of prostate cancer trials, including the meta-analysis of the trials with maximal androgen blockade. The conclusions drawn out of this large pool of experience show the complexity of the clinical research questions. Global collaboration and megatrials with the development of surrogate endpoints and the emphasis on quality of life may prove to be as important as the sacred overall survival endpoint.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Castration; Cyproterone Acetate; Diethylstilbestrol; Doxorubicin; Epirubicin; Estramustine; Flutamide; Humans; Imidazoles; Male; Medroxyprogesterone Acetate; Methotrexate; Mitomycin; Neoplasms, Hormone-Dependent; Procarbazine; Prostatic Neoplasms; Vindesine

The purpose of this study was to evaluate the antitumor activity of vinorelbine and oral estramustine phosphate in patients with metastatic, hormone-refractory prostate cancer. We evaluated the activity of this association using the following schedule: estramustine phosphate 600 mg/m2/day orally days 1-42 and vinorelbine 25 mg/m1 days 1, 8, 22, 29 cycles repeated every 56 days. Twenty-five patients were included in the study, 24 being evaluable for response and 25 for toxicity. Out of 5 patients with measurable disease, none had an objective response. Of the 24 assessable patients with bone metastases, 9 patients had a > or = 65% decline in pretreatment prostate-specific antigen (PSA) level, stable disease was observed in 10 and 5 patients progressed. Toxicities were minimal. Anemia was observed in 5 patients, alopecia in 4 and nausea and vomiting was observed in 6 patients. Anorexia and weight loss of more than 10% were observed in 2 patients. This combination is active and well tolerated in hormone-resistant prostate cancer. These results support the therapeutic strategy of combining agents that impair microtubule function.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate; Vinblastine; Vinorelbine

Thirty-one patients with progressive metastatic prostate cancer refractory to first- or second-line hormonal therapy were treated with a combination of daily oral estramustine phosphate (600 mg) and weekly intravenous doxorubicin (20 mg/m2). Eighteen (58%) patients demonstrated a biologic response with a 50% or more serum prostate-specific antigen decline. The median duration of biologic response was three months. Five (45%) of the 11 patients with measurable lesions achieved a partial response in liver or retroperitoneal lymph nodes. The median duration of these objective responses was four months. Of 22 patients who required analgesics at the onset of the study, six (27%) achieved a significant reduction of pain. The combination of doxorubicin and estramustine phosphate was tolerated on an outpatient schedule. The occurrence of severe toxicities required suspension of therapy in six patients. At the end of the observation time, all patients but one had died, 29 of progressive prostatic cancer and one of toxicity. The median survival time from the onset of chemotherapy was 12 months. The administration of weekly doxorubicin with phosphate estramustine appears to be a safe combination for those patients with hormone-resistant prostate cancer who require chemotherapy. The benefit of chemotherapy should be investigated using relevant quality-of-life criteria in future trials.

Topics: Adult; Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Analysis

We compared the effect of 560 mg. estramustine phosphate daily to placebo as a supplement to standard palliative therapy in patients with progressive disease after bilateral orchiectomy as first line therapy for metastatic prostate cancer.. In a double-blind multicenter study 131 patients with progressing metastatic hormone refractory prostate cancer were randomized to receive 280 mg. estramustine phosphate 2 times daily versus placebo. End points were clinical progression and death. Adverse events, decrease in prostate specific antigen (PSA) and subjective response were also assessed.. Adverse events were common in both groups but breast tenderness/gynecomastia and diarrhea were more frequent among patients in the estramustine phosphate group. Subjective responses were few (9 of 50 estramustine phosphate and 4 of 57 placebo cases, p = 0.15). Median observation time for survival was 43 months and 124 patients died. Median time to subjective progression and median overall survival did not differ significantly between the 2 groups at 4.6 and 9.4 months in the estramustine phosphate group versus 5.0 and 6.1 months in the placebo group. Of 61 patients in the estramustine phosphate group 29 achieved a reduction in PSA of more than 25% at 1 month of followup compared to only 3 of 68 receiving placebo. A decrease in PSA after 1 month correlated significantly with survival.. Although this study did not prove estramustine phosphate to be superior to placebo in terms of protocol end points, it generates the hypothesis that prolonged survival may be achieved with estramustine phosphate treatment in a subgroup of patients and that this may be predicted by a decrease in PSA after 1 month of therapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Double-Blind Method; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Orchiectomy; Postoperative Care; Prostatic Neoplasms; Survival Rate

Based on the theory that hormone-resistant cells are present in all metastatic patients, early administration of chemotherapy appears to be logical and its use is supported by experimental studies. Therefore, trials with combined hormonal and cytotoxic treatment as primary therapy should be conducted. In the present trial, the efficacy and tolerance of estramustine phosphate (EMP) as a chemotherapeutic agent in addition to hormonal treatment (orchiectomy) was studied in patients with metastatic and nonmetastatic prostate cancer not previously treated. EMP was chosen because it produces few serious adverse reactions and no cumulative toxicity.. Four hundred nineteen patients were included in a 1.5-year period starting in January 1989. Patients with locally advanced prostate cancer or with bone metastases were randomized to orchiectomy (O) or orchiectomy followed by EMP (O + E), given until progression.. Analysis of the total group showed no significant difference in time to progression between the treatment groups. Because the course of the disease is different in patients with either T4 tumor only or with lymph node metastases only (M0) as compared with patients with bone metastases (M1) and because the number of progressions in the M0 patients was low, corresponding analyses were performed for these subgroups as well. In the M1 patients, there was a tendency for a longer time to progression in the O + E group than in the O group, but there was no indication of a difference between the groups with regard to survival. In the M0 patients, there was no indication of any difference in results between the treatments. Multivariate analysis of prognostic factors showed pain, alkaline phosphatase, metastasis status, and tumor stage to be significant factors. There was a relation between age and drug treatment in that a significant beneficial effect of EMP in terms of prolonged progression-free interval as well as survival was evident in younger patients (aged less than 73 years) with metastatic disease. Tumor stage was also of importance for the drug effect; T0 to T3 patients who received EMP survived longer than those who were treated with orchiectomy only. The most common adverse reaction was nausea in the O + E group, which led to discontinuation of the drug in 7 patients. Cardiovascular problems are not uncommon in this age group, and there was a higher incidence of cardiovascular events, predominantly cardiac failure, in the O + E group, leading to treatment interruption in 16 patients.. Our results indicate that future studies of hormono/chemotherapy should focus on younger patients with bone metastases.

Topics: Aged; Aged, 80 and over; Bone Neoplasms; Combined Modality Therapy; Disease Progression; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Prognosis; Prostatic Neoplasms; Survival Rate

Between 1984 and 1989, 197 patients with T1-4, NX, M1, G2-3 or G3 prostate cancer were randomized to treatment with 560 mg estramustine phosphate (EMP, Estracyt, Emcyt) or 3 mg diethylstilbestrol (DES) per day in a double blind study with stratification on presence or absence of cancer pain at start. A total of 194 patients were evaluated for efficacy of therapy. Time to progression (p = 0.054), to treatment failure (p = 0.036), cancer-specific survival (p = 0.068) as well as overall survival (p = 0.021) were longer in the DES group. There were more patients with prognostic parameters indicating bad prognosis in the EMP group. This trial was designed to study whether EMP had better effect than DES as the primary treatment of high-grade, disseminated prostate cancer. The results did not confirm this hypothesis. On the contrary, treatment with DES had relatively good effect on this very aggressive form of prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Biopsy, Needle; Cause of Death; Diethylstilbestrol; Double-Blind Method; Estramustine; Follow-Up Studies; Humans; Male; Neoplasm Staging; Palliative Care; Prostate; Prostatic Neoplasms; Survival Rate

Twenty-four assessable patients with hormone-resistant prostate cancer (HRPC) were to receive daily doses of oral estramustine phosphate (EMP), 10 mg kg(-1), and intravenous epirubicin (EPR) infusions, 100 mg m(-2), every third week up to a cumulative dose of 500 mg m(-2). Biochemical response [> or = 50% reduction in pretreatment serum prostate-specific antigen (PSA) after three cycles of > or = 3 weeks' duration] was demonstrated in 13 of 24 patients included (54%). No objective response (WHO criteria) was observed, although seven of nine evaluable patients achieved a > or = 50% serum PSA reduction. Subjective improvement (pain score, performance status) occurred in 7 of 24 patients, whereas nine patients progressed subjectively. There was no correlation between subjective and biochemical response. Biochemical progression (> or = 50% increase of nadir PSA) occurred after a median of 12 weeks. All but two patients were alive after a median follow-up time of 8.7 months for surviving patients (range 3.3-13.2). Eight patients experienced grade 3/4 leucopenia, with no indication of cumulative myelosuppression. Cardiovascular toxicity was experienced by four patients. Two patients developed angioedema twice, in one patient requiring hospitalization at the intensive ward. Based on this limited series, the combination of EPR and EMP in patients with HRPC is tolerable and appears to be effective in terms of significant PSA reduction. The results warrant further investigations of the two drugs and, in particular, of the clinical significance of > or = 50% PSA decrease in patients with HRPC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Epirubicin; Estramustine; Gastrointestinal Diseases; Gonadotropin-Releasing Hormone; Heart Diseases; Humans; Leukopenia; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Thrombocytopenia

Hormone-refractory prostate cancer is characterized by a low response rate following second-line therapy. Encouraging results have been reported in Phase II studies with estramustine associated with vinblastine or etoposide. Vinorelbine is a new semisynthetic vinca alkaloid that has demonstrated activity in prostate cancer. We therefore evaluated the activity of the following schedule: estramustine, 400 mg/m2 orally days 1-42; etoposide, 50 mg/m2 orally days 1-14; and 28-42; vinorelbine, 20 mg/m2 days 1, 8, 28, and 35; cycles being repeated every 8 weeks. Twenty-five patients have been included and are assessable for response and side effects. Patient characteristics were as follows: median age, 71 years (range 55-81); ECOG performance status 0-2; nonosseous disease, 3 cases; bone metastases, 23 cases. Sixty-two cycles have been delivered. Two patients with measurable disease and six patients with bone disease had a partial remission for an overall response rate of 32% (95% confidence interval 15-53%). Seven patients had stabilization of disease and 10 had progression of disease. Median duration of response was 3 months (range 2-5). Prostate-specific antigen in 14 patients (56%) decreased from baseline by at least 50%. Toxicity was manageable. Neutropenia was mild, with only three cases of grade III-IV toxicity. Two patients had severe anemia. The results of this study indicate that the schedule is active and well tolerated in hormone-refractory prostate cancer patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Drug Administration Schedule; Estramustine; Etoposide; Humans; Male; Middle Aged; Neutropenia; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Vinblastine; Vinorelbine

To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC).. Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously.. Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks.. The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Estramustine; Humans; Infusions, Intravenous; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Survival Analysis; Treatment Outcome

We previously demonstrated that the combination of oral estramustine (15 mg/kg/day) and oral etoposide (50 mg/m2/day) is effective first-line therapy for the treatment of hormone refractory prostate cancer. We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment.. Estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up.. Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival.. We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.

Topics: Administration, Oral; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Prostatic Neoplasms; Survival Rate

We previously developed a novel and effective therapy for hormone-refractory prostate cancer using the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced, hormone-refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays, and then demonstrated their effectiveness in a phase I-II clinical trial, where they were shown to produce a 50% complete and partial response rate in patients with bidimensionally measurable disease. In preclinical studies, we had demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Expanding these investigations, we determined that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule inhibitor, interacts with estramustine and etoposide, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cells. These studies led us to conduct a phase II clinical trial of paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer. Preliminary results demonstrate that this is an active regimen, with 57% of patients demonstrating a response to therapy as measured by a decrease in pretreatment prostate-specific antigen levels of greater than 50%.

Topics: Adenocarcinoma; Administration, Oral; Alopecia; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; DNA Replication; DNA, Neoplasm; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Estramustine; Etoposide; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Microtubules; Nuclear Matrix; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Remission Induction; Tumor Cells, Cultured

Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC).. Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression.. Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival.. We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.

Topics: Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Neoplasms; Combined Modality Therapy; Confidence Intervals; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Estramustine; Humans; Hydrocortisone; Ketoconazole; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radionuclide Imaging; Survival Analysis; Vinblastine

In 1978 the National Prostate Cancer Project launched two protocols evaluating adjuvant therapy following surgery (Protocol 900) or irradiation (Protocol 1,000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy. Following definitive treatment, patients were randomized to either cyclophosphamide 1 gram/m2-IV every 3 weeks for 2 years, estramustine phosphate 600 mg/m2-po daily for up to 2 years, or to observation only. Patient accession closed in 1985 and includes 184 to Protocol 900 (170 evaluable) and 253 to Protocol 1,000 (233 evaluable). Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900, 63% in Protocol 1,000. Median progression-free survival (PFS) for patients with nodal involvement in Protocol 1,000 receiving estramustine phosphate adjuvant was longer (37.3 mo) compared to cyclophosphamide (30.9 mo) and to no treatment (20.9 mo). Median PFS for patients with limited nodal disease in Protocol 1,000 was longer (39.9 mo), regardless of adjuvant, compared to extensive nodal disease (20.7 mo). However for patients with extensive nodal involvement, those receiving adjuvant estramustine phosphate experienced a significantly longer median PFS (32.8 mo) compared to adjuvant cyclophosphamide (22.7 mo) and no adjuvant (12.9 mo). We conclude that adjuvant estramustine phosphate is of benefit in prostate cancer patients with extensive pelvic node involvement receiving irradiation as definitive treatment.

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Cyclophosphamide; Estramustine; Humans; Lymphatic Metastasis; Male; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Survival Analysis

Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse.. All patients underwent staging pelvic lymph node dissection. Following definitive treatment, patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years, estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only. Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable).. Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols).. With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1).

Topics: Adenocarcinoma; Antineoplastic Agents, Alkylating; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Estramustine; Humans; Lymph Node Excision; Male; Neoplasm Recurrence, Local; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Radiotherapy, High-Energy

The effectiveness of a chemotherapy regimen including cisplatin, epirubicin, and estramustine phosphate was evaluated in a series of young patients with prostate cancer.. 28 patients with a histological diagnosis of prostatic carcinoma, age < 70 years, performance status (PS) < 2, hormone-refractory status, life expectancy > 3 months, were treated with cisplatin 60 mg/m2 i.v. and epirubicin 60 mg/m2 i.v. every 3 weeks for six cycles. Estramustine phosphate was administered at a dosage of 10 mg/kg p.o. in two divided daily doses during intravenous chemotherapy and until progression thereafter. The response was assessed after three cycles of chemotherapy, evaluating again the disease parameters. In case of partial remission or stable disease, treatment was continued for three additional cycles. The median age was 61.5 years, the median PS was 70.. 11 partial remissions, 13 patients with stable disease, and 4 progressions were noted. The response rate (only partial remissions) was 39% (95% confidence limits 21-57%). The median duration of the partial remissions) was 11 (range 6-25) months. A subjective improvement of symptoms was observed in 17 of 19 patients. Toxicity was acceptable with no deaths. The median overall survival was 15 months.. The combination studied had activity in young prostate cancer patients, and our results suggest that this subset of patients needs specifically devised chemotherapy regimens.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Epirubicin; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate; Time Factors; Treatment Outcome

Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.

Topics: Administration, Oral; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analysis of Variance; Antineoplastic Agents, Hormonal; Biological Availability; Bone Neoplasms; Carcinoma; Clodronic Acid; Drug Synergism; Drug Therapy, Combination; Estramustine; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Pain; Prostatic Neoplasms

We conducted a multicentric randomized trial to compare bilateral orchiectomy versus bilateral orchiectomy plus etoposide or estramustine phosphate as first-line therapy for advanced prostatic cancer (stage D2).. From January 1991 to December 1992 a total of 46 newly diagnosed cases (registered cases) of advanced (stage D2) prostatic cancer was randomized into 3 groups as follows; Group A: bilateral orchiectomy and 25 mg/day of etoposide every 2 weeks for 6 months. Group B: bilateral orchiectomy and 560 mg/day of estramustine phosphate for 6 months. Group C: bilateral orchiectomy alone. One of group A and one of group B were ineligible cases, so 44 were eligible. In the eligible cases, ages were ranged from 54 to 90 (mean of 71.2) years old. No significant difference of patients' characteristics was found among 3 groups and median follow-up period was 25 months. Response was evaluated based on the response criteria according to Japanese urological association. Specifically, a central pathologist who blinded to the treatment was employed for evaluating pathological response at six months.. Of the 44 eligible patients, 33 and 25 were evaluated for clinically and pathological analyses, respectively. Clinical response rates were 80% (12/15) of group A, 100% (4/4) of group B and 78.6% (11/14) of group C. No significant difference in the clinical response and survival rate was shown among the three groups. Significantly higher frequencies of side effects were noted in the grop B compared to the other two groups (p < 0.05) and cardiovascular complications were the most frequent in group B. Favorable pathological response was obtained in all of group B, but not statistically significant compared with 7/21 (33.3%) of response rate in group A and C. The pathological response was significantly correlated with the clinical one in all patients (p < 0.01). While 8 of 11 patients (73%) with pathological response grade 1, 2 and 3 achieved clinical PR (partial response) or CR (complete response), only 5 of 14 (36%) with grade 0 received PR or CR.. We conclude that low dose administration of etoposide or estramustine phosphate dose not improve clinical response and survival in a short term in castrated patients, but increases the adverse effects due to the drugs in these patients. In addition, the pathological evaluation at 6 months after treatment appears to reflect the clinical response at that time in newly diagnosed patients with advanced prostatic cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Drug Administration Schedule; Estramustine; Etoposide; Humans; Male; Orchiectomy; Prostatic Neoplasms; Survival Rate

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Fatigue; Hematologic Diseases; Hormones; Humans; Male; Nausea; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

We investigated the effect of neoadjuvant treatment before radical prostatectomy for clinically localized prostate cancer.. A total of 130 patients with stages T2b and T3 prostate cancer was randomized in a multicenter study: 62 underwent immediate radical prostatectomy and 65 received 560 mg. estramustine phosphate daily for 6 weeks preoperatively.. For clinical stage T2b tumors the neoadjuvant treatment resulted in a significant decrease in positive surgical margins compared to the nonpretreated group. This difference was not found for clinical stage T3 tumors. The impact on progression and survival still must be analyzed.. Neoadjuvant treatment can be beneficial for clinical stage T2 prostate cancer. Optimal treatment for stage T3 tumors remains controversial.

Topics: Aged; Chemotherapy, Adjuvant; Estramustine; Humans; Male; Middle Aged; Neoplasm Staging; Preoperative Care; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Recently, there has been increased interest in the application of preoperative endocrine therapy prior to radical prostatectomy for locally advanced cancer in order to enhance surgical curability and increase survival. Between 1986 and 1993, 40 patients with prostate cancer were given endocrine therapy before radical prostatectomy. Fifteen patients had stage B2 disease and 25 stage C. The median duration of preoperative endocrine therapy was 3.8 months, and all the patients subsequently underwent radical prostatectomy, pelvic lymphadenectomy and castration. There was an average 25.5% (0-71.8%) decreases in the maximal cross-sectional area of the prostate gland as determined by transrectal ultrasonography. Twenty-four of 25 patients with elevated levels of serum prostate-specific antigen (PSA) showed normal values after preoperative endocrine therapy. Evaluation of treatment-related histological effects, divided into three grades, revealed that 17 patients had pronounced, 11 moderate and 12 poor or no regression. Thirteen of the 40 patients (33%) demonstrated pathological downstaging of disease status from the diagnosis made at the initial clinical examination. After a median follow-up period of 36 months (3-100 months), 36 of the 40 patients are disease-free; two died of cancer 43 and 50 months after surgery, respectively. These results suggest that preoperative endocrine therapy may play an important role in the management of locally advanced prostatic cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Chlormadinone Acetate; Diethylstilbestrol; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Lymph Node Excision; Male; Middle Aged; Neoplasm Recurrence, Local; Preoperative Care; Prostatectomy; Prostatic Neoplasms

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Female; Humans; Male; Neoplasms; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms

The effect of a medroxyprogesterone acetate (MPA) plus epirubicin combination versus estramustine phosphate was evaluated in 149 prospectively randomized patients with hormone-resistant prostatic cancer. The estimated probability of being free from progression after 1 year was 17% for the patients treated with estramustine and 29% for the MPA-epirubicin group. There is a significant difference between the two groups regarding risk of progression (p = 0.013). However, no difference in survival was recorded (p > 0.30) with about 60% of the patients dead during the first year in both groups. Progression was highly correlated to sedimentation rate (p < 0.001) and to performance index (p = 0.002). Heart failure occurred in a substantial number of patients in both groups which must be considered before starting therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Epirubicin; Estramustine; Heart Failure; Humans; Male; Medroxyprogesterone Acetate; Prospective Studies; Prostatic Neoplasms; Recurrence

From November 1978 to July 1984, 285 men with previously untreated, localized prostate cancer were consecutively randomized in an open multicenter study. The main objective was to determine if early endocrine treatment prolongs the interval to metastasis and/or cancer related or overall survival. Patients were randomized to receive either 80 mg. polyestradiol phosphate by intramuscular injection every 4 weeks plus 50 micrograms ethinylestradiol 3 times daily or 280 mg. estramustine phosphate 2 times daily, or for surveillance only but with deferred endocrine treatment at progression to metastatic disease. From 1983 further inclusion into the polyestradiol phosphate plus ethinylestradiol group was closed because of a high frequency of cardiovascular complications and thereafter 13 patients were instead randomized to a new treatment group with 80 mg. polyestradiol phosphate only by intramuscular injection every 4 weeks. Mean age was 70 years for 228 evaluable patients: 66 in the polyestradiol phosphate plus ethinylestradiol group, 74 in the estramustine phosphate group and 88 in the deferred treatment group, respectively. Mean followup for 100 patients alive on August 31, 1993 was 144 months (range 111 to 180). During the observation period 51 patients had metastasis. There was no difference in interval to metastasis (p = 0.07) among the 3 groups, although there was a tendency for a higher probability of metastases in the deferred treatment group. A total of 128 patients (56%) died during the observation period and prostatic cancer was considered to be the cause of death in 46 (20%). There was a significant difference (p = 0.03) among the 3 groups in the probability of dying of prostatic cancer, with the highest risk in the surveillance group but we found no significant difference in overall survival. The relevance of different prognostic factors and their interaction with treatment was also evaluated. These analyses were applied to the entire patient group as well as to the different subgroups. We found that patients with moderately well differentiated cancer (stage greater than T0a) who received early treatment with estramustine phosphate had the lowest risk of metastases or death from prostatic cancer, while those with well differentiated cancer (stage greater than T0a) did best on early polyestradiol phosphate plus ethinylestradiol treatment.

Topics: Adenocarcinoma; Aged; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Follow-Up Studies; Humans; Male; Middle Aged; Prostatic Neoplasms; Risk Factors; Time Factors; Treatment Failure

During the years 1988-1991 sequential serum prostate-specific antigen (PSA) determinations were performed during systemic treatment of hormone-resistant prostate cancer. The following drugs were used: prednisone (5 mg 4 times per os daily, 8 patients); flutamide (250 mg 3 times per os daily, 13 patients); estramustine phosphate (280 mg 2-3 times per os daily, 12 patients), and epirubicin (100 mg/m2 i.v. every 3rd week, 18 patients). In 3, 3, 4 and 6 patients, respectively, a PSA reduction of > or = 50% was observed during treatment, which in 12 patients was combined with pain relief and improvement in the performance status. Though the exact mechanism of PSA reduction and its clinical significance are not completely understood, the findings suggest that hormone-resistant prostate cancer still contains hormone-sensitive tumor cells. The 4 drugs used in this study seem to be equally effective in achieving a PSA reduction of > or = 50%.

Topics: Aged; Biomarkers, Tumor; Combined Modality Therapy; Epirubicin; Estramustine; Flutamide; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy.. Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression.. Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria. Of 24 patients with disease limited to bone, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Five men (21%) demonstrated a decrease of at least 75% in pretreatment PSA levels and 14 (58%) demonstrated at least a 50% decrease; the median survival duration has not been reached in these patients. Pretreatment performance status is an important predictor of survival.. We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Estramustine; Etoposide; Follow-Up Studies; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Survival Rate

Out of 62 patients with hormone-refractory metastatic prostate cancer, 34 received rescue treatment with estramustine phosphate and 28 received non-steroidal symptomatic treatment. All patients undergoing symptomatic treatment experienced increased PSA levels while in 16 (47%) patients treated with estramustine phosphate, PSA decreased between 13-96%. In 11 cases (32.3%) the decline in PSA was higher than 50%. In 5 (14.7%) the decline was lower than 50% and in 18 cases (53%) PSA levels were increased. SCR rate was 82%, 60% and 6% respectively while OCR were 36.4%., 0% and 0% respectively. No clinical response was seen in patients undergoing symptomatic treatment. A decline in PSA levels higher than 50% 12 weeks after treatment appears to be a "good prognosis" factor related to the best clinical response rates and survival.

Topics: Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Survival Rate

Estramustine phosphate (EMP), a nor-nitrogen mustard carbamate derivative of estradiol-17 beta-phosphate, causes G2/M phase arrest in treated cells through its specific binding to microtubule associated proteins. Since cells in the G2/M phase are the most radiosensitive, cell culture experiments were performed to determine whether EMP would enhance the radiosensitivity of related human tumor cells. Based on the cell culture findings and well known pharmacokinetic data in humans, a Phase II prospective study of concomitant radiotherapy (RT) and EMP plus Velban for locally advanced carcinoma of the prostate was carried out.. Three established human tumor cells, DU-145 cells (prostate), MCF-7 cells (breast), and U-251 cells (malignant glioma), were used to determine cell survival curves with and without the drug. Flow cytometry was used to obtain the cell cycle distribution of cells that were exposed to the drug for periods of 1 day to 1 week. Patients with locally advanced prostate cancer (Stages B2, C, D1) were entered into the Phase II study. All patients received a total tumor dose of 65-70 Gy over 7 weeks. Oral EMP was administered daily and Velban was administered weekly, concomitantly during the course of RT.. Radiosensitization was dependent on the exposure time and the drug concentration prior to radiation. No radiosensitization was obtained when cells were exposed to the drug after irradiation. The enhancement ratios varied from 1.3-1.6 at the 10% survival level. All patients who received the combined RT and EMP plus Velban achieved complete response (n = 27). The rate of PSA (prostate specific antigen) reduction was very prompt compared to that of the RT alone group. There was not disproportionately enhanced side effects for the combined regimen.. EMP enhances radiation induced cytotoxicity in several human tumor cells in culture. The effect is most significant after prolonged exposure to the drug before irradiation. Documented G2/M phase cell cycle block by EMP is the likely mechanism of radiosensitization. The preliminary clinical findings with the combined RT and drugs are highly encouraging.

Topics: Adenocarcinoma; Cell Survival; Estramustine; Female; Humans; Male; Prospective Studies; Prostatic Neoplasms; Radiation-Sensitizing Agents; Tumor Cells, Cultured

To compare pure hormonal treatment (orchiectomy plus flutamide) versus hormonal plus cytostatic treatment (orchiectomy plus estramustine phosphate [EMP]) as first-line therapy for advanced prostatic cancer.. From October 1985 to December 1991 a total of 99 patients were enrolled: 49 received orchiectomy plus EMP, 2 x 280 mg/day; 50 received orchiectomy plus flutamide, 3 x 250 mg/day.. Of the 99 enrolled patients, 93 were evaluable for toxicity and 82 for efficacy. The median time to progression was 161 weeks for EMP versus 120 weeks for flutamide (p = 0.75, not significant). For distant metastases, bone pain, and poor performance status, treatment with EMP showed significantly better results than the flutamide group. The most frequent side effects were gastrointestinal for EMP and hot flushes for flutamide.. For patients with advanced undifferentiated prostatic cancer and poor prognostic factors, treatment with EMP seems to show significant benefit.

Topics: Aged; Combined Modality Therapy; Estramustine; Flutamide; Humans; Male; Orchiectomy; Prognosis; Prostatic Neoplasms; Risk Factors; Time Factors

To determine if initial chemo-hormone therapy (estramustine phosphate) of metastatic prostate carcinomas can lengthen the period until progression, compared with hormone treatment (goserelin) alone? The time to progression, side effects and prognostic factors were assessed.. The prospective phase III study (II 86 until V 91) involved 243 patients randomized consecutively in two groups. Progress was assessed according to NPCP criteria.. The following prognostic factors were established to be significant: metastatic status, metastatic bone pain, alkaline phosphatase and performance status. No difference was observed between the two methods of treatment in time to progression. However on stratifying according to groups with the same prognostic factors, progression in the high risk group occurred at a later stage during treatment with estramustine than during pure hormone treatment. The quality of life was clearly more heavily restricted by side effects from estramustine.. Thus, when comparing these treatments, there were no statistically significant differences. Patients in the high risk groups with unfavorable prognosis factors benefitted from the chemo-hormone treatment with estramustine phosphate.

Topics: Adenocarcinoma; Aged; Estramustine; Goserelin; Humans; Male; Prognosis; Prospective Studies; Prostatic Neoplasms; Risk Factors; Time Factors

127 patients with a clinical stage T2b and T3 prostate cancer were randomized in order to undergo either a radical prostatectomy alone or a radical prostatectomy after hormonal treatment (560 mg of estramustine phosphate daily for 6 weeks) in a prospective multi-center study. The clinical or radiological evaluation of an eventual downstaging being extremely difficult, the authors compared in the 2 groups the influence on the surgical act and the number of positive surgical margins at pathological examination of the resected specimen. There was no significant difference between the 2 groups concerning the surgery (duration of the procedure, blood transfusion, degree of difficulty). For clinical T2 prostate tumors the number of positive surgical margins was significantly lower in the group that had preoperative hormonal treatment. In the group with clinical T3 prostate cancer this difference was not found. The influence of positive margins on the later development of local or systemic recurrence and on survival still has to be awaited. At this moment one could conclude that only patients with a T2 prostate cancer benefit of a preoperative hormonal treatment.

Topics: Estramustine; Humans; Male; Prospective Studies; Prostatectomy; Prostatic Neoplasms

Clodronate relieves bone pain in patients with skeletal metastases. Since the pain relieving mechanism of clodronate may be associated with the antiosteoclastic activity, we have investigated whether the drug has simultaneous actions on bone resorption and pain. Although osteosclerotic metastases are characteristic of prostate carcinoma, bone resorption is also accelerated. The resorbing process can be investigated using a specific immunoassay for ICTP (cross-linked carboxyterminal telopeptide region of type I collagen) which allows the measurement of the degradation of type I collagen in serum samples. We have also determined serum concentration of PICP (carboxyterminal propeptide of type I procollagen) which reflects the synthesis of type I collagen (osteoid). Patients who have relapsed after first-line hormonal therapy, were randomised to receive estramustine phosphate (E) with or without clodronate (C) (E + C, n = 50; E, n = 49). The dose of E was 560 mg and that of C 3.2 g for the first month, thereafter 1.6 g. We saw elevated ICTP and PICP levels in the majority of the patients. A transient decrease in ICTP values occurred simultaneously with pain relief. The changes were more accentuated in the E + C than in the E group but the difference was not significant. In each group serum phosphate concentration decreased markedly (P = 0.001) whereas the activity of alkaline phosphatase remained increased, both indicating a development of osteomalacia during E therapy. The short-term antiosteoclastic effect of C may be explained by the dose reduction, hyperosteoidosis and osteomalacia which inhibit the binding of C on the crystal surfaces and by the late phase of disease.

Topics: Administration, Oral; Aged; Aged, 80 and over; Bone Neoplasms; Bone Resorption; Clodronic Acid; Collagen; Estramustine; Humans; Male; Middle Aged; Pain; Palliative Care; Peptide Fragments; Procollagen; Prostatic Neoplasms

A total of 171 patients with progressive metastatic prostate cancer following hormonal therapy was randomized to receive either 560 to 700 mg. estramustine orally per day or 15 mg./m.2 mitomycin C by intravenous infusion every 6 weeks. The patients were recruited during a 2.5-year period, and 70% had undergone more than 1 previous therapy for prostate cancer, with some having received as many as 5 different previous treatments. The overall results were disappointing. The median time to progression was 5 months and 50% of the patients died within 10 months. There was no difference in efficacy between the 2 treatment arms. Toxicity was severe in both arms but appeared earlier in those patients receiving estramustine, leading to a tendency for earlier deterioration in performance status. In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time.

Topics: Aged; Estramustine; Europe; Humans; Male; Middle Aged; Mitomycin; Multivariate Analysis; Prospective Studies; Prostatic Neoplasms; Survival Analysis

In 1978, the National Prostatic Cancer Project launched two protocols evaluating adjuvant therapy after surgery (Protocol 900) or irradiation (Protocol 1000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy.. After definitive treatment, the patients were randomized either to receive cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years or estramustine phosphate 600 mg/m2 orally daily for up to 2 years or to undergo observation only. Patient accession closed in 1985 and includes 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable).. Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900 and 63% in Protocol 1000. The median progression-free survival (PFS) and survival were greater for patients in Protocol 900 compared with 1000, regardless of the adjuvant therapy. This reflected the greater proportion of patients with lower pathologic stage disease in the surgically treated group. The median PFS was significantly greater for all patients in Protocol 1000 receiving estramustine phosphate adjuvant (48.2 months) compared with patients randomized to receive cyclophosphamide (35.6 months). The median PFS for patients with nodal involvement in Protocol 1000 who received estramustine phosphate adjuvant was prolonged significantly (37.3 months) compared with no treatment (20.9 months). The median PFS for patients with limited nodal disease in Protocol 1000 was longer (39.9 months), regardless of the adjuvant therapy, compared with those with extensive nodal disease (20.7 months). However, in the latter patient group, those receiving adjuvant estramustine phosphate had a significantly longer median PFS (32.8 months) compared with those receiving adjuvant cyclophosphamide (22.7 months) or no adjuvant therapy (12.9 months).. Adjuvant estramustine phosphate was beneficial in patients with prostate cancer and pelvic node involvement who received irradiation as definitive treatment.

Topics: Chemotherapy, Adjuvant; Cyclophosphamide; Drug Administration Schedule; Estramustine; Humans; Incidence; Lymphatic Metastasis; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Prostatic Neoplasms; Survival Analysis

Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone therapy with estramustine were treated. Of the 33 evaluable patients, three patients had stable disease and two had a partial tumour response according to National Prostatic Cancer Project criteria. Twenty-five patients (58%) showed improvement in pain and urinary symptoms. Ten patients (23%) had side effects requiring cessation of therapy. These results show that estramustine has a limited role in the treatment of advanced prostate cancer and that therapy is frequently associated with intolerable side effects.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Cohort Studies; Disease-Free Survival; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

The combination of estramustine phosphate and vinblastine sulfate, 2 agents with separate and unique antimicrotubular effects, has demonstrated additive cytotoxicity against the DU145 human prostate derived cell line in vitro. We evaluated this combination in 25 patients with progressive hormone refractory prostate cancer. Of 24 patients with an elevated prostate specific antigen (PSA) level at the start of treatment 13 (54%, 95% confidence limits 34 to 74%) had a greater than 50% decrease in PSA levels on at least 3 consecutive biweekly determinations. The median decrease in PSA in responding patients was 64% (mean 71.7%) and the median duration of response was 7 months. In 5 patients with bidimensionally measurable disease 2 partial responses were observed. Treatment was well tolerated, with mild and manageable toxicity. This is a well tolerated outpatient treatment regimen for patients with hormone-refractory prostatic cancer which deserves further investigation.

Topics: Aged; Aged, 80 and over; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Diethylstilbestrol; Estramustine; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Megestrol; Megestrol Acetate; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Vinblastine

Estramustine phosphate (EMP) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro. Their modest single-agent activities in hormone-refractory prostate cancer, nonoverlapping toxicities, and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer.. Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously (IV) once a week for 6 weeks. Courses were repeated every 8 weeks. Response assessment was based on a change in serum prostate-specific antigen (PSA) levels and was correlated with change in pain scores.. PSA decreased from baseline by at least 50% in 22 patients (61.1%) and by > or = 75% in eight patients (22.2%). A 50% or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score, performance status, and measurable soft tissue disease (if present) was required for a partial response (PR), which occurred in 11 patients for an overall response rate of 30.5% (95% confidence interval, 15.6% to 45.6%). In seven patients with measurable nonosseous disease, there was one PR (14%) and one minor response (MR). In 28 patients with assessable pain, major pain responses occurred in 12 (42.9%). PSA response (> or = 50% decrease times three measurements) was predictive of major pain response with a 93.7% specificity, a 50% sensitivity, and a positive predictive value of 85.7%.. We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance; Estramustine; Gonadal Steroid Hormones; Humans; Male; Microtubules; Middle Aged; Pain Measurement; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Vinblastine

Although osteosclerotic metastases are characteristic of prostatic carcinoma, bone resorption is also accelerated. Since clodronate inhibits bone resorption and relieves bone pain, we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy. All patients received estramustine phosphate orally. Simultaneously they were randomly allocated to clodronate (36) and placebo (39) groups. Clodronate was given by mouth. The dose was 3.2 g for the first month, thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain. The use of analgesics stopped in 38% of patients on clodronate and in 18% on placebo which effect probably belongs to estramustine phosphate. Serum calcium concentration decreased more markedly in the clodronate group. Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups. No significant differences were seen in median survival or survival rates between the groups.

Topics: Administration, Oral; Aged; Analgesics; Bone Neoplasms; Calcium; Clodronic Acid; Estramustine; Humans; Male; Pain; Prostatic Neoplasms

Two hundred patients with prostatic cancer were enrolled in our previous study between 1984 and 1987. In this study, 96 patients of them were observed for 1 year or more after oral administration of Estracyt (estramustine sodium phosphate). Of these 96 cases, 33 patients were treated with Estracyt as primary treatment and 63 patient had been treated with other treatments before Estracyt treatment. Twelve patients were treated only with Estracyt and 84 patients also received other treatments. Thirty-eight patients were on primary therapy, 37 patients were on maintenance therapy, and 11 patients were on primary therapy, 37 patients were on maintenance therapy, and 11 patients were on the re-activated stage therapy and 10 patients were others. In conclusion, among the 67 cases in which the due judgement of the effect was possible, Estracyt was markedly effective in 10 cases (14.9%), effective in 16 cases (23.9%), slightly effective in 15 cases (22.4%) and ineffective in 26 cases (38.8%). The survival rate was 92.6% at the first year, 66.0% at the third year and 46.3% at the fifth year in the follow-up study. Adverse reactions were observed in 22 cases (22.9%), among which the administration was discontinued in 3 cases.

Topics: Aged; Aged, 80 and over; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Remission Induction; Survival Rate; Time Factors

Topics: Epirubicin; Estramustine; Humans; Male; Mitomycin; Prospective Studies; Prostatic Neoplasms

We compared the effect and toxicity of estramustine phosphate and weekly low-dose epirubicin in a prospective randomized trial in 41 patients with metastatic prostate cancer refractory to hormonal manipulation. No significant difference between treatment modalities was seen. Palliation was reached in over 60% of patients. The median survival was 15 months in both groups. Toxicity was mild. Further, we investigated the effect of epirubicin after the failure of preceding estramustine phosphate therapy in additional 20 patients. Pain relief was achieved in 50% of these patients. The median survival was 10 months. Toxicity was acceptable.

Topics: Aged; Epirubicin; Estramustine; Humans; Male; Middle Aged; Palliative Care; Prospective Studies; Prostatic Neoplasms

From June 1984 to March 1988, patients with newly diagnosed stage D2 prostate cancer were treated with protocol 1. This comprised oral hormonal agents either diethylstilbestrol diphosphate (Honvan: 300 mg/day) or estramustine phosphate (Estracyt: 560 mg/day), or chlormadinone acetate (Prostal: 100 mg/day), plus intravenous cyclophosphamide (CPM, 0.5-1 g/m2) every 3-4 weeks. From May 1988, protocol 2 was used in a randomized study of castration alone versus castration plus intravenous methotrexate (MTX, 20 mg/m2) every 2 weeks. Forty-nine of 53 patients who underwent the two protocols were evaluable for the response. The response rates according to the NPCP criteria were 92% (11/12) for Honvan, 100% (9/9) for Estracyt, 78% (7/9) for Prostal and castration plus MTX, and 80% (8/10) for castration alone. There were no significant differences among these treatments. The median response duration and survival time (months) were 16 and 44, respectively, for Honvan, 19 and 37 for Estracyt, 12 and 43 for Prostal, 11 and 15 for castration plus MTX, and 13 and 13 for castration alone. The short survival times of the castration alone and castration plus MTX groups were due to a short follow-up period. There were no statistical differences among the oral hormonal agent plus CPM groups. However, the 2-year survival rate (Kaplan-Meier method) was higher in the CPM and MTX groups than in the castration alone group. Survival was longer in the good performance status (P.S.) group than the poor P.S. group (p less than 0.05 by Wilcoxon test) and in the responders than the non-responders (p less than 0.01). Side effects were not excessive in the chemotherapy groups and patient compliance was good.

Topics: Administration, Oral; Aged; Aged, 80 and over; Castration; Chlormadinone Acetate; Combined Modality Therapy; Cyclophosphamide; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Humans; Infusions, Intravenous; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Neoplasms; Survival Rate

A series of 105 patients with metastatic prostatic cancer, having progressed on first-line hormonal treatment, were randomised to high-dose medroxyprogesterone acetate (MPA) 1000 mg i.m. daily for 15 days, followed by 1000 mg weekly (53 patients), or to estramustine 280 mg per os twice daily (52 patients). The treatment was discontinued because of side effects in 3 of 51 evaluable MPA-treated patients and in 8 of 51 evaluable estramustine-treated patients. Progression-free survival was short in both groups and no statistically significant difference between them was observed. After 1 year, 70% of the patients had died and there was no statistically significant difference between the 2 treatments in the cumulative observed survival rates. According to modified SPCG criteria, remissions lasting from 12 to 56 weeks were noted in 13 MPA-treated patients and in 4 estramustine-treated patients. This difference was statistically significant. After cross-over, 6 of 33 patients in the MPA group had a remission compared with 1 of 24 in the estramustine group. It was concluded that the response rate, considering both subjective and objective response criteria, was better with MPA and the side effects were fewer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Delayed-Action Preparations; Estramustine; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Prognosis; Prostatic Neoplasms; Time Factors

Twenty-four previously untreated patients with carcinoma of the prostate were prospectively randomized to one of the following treatments: (1) ethinyl oestradiol combined with polyoestradiol phosphate (EE/EP); (2) estramustine phosphate (EM); (3) bilateral orchiectomy. The effects on some plasma proteins related to haemostasis were studied by measuring the concentrations of alpha-1-antitrypsin, orosomucoid, haptoglobin, antithrombin III, C1-inhibitor and von Willebrand's factor before and 3 months after the start of treatment. Orchiectomy induced a reduction of alpha-1-antitrypsin and haptoglobin, while the other studied proteins were unaffected. It was found that both EE/EP and EM treatment induced significant decreases of orosomucoid, haptoglobin, antithrombin III and C1-inhibitor, while the same treatment increased the plasma concentration of alpha-1-antitrypsin. None of these treatments showed any influence on the plasma concentration of the von Willebrand factor. No differences were observed between EE/EP and EM for any of the studied proteins, suggesting comparable oestrogenic effects of these forms of treatment in patients with prostatic carcinoma. The findings are discussed in relation to the proposed difference in thromboembolic complications between EE/EP and EM treatments of prostatic carcinoma patients.

Topics: Aged; Blood Coagulation Factors; Blood Proteins; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Hemostasis; Humans; Male; Orchiectomy; Prostatic Neoplasms

This is a presentation of some preliminary data from SPCG-I, a multicenter study started in 1984 by the Scandinavian Prostatic Cancer Group. It is a randomized double-blind study comparing estramustine phosphate and diethylstilbestrol in the primary treatment of 195 patients with T1-4, NX, M1, G2-3 prostatic cancer. The code is not yet broken. This presentation describes the impact of the pretreatment parameters performance status, pain, tumor burden, grade and DNA-ploidy of the prostate tumor, on time to progression and overall survival. DNA studies have so far only been completed in 66 of the 195 patients. For the whole group of 195 patients, pain (p less than 0.004) and tumor grade (p less than 0.02) had the most significant impact on time to progression, and performance status (p less than 0.01) and grade (p less than 0.03) on overall survival. In the small group of 66 patients where the DNA pattern of the primary tumor was evaluated, no parameter had any significant correlation to time to progression and overall survival. This study is still continuing.

Topics: Diethylstilbestrol; DNA, Neoplasm; Estramustine; Follow-Up Studies; Humans; Male; Ploidies; Prognosis; Prostatic Neoplasms; Survival Analysis

Between September 1982 and May 1984, combination chemotherapy with cis-platinum, peplomycin and adriamycin was administered to 12 patients with histologically confirmed adenocarcinoma of the prostate and progressive disease with evaluable parameters. Cis-platinum (CDDP) 20 mg/sqm was administered intravenously on Days 1-5, peplomycin 5 mg/sqm by 24-hour continuous drip infusion on day 1-5 and adriamycin 25 mg/sqm on Day 1. This course was repeated every 28 days. The dose and schedule were modified by hematologic toxicity or other side effects. One patient refused therapy because of severe nausea and vomiting; therefore 11 patients were eligible for response evaluation. Of the 11 patients, two had a documented PR, five had SD and four had PD. Ten patients whose disease eventually progressed received a second line of therapy consisting either of estramustine or estrogen. Of these ten patients, 6 had a documented PR, one had SD and three had PD. It is concluded that this combination chemotherapy regimen may prime advanced prostatic cancer to respond to hormonal therapy, even though it has only a limited effect on advanced prostatic cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Doxorubicin; Estramustine; Estrogens; Humans; Male; Middle Aged; Peplomycin; Prostatic Neoplasms

Patients with hormone escaped advanced progressive prostate cancer were randomized either to receive either high-dose Estramustine phosphate orally or Mitomycin C by i.v. injection every 6 weeks until signs of progression or death supervened. Patients on both arms progressed rapidly, with a median time to progression of 5 months and a median length of survival of only 10 months. Toxicity was very considerable in both arms.

Topics: Antineoplastic Combined Chemotherapy Protocols; Estramustine; Europe; Humans; Male; Mitomycin; Mitomycins; Prostatic Neoplasms; Risk Factors; Survival Analysis

A prospective randomized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer. A total of 79 patients were included. One group was treated with estramustine phosphate, another with Epirubicin plus Medroxyprogesterone acetate (MPA), while the third arm consisted of Epirubicin plus placebo. Best palliation was obtained by the combination of Epirubicin and MPA. This combination also seemed to be associated with the longest response duration.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Therapy, Combination; Epirubicin; Estramustine; Humans; Injections, Intravenous; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Norway; Placebos; Prospective Studies; Prostatic Neoplasms; Remission Induction

72 patients with hormone resistant, progressing prostatic cancer completed a self-administered questionnaire to assess subjective morbidity and quality of life before they were entered into a phase III trial of estramustine (34) vs. mitomycin (38). At least one post-treatment assessment was available in 43 patients. This considerable degree of non-compliance is explained by practical problems related to completion and collection of the questionnaires in these rapidly deteriorating patients. Doctors underestimated subjective morbidity (pain, decreased performance status, nausea) in 30-50% of the cases. Decreased functional status, fatigue and pain were identified as the most frequent major morbidities before study entry. In most patients, treatment did not reduce this morbidity. The routine application of self-administered quality of life questionnaires has considerable practical problems but yields clinically worthwhile information about subjective morbidity. Simple but relevant monitoring of subjective morbidity by the patient should be mandatory in cancer trials where palliation is a major endpoint.

Topics: Attitude of Health Personnel; Attitude to Health; Drug Resistance; Estramustine; Hormones; Humans; Male; Mitomycins; Neoplasm Metastasis; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires

Topics: Acid Phosphatase; Alkaline Phosphatase; Antineoplastic Agents; Estramustine; Hormones; Humans; Male; Multivariate Analysis; Prognosis; Prostatic Neoplasms

The effect of milk and food on the pharmacokinetics of estramustine phosphate was investigated in six patients with prostatic cancer. In a randomized three-way cross-over study, the patients were given single doses of the drug together with low calcium water, low calcium food and milk. The evaluation was based upon the plasma concentration of two metabolites, estromustine and estrone, as parent drug could not be detected in plasma. The tmax and lag time of estromustine were significantly increased by milk and food intake and Cmax and AUC were significantly decreased. In comparison with water, the AUC of estromustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding figures for the peak values were 32 and 57%, respectively. The effect of milk and food intake on the pharmacokinetics of estrone was similar. Studies in vitro demonstrated that the dissolution of estramustine phosphate disodium was markedly impaired in the presence of calcium. It was concluded that the rate and extent of absorption of estramustine phosphate were decreased when the drug was taken with milk or food due to the formation of a poorly absorbable calcium complex. To obtain high and reproducible absorption of Estracyt, the drug should not be taken together with milk, milk products or other calcium-rich food or drugs.

Topics: Aged; Animals; Biological Availability; Chromatography, Gas; Estramustine; Estrone; Food; Humans; Male; Middle Aged; Milk; Nitrogen Mustard Compounds; Prostatic Neoplasms; Radioimmunoassay; Random Allocation; Solubility

The European Organization for Research on Treatment of Cancer Genitourinary Group performed a multivariate statistical analysis of prognostic factors based on 436 patients entered between 1976 and 1981 in 2 randomized prospective trials that compared 4 different hormonal treatment regimens. Only previously untreated patients with advanced (stage T3/T4/M0 or M1) prostatic cancer were eligible. After identification of prognostic factors by means of univariate analyses a multivariate analysis using Cox's proportional hazards regression model was done. This test identified performance status (according to the Eastern Cooperative Oncology Group scale) as the most important factor, followed by acid phosphatase (more than 2 times normal) for stage M0 cancer patients, and alkaline phosphatase, T category and the presence or absence of associated chronic disease for stage M1 cancer patients. Based on these 4 variables nonbedridden patients with metastatic disease can be divided into 2 groups: poor and good risk patients, with median survivals of 1 and 3 years, respectively. This study shows that routine clinical and laboratory data already provide an excellent indication as to the prognosis.

Topics: Adult; Aged; Aged, 80 and over; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Europe; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Multicenter Studies as Topic; Nitrogen Mustard Compounds; Prognosis; Prospective Studies; Prostatic Neoplasms; Random Allocation; Statistics as Topic

Topics: Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

The present study was designed to investigate the efficacy of various combinations of chemotherapeutic agents in the treatment of prostatic cancer in a group refractory to antiandrogenic therapy (Group 1) and in a previous untreated group (Group 2). Therapeutic combinations of Estracyt (E) + Peplomycin (P) + Doxorubicin (Do) and P + Do + 5 FU (F) in Group 1 and E + P, Honvan (Ds) + P and E in Group 2 were carried out. The main objectives of this study were estimations of the efficacy of E and P in relation to the refractory cases of Group 1 and the efficacy of the combination E + P, in Group 2. This is the first such prospective, randomized, controlled study to be carried out in Japan in relation to prostatic cancer. The results obtained in the present study indicated that chemotherapeutic regimens including E provide some enhanced efficacy, but that the efficacy with regard to refractory cases is poor (23.1-27.3%), as has been reported of studies conducted in the USA and Europe. With regard to previously untreated cases, the E + P regimen achieved a relatively higher response rate than the other treatments (72.7 vs 44.5 or 50.0%). In the comparison of survival times and survival curves, there were no statistically significant differences among the various treatment subgroups. A comparison of survival curves revealed the interesting finding that the PAP-related response showed a clear correlation to the survival curves of Group 2 patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Diethylstilbestrol; Doxorubicin; Estramustine; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Staging; Nitrogen Mustard Compounds; Peplomycin; Prospective Studies; Prostatic Neoplasms; Random Allocation

Topics: Antineoplastic Agents; Carcinoma; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Drug Administration Schedule; Estramustine; Europe; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Prostatic Neoplasms; Random Allocation

Topics: Antineoplastic Combined Chemotherapy Protocols; Castration; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Prostatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Heart; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Prostatic Neoplasms

The results of orchiectomy + flutamide (n = 28) versus orchiectomy + estramustine (n = 27) in the initial therapy of advanced prostatic cancer were compared in a prospective randomized study. The minimum observation period was one year. In the group orchiectomy + flutamide the incidence of side effects was 25%, the response rate (complete + partial remission) was 28% and the progression rate was 18%. 5 patients (18%) died within the first year. In the group orchiectomy + estramustine the incidence of side effects was 22%, the response rate (complete + partial remission) was 29% and the progression rate was 33%. 2 patients (7%) died within 1 year of treatment. There is no significant difference either in the response rate or the progression rate between the two groups.

Topics: Aged; Aged, 80 and over; Anilides; Clinical Trials as Topic; Combined Modality Therapy; Estramustine; Flutamide; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Orchiectomy; Prospective Studies; Prostatic Neoplasms; Random Allocation

Both anticancer and adverse reactions of Estracyt were investigated by oral administration to 200 patients with prostatic cancer. Two capsules of Estracyt were given twice a day and the administration was principally continued for more than six months. The 200 patients consisted of 68 and 132 patients who were previously untreated and treated, respectively. Thirty seven cases had been treated only with Estracyt and 132 cases also received other treatments. Seventy-five cases were of primary therapy, 71 cases were of maintenance therapy, and 27 cases were of the re-activated stage therapy and 27 cases were of other categories. In conclusion, among the 190 cases for which the due judgement of the effect was possible, Estracyt was markedly effective in 40 cases (21.1%), effective in 43 cases (22.6%), slightly effective in 38 cases (20.0%) and ineffective in 69 cases (36.3%). Adverse reactions were observed in 67 cases (33.5%), among which the administration was discontinued in 18 cases.

Topics: Administration, Oral; Aged; Aged, 80 and over; Clinical Trials as Topic; Double-Blind Method; Estramustine; Humans; Male; Middle Aged; Multicenter Studies as Topic; Nitrogen Mustard Compounds; Prostatic Neoplasms

Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg x 3) (F) or with estramustine (280 mg x 2) (E). Clinical examination, bone scan, laboratory measurements were performed before randomization and at regular intervals thereafter. During an observation period of between 1 and 2.5 years, F was discontinued in one case (7%) because of icterus, and E in three cases (20%) because of CV complications. Of the remaining 14 F-treated patients, 13 responded initially. Eleven of them relapsed, and five died of cancer. In the corresponding group of 12 E-treated patients, there were 11 primary responders. Of these, only two relapsed and died, as did the only nonresponder. The difference between the two groups with regard to relapse is significant (p less than 0.01), but not with regard to mortality. In the present material, there was an initial favorable response to F without signs of CV complications and with maintained libido in most cases. However, due to the significantly increased risk for relapse compared with E, F cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

Topics: Adenocarcinoma; Aged; Anilides; Bone Neoplasms; Estramustine; Flutamide; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prospective Studies; Prostatic Neoplasms; Random Allocation; Time Factors

A prospective randomized trial for metastatic prostatic cancer in 220 patients who were refractory to hormone therapy was conducted by the National Prostatic Cancer Project from 1984 to 1985. As of July, 1986, the evaluation of these patients reflected no difference in response to either estramustine phosphate (Emcyt) or flutamide. Toxicities were minimal, and the observed survival and progression-free survival intervals were noteworthy in view of the overall prospects for such patients. Future studies dealing with specific quality of life issues seem to be indicated by our results.

Topics: Anilides; Carcinoma; Clinical Trials as Topic; Estramustine; Flutamide; Hematologic Diseases; Humans; Male; Nausea; Nitrogen Mustard Compounds; Prospective Studies; Prostatic Neoplasms; Random Allocation; Vomiting

Topics: Antineoplastic Agents; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Estramustine; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

The influence on the specific cell-mediated immunity (CMI) of the carcinoma of the prostate gland by the contra-sexual hormone therapy with Cytonal, Estrazyt and Turisteron is controlled. For this purpose the macrophage-electrophoresis-mobility test on the basis of allogenic tumour-associated antigen of the carcinoma of the prostate gland is used. As a result the use of Cytonal at least in the dosage hitherto used is no longer worth being advocated. Turisteron and Estrazyt, respectively, taking into consideration their pharmacokinetics and indication, prove to be immunologically optimal and without hesitation, respectively. Turisteron is the basic therapeutic in the androgen-dependent carcinoma of the prostate gland. Estrazyt should be reserved to primarily and secondarily hormone-refractory tumours. For the application of Estrazyt an additive immune stimulation seems to be worth taking into consideration.

Topics: Aged; Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Diethylstilbestrol; Estramustine; Ethinyl Estradiol; Humans; Immunity, Cellular; Macrophages; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Topics: Carrier Proteins; Clinical Trials as Topic; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms; Prostatic Secretory Proteins

Topics: Clinical Trials as Topic; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prospective Studies; Prostatic Neoplasms; Random Allocation

The efficacy and side effects of flutamide were compared with estramustine in patients with advanced prostatic carcinoma. Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg X 3) or with estramustine (280 mg X 2). Clinical examination, bone scan, laboratory measurements, including coagulation studies were performed prior to randomization, every three months during year one, and at six-month intervals thereafter. The two groups were comparable with respect to age and tumor characteristics. However, more patients presented with skeletal pain among those later treated with flutamide. During an observation period of between one and two and one-half years, flutamide was discontinued in 1 case (7%) because of icterus, and estramustine in 3 cases (20%) because of CV complications. Of the remaining 14 flutamide-treated patients, 13 responded initially. Eleven of them relapsed, and 5 died of cancer. In the corresponding group of 12 estramustine-treated patients, there were 11 primary responders. Of these, only 2 relapsed and died as did the only nonresponder. The difference between the two groups with regard to relapse is significant (P less than 0.01), but not with regard to mortality. All estramustine-treated patients lost their libido, whereas only 20 per cent of the patients treated with flutamide did so. In the present limited material there was an initial favorable response to flutamide without signs of CV complications and with maintained libido in most cases. However, due to significantly increased risk for relapse compared with estramustine, flutamide cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Anilides; Bone Neoplasms; Estramustine; Flutamide; Humans; Libido; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

Topics: Aged; Body Weight; Cardiovascular Diseases; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Europe; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Thirty previously untreated patients with carcinoma of the prostate were prospectively randomised to one of the following treatments: ethinyl oestradiol (Etivex) combined with polyoestradiol phosphate (Estradurin); estramustine phosphate (Estracyt); bilateral orchiectomy. Oestrogenic effects were measured by blood levels of pregnancy zone protein, sex hormone binding globulin, LH, FSH and prolactin. During a follow-up period of 6 months, estramustine phosphate and ethinyl oestradiol/polyoestradiol phosphate induced comparable changes in these proteins, suggesting comparable oestrogenic effects of these two forms of treatment in patients with prostatic carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Estradiol; Estramustine; Ethinyl Estradiol; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Nitrogen Mustard Compounds; Orchiectomy; Pregnancy Proteins; Prolactin; Prostatic Neoplasms; Sex Hormone-Binding Globulin

From July, 1980, to June, 1983, 319 patients with newly diagnosed metastatic prostatic cancer were randomized to one of three treatment protocols: diethylstilbestrol (DES) or bilateral orchiectomy, cyclophosphamide plus 5-fluorouracil plus DES, and estramustine phosphate (Emcyt). Ninety-three per cent of 296 patients were eligible for evaluation. This report shows no difference in survival, disease-free progression time, or status regarding pain at entry. Other prognostic factors failed to reveal any difference within any of the treatment protocols.

Topics: Blood Platelets; Carcinoma; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Estramustine; Fluorouracil; Humans; Leukocytes; Male; Nitrogen Mustard Compounds; Orchiectomy; Prostatic Neoplasms; Random Allocation

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Cardiovascular Diseases; Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Europe; Gastrointestinal Diseases; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

In a prospective multicenter study, 244 men with highly or moderately differentiated prostatic cancer in stage I, II or III (VACURG) were consecutively randomized to three groups of treatment: Group A (77 patients) received polyestradiol phosphate (Estradurin, Leo) 80 mg i.m. every fourth week + ethinyl estradiol (Etivex, Leo) 150 micrograms daily, group B (72 patients) estramustine phosphate (Estracyt, Leo) 280 mg twice daily, and group C (76 patients) no therapy. Only men without current or previous other malignancy and without cardiovascular disease were admitted to the study. After 4 1/2 years 125 of the 244 patients had left the study, 9 because of cancer progression (stage IV, VACURG). The most serious complications were cardiovascular, including ischemic heart disease, cardiac decompensation, cerebral ischemia and venous thromboembolism, which occurred in 24 patients from group A and 9 from group B as compared to only one patient in group C. The subgroup superficial or deep venous thrombosis comprised 11 group A and 2 group B patients. Estrogens (E + e) offered as palliative treatment to patients with non-generalized prostatic carcinoma is burdened with a high incidence of serious cardiovascular complications.

Topics: Aged; Cardiovascular Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prospective Studies; Prostatic Neoplasms; Random Allocation

In a double-blind, crossover comparison, 236 patients with metastatic prostate cancer were randomized to receive estramustine phosphate (EMP) or diethylstilbestrol (DES). Previously castrated patients (66) were separately randomized. Patients kept taking their first drug until progression was proved by objective studies, at which time alternative treatment was begun. The primary determinant of efficacy was the duration between start of therapy and date of objective progression. Uncastrated patients treated with EMP had a significantly longer duration without progression than those treated with DES (p less than 0.01). The following subcategories of entry were further evaluated: little or no pain, moderate to severe pain, little reduction in activity, significant reduction in activity, presence or absence of cardiovascular disease, age above or below 70 years, and "good" or "bad" histology. For all but the last category, EMP was statistically superior to DES. Patients who underwent orchiectomy less than 3 months before randomization had nonprogression rates similar to those for noncastrated men in both groups. Secondary (crossover) therapy was less effective than first therapy in both groups: 46% of patients receiving EMP and 40% receiving DES had no progression at 6 months. Clinical and laboratory adverse experiences were similar for both drugs, except that gastrointestinal disturbances were more common in the EMP group.

Topics: Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Orchiectomy; Patient Compliance; Prostatic Neoplasms; Random Allocation

Life expectancy of patients with prostatic cancer is varying from one case to another and, sometimes, these patients have a very long life expectancy. Less than a third of this patients are dying from their cancer. This notion implies to be very careful in the choice of aggressive treatments. Isolated or combined chemotherapy assays permitted to select cyclophosphamide, methotrexate, cis-platinum or estramustine phosphate as active drugs in the treatment of prostatic cancer. But the randomized studies, in Europe or in U.S.A., are not demonstrative enough to propose these drugs for a routine treatment. Cancer of the prostate is usually represented by cellular groups that are more or less sensitive to the different kind of available treatments. Perhaps in the future the best results of treatment will be the association of chemotherapy-radiotherapy and hormonotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Estradiol; Estramustine; Humans; Male; Prostatic Neoplasms

Serial transrectal needle biopsies were taken from 146 patients (657 specimens) with advanced prostatic cancer (T3/T4, M1/MO) admitted to a trial of two forms of oestrogen therapy. Histological grading by Gleason and Mostofi techniques on the initial biopsy showed no correlation either with extent of disease or its eventual outcome on treatment. Change in grade was dissociated from the response of bone metastases to hormone treatment and did not appear to influence survival. However, the prognosis of 16 patients showing clearance of tumour from their serial biopsies was generally good.

Topics: Aged; Bone Neoplasms; Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Humans; Male; Middle Aged; Prognosis; Prostate; Prostatic Neoplasms; Time Factors

Topics: Castration; Clinical Trials as Topic; Cyproterone; Diethylstilbestrol; Estramustine; Humans; Male; Medroxyprogesterone; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Ninety-five patients with prostatic carcinoma, stages A-D and of all histological grades were randomized between a continuous and an intermittent treatment regimen of Estracyt (estramustine phosphate). 77 patients were evaluated (46 with continuous and 31 with intermittent therapy). Remissions were seen in 13 (28%) and (13%), respectively. Stable disease was recorded in 30 (65%) and 24 (77%), respectively. Progression experienced 3 (6%) and 3 (10%) respectively. 19% were unable to continue therapy due to intolerable gastrointestinal side effects (7 patients receiving continuous and 8 patients receiving intermittent therapy).

Topics: Aged; Alanine Transaminase; Aspartate Aminotransferases; Clinical Trials as Topic; Digestive System; Drug Administration Schedule; Estramustine; Gynecomastia; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

We have investigated a group of 30 patients with newly diagnosed metastatic carcinoma of the prostate who were randomly assigned to receive, as primary treatment, either diethylstilbestrol (DES) or estramustine phosphate (Emcyt). Clinical response was assessed following the guidelines of the National Prostatic Cancer Project and the Eastern Cooperative Oncology Group. Effective reduction in the levels of androgens was noted in all patients in both groups regardless of response. During the follow-up period (ranging between 2-5 years) relapses were noted despite the presence of androgen levels at or below castrate values. The most relevant endocrine observation was the detection of early elevations in serum prolactin in a majority of patients. It was noted, however, that those patients in whom hyperprolactinemia did not occur or appeared only briefly at the beginning of therapy, experienced a prolonged, symptom-free survival. Persistent hyperprolactinemia, on the other hand, carried an ominous prognosis. The differences in survival between normoprolactinemic and hyperprolactinemic groups carried statistical significance.

Topics: Carcinoma; Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prolactin; Prostatic Neoplasms; Random Allocation; Testosterone

Plasma testosterone, oestradiol, luteinising hormone (LH) growth hormone and prolactin were measured serially in 140 patients with advanced prostatic carcinoma (T3, T4, MI and MO) randomised in a trial of diethylstilboestrol 3 mg/day against estramustine 560 mg/day. Both drugs suppressed plasma testosterone and LH and increased plasma growth hormone and prolactin, though estramustine induced a greater rise in prolactin. Oestradiol levels fell on stilboestrol but were considerably elevated on estramustine. Initial hormone levels reflected neither the extent of disease nor the response to treatment. The data also showed that close attention should be given to plasma LH in identifying patients who are unreliable, since intermittent hormone dosage caused an exaggerated rise even when plasma testosterone remained at castrate levels.

Topics: Aged; Clinical Trials as Topic; Diethylstilbestrol; Estradiol; Estramustine; Growth Hormone; Hormones; Humans; Luteinizing Hormone; Male; Middle Aged; Nitrogen Mustard Compounds; Patient Compliance; Prolactin; Prostatic Neoplasms; Random Allocation; Testosterone

Six prospective studies in the field of prostatic carcinoma have been carried out to date by the EORTC Urological Group. In three phase II studies, adriamycin, procarbazine, vindesine, and mitomycin C have been studied. Two of the three protocols have been completed. In three phase III studies, 3 mg of diethylstilbestrol (DES) is compared to cyproterone acetate (CPA), medroxyprogesterone acetate (MPA), and Estramustin phosphate (Estracyt). These two protocols have been closed to entry. The current protocol compares DES, 1 mg, to castration and to cyproterone acetate plus castration. From the phase II studies, no drug has emerged that is recommended for treatment of hormone-resistant prostatic cancer. The endocrine protocols, designed for the primary treatment of T3, T4, and M1 carcinoma of the prostate, have resulted in several important observations. Responses to DES, 3 mg/day, and to Estracyt were very similar and amounted to 25-30%. There was somewhat less objective response in the CPA and significantly less (P = 0.005) in the MPA group. It has become evident that DES at a dosage of 3 mg/day carries a significantly higher risk of overall cardiovascular toxicity than does cyproterone acetate, but severe cardiovascular complications did not differ between treatment groups. Up to now, no differences in survival were observed within the different treatment groups. Grade, local tumor extension, and performance were found to have a significant impact on survival.

Topics: Castration; Clinical Trials as Topic; Combined Modality Therapy; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Doxorubicin; Estramustine; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Mitomycin; Mitomycins; Procarbazine; Prostatic Neoplasms; Random Allocation; Vinblastine; Vindesine

The national Prostatic Cancer Project has evaluated single and combination chemotherapeutic agents for the treatment of patients with advanced prostatic cancer that has been unresponsive to hormonal therapy. Although regression rates have been modest, a number of drugs have shown some efficacy and are now undergoing testing in combination. Current trials of the LH-RH agonists and the antiandrogen flutamide are in progress. These trials have demonstrated a role for chemotherapy in the treatment of the patient who has failed hormonal therapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carmustine; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Doxorubicin; Estramustine; Fluorouracil; Humans; Imidazoles; Lomustine; Male; Methotrexate; Mitomycin; Mitomycins; Prednimustine; Prednisone; Procarbazine; Prostatic Neoplasms; Random Allocation; Streptozocin; Vincristine

Estramustine phosphate is approved by the Food and Drug Administration for oral use in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a conjugate of 17 beta-estradiol and the carbamate of nitrogen mustard. Although its therapeutic efficacy has been demonstrated, it is not clear to what extent each constituent contributes to estramustine's effectiveness. Estramustine phosphate therapy achieves objective response rates of 60-90 percent in advanced stage D prostatic cancer patients with no prior hormonal therapy. These results are consistent with those obtained with conventional hormonal therapy in similar patient populations. Therapeutic efficacy does not appear to increase when estramustine is used concurrently with other cytotoxic chemotherapeutic agents. An objective response rate of 20-30 percent can be anticipated in patients refractory to conventional hormonal therapy. It is in this group, the estrogen-resistant patients, that estramustine shows the most promise. Adverse effects of estramustine are similar to those of diethylstilbestrol. Gastrointestinal and cardiovascular side effects appear to be the most important and may be severe enough to require discontinuation of therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiovascular System; Clinical Trials as Topic; Costs and Cost Analysis; Digestive System; Estramustine; Female; Humans; Kinetics; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Clinical Trials as Topic; Estramustine; History, 20th Century; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Sweden

Topics: Antineoplastic Combined Chemotherapy Protocols; Castration; Clinical Trials as Topic; Combined Modality Therapy; Drug Evaluation; Estramustine; Humans; Male; New York; Nitrogen Mustard Compounds; Prostatic Neoplasms; Radiotherapy Dosage; Time Factors

Topics: Belgium; Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Humans; Male; Neoplasm Staging; Nitrogen Mustard Compounds; Prognosis; Prostatic Neoplasms; Random Allocation; Time Factors; United Kingdom

Topics: Bone Neoplasms; Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors; Wisconsin

Topics: Administration, Oral; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Estramustine; Humans; Injections, Intravenous; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

In May 1978, the National Prostatic Cancer Project Treatment Subgroup activated its first clinical trial evaluating adjuvant chemotherapy (Protocol 900). This protocol is a comparison of long-term adjuvant chemotherapy with cyclophosphamide, estramustine phosphate, or no additional treatment in patients with definitive surgical therapy for adenocarcinoma of the prostate. To date, 128 patients have been entered with an entry rate of approximately 2.2 patients per month. One hundred five patients form the basis of this report, with 96 patients still on active therapy. Estramustine phosphate has been administered at a dose of 600 mg/m2 orally daily in three divided doses. The cyclophosphamide is administered 1 g/m2 intravenously every 3 weeks. Results are still preliminary; only two evaluable patients have died. Approximately two-thirds of patients entered have had negative lymph nodes. Recurrent disease has been documented in 15 patients, including eight receiving cyclophosphamide, three receiving estramustine phosphate, and four on the no-treatment arm. The recurrence rate has been disproportionately high (50%) in patients receiving cryosurgery rather than radical prostatectomy (12%). Maximum survival has reached 241 weeks. Side effects have consisted of leukopenia in patients receiving cyclophosphamide (56%), and nausea and vomiting with cyclophosphamide (85%), and estramustine phosphate (36%). This study continues with patient entries now over one-half of the number anticipated in the original study design.

Topics: Adenocarcinoma; Adult; Aged; Cardiovascular Diseases; Clinical Trials as Topic; Combined Modality Therapy; Cryosurgery; Cyclophosphamide; Estramustine; Follow-Up Studies; Humans; Leukopenia; Lymph Node Excision; Male; Middle Aged; Multi-Institutional Systems; Nausea; Nitrogen Mustard Compounds; Prognosis; Prostatectomy; Prostatic Neoplasms; Random Allocation; Vomiting

Topics: Aged; Clinical Trials as Topic; Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Retrospective Studies; Testis

Topics: Antineoplastic Agents; Castration; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Prognosis; Prostatic Neoplasms; Random Allocation; Registries

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

Topics: Aged; Cisplatin; Clinical Trials as Topic; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prognosis; Prostatic Neoplasms; Random Allocation

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

Topics: Aged; Cisplatin; Clinical Trials as Topic; Estramustine; Hormones; Humans; Male; Methotrexate; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Patients with advanced prostate carcinoma that had been stabilized by orchiectomy (ORCH) or hormone therapy for at least 3 months, were randomized to either diethylstilbestrol (DES) alone or DES plus Cytoxan or DES plus Emcyt. A total of 188 patients were randomized between July, 1976 and February, 1982 of which 161 were evaluable for objective response to treatment. Objective response rates, response duration, or survival experiences were not demonstrably different between treatment arms, either for all patients or within good or poor prognosis groups determined by initial pain or acid phosphatase level. Subjective improvements in performance status were small for each treatment. Pain relief was somewhat greater in the chemotherapy-hormone combinations than in the DES/ORCH, but the advantage was not statistically significant. Side effects were primarily nausea and vomiting and leukopenia, mostly in the DES + Cytoxan arm. The duration of stabilization prior to entry did not influence response overall, although there were opposing trends within each of the two chemotherapy arms. The premise for combining antitumor agents with hormones before hormone failure is still felt to be a more logical approach than waiting for the ultimate hormone failure, and a combination of hormones plus two antitumor agents is being evaluated in a subsequent ongoing trial where a more rigid design limits the duration of the preentry period of hormone stabilization.

Topics: Aged; Castration; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Cisobitan, an organosilicon compound with estrogenic and antigonadotropic properties has been evaluated clinically in comparison with an estrogen preparation. In a multicenter study a total of 140 patients with well and moderately well differentiated prostatic cancer were randomly allocated to treatment with Cisobitan or Estradurin/Etivex, 70 to each group. Of 34 patients with poorly differentiated prostatic cancer 18 were given Cisobitan--and 16 were given Estracyt-treatment. Among the patients with well and moderately well differentiated prostatic cancer there were, disregarding mortality, no major differences in subjective, objective or laboratory response to the two kinds of treatment. The pattern of side effects was similar, but oedema requiring diuretics occurred more often in the estrogen treated group. There was a significant difference in mortality at 12 months between the groups, two in the Cisobitan group and ten in the estrogen treated group. Cancer was the cause of death in two patients in the estrogen treated group. All other patients succumbed in cardiovascular diseases. At 24 months the difference in mortality rate was less pronounced: Another ten patients had died in the Cisobitan treated group and seven among the estrogen treated patients. Cancer was responsible for the deaths in seven of the Cisobitan patients compared to four of the estrogen treated patients. Within three years one more patient in both groups had died. Of the 34 patients with poorly differentiated cancer, twelve were alive at the 24 months' follow up, six in the Cisobitan group and six in the Estracyt group.

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Gonadotropins; Humans; Male; Prostatic Neoplasms; Random Allocation; Silicones; Siloxanes

Patients with locally advanced (category T3-4 of the TNM system) and metastatic prostatic cancer, not previously treated, seen by one of the authors (P.H.S.) have been entered into EORTC Protocol 30762 which has compared the therapeutic effects of estramustine phosphate (Estracyt) and of diethyl-stilboestrol (DES) as primary treatment. A gradual and as yet unexplained rise in the total leucocyte count was seen in patients treated with estramustine phosphate. This was always apparent within 2 months of starting treatment and did not change significantly thereafter unless treatment was stopped, when the raised values soon returned to normal. In four patients in whom the white cell count rose to levels above the normal range a neutrophil leucocytosis was always reported. The cause of this is not yet understood.

Topics: Clinical Trials as Topic; Diethylstilbestrol; Estramustine; Humans; Leukocyte Count; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

A controlled, randomized trial of estramustine phosphate versus stilbestrol has been conducted in patients with previously untreated adenocarcinoma of the prostate. Both drugs were equally effective in decreasing serum testosterone and acid phosphatase levels. No therapeutic advantage of estramustine over stilbestrol was noted. At 3 months, 50% of tumours treated with stilbestrol had regressed compared with 36% treated with estramustine, at 1 year the rates were 50% and 21% respectively and at 2 years 50% and 9%. However, there was no difference in objective stabilization and regression rates between the two groups or in therapeutic failure rates.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prolactin; Prostatic Neoplasms; Random Allocation; Testosterone

Based on the pertinent literature, this paper discusses the results of cytostatic therapy for advanced prostatic cancer published so far with special consideration given to the extensive experience of the National Prostatic Cancer Project (NPCP) in the United States. Endoxan and 5-Fluoro-uracil, each as a monotherapy, haven proven still to be the optimal cytostatic therapies in secondary treatment following hormone resistance. Moreover, our own results reached with 33 patients on chemotherapy with Endoxan or 5-Fluoro-uracil, resp., are reported, in particular those in 24 of the 33 patients receiving these drugs as a third therapy after previous hormone resistance and secondary Estracyt resistance. Especially with regard to pain relief, we obtained good results in 50% of cases. The average survival period of the patients on third therapy was 6.7 months. Side effects prevailed in the gastrointestinal tract and the hemopoetic system. The results with Endoxan and 5-Fluoro-uracil as primary therapies have thus far been unsatisfactory with regard to therapy response and drug tolerance.

Topics: Aged; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Estramustine; Estrogens; Fluorouracil; Humans; Male; Middle Aged; Prostatic Neoplasms; Random Allocation; Time Factors

Topics: Animals; Cardiovascular System; Carrier Proteins; Castration; Clinical Trials as Topic; Diethylstilbestrol; DNA; Estramustine; Humans; In Vitro Techniques; Lymphocytes; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Time Factors; Tissue Distribution

Topics: Capsules; Carcinoma; Castration; Clinical Trials as Topic; Diethylstilbestrol; Double-Blind Method; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Castration; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Diethylstilbestrol; Drug Evaluation; Estramustine; Fluorouracil; Humans; Male; Nitrogen Mustard Compounds; Prednimustine; Prostatic Neoplasms; Tablets; Time Factors; Vincristine

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rats

Experiences resulting from Emcyt therapy in patients with both newly diagnosed and hormone refractory advanced prostate cancer, as well as on adjuvant to surgery or radiotherapy in earlier disease are presented. Data from trials of the National Prostatic Cancer Project (NPCP) and a series from Roswell Park Memorial Institute (RPMI) were divided into short-term (up to twenty weeks and up to fifty-two weeks in adjuvant trials) and long-term therapy. Baseline disease and patient characteristics and toxicities encountered in these two treatment-duration groups were compared. Patients in a more favorable health or disease status and/or responded to therapy were more frequently in the long-term group. Patients in the long-term group tended to have higher over-all incidences of toxicity; and although many had occurrences begin as early as those in the short-term group, they were able to tolerate the therapy for relatively long periods. The agent is thus both effective and can be given safety for long periods of time.

Topics: Acid Phosphatase; Alkaline Phosphatase; Anorexia; Cardiovascular Diseases; Clinical Trials as Topic; Diarrhea; Drug Administration Schedule; Estramustine; Humans; Male; Nausea; Neoplasm Staging; Nitrogen Mustard Compounds; Probability; Prostatic Neoplasms; Time Factors; Vomiting

Topics: Clinical Trials as Topic; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Ten patients with previously untreated prostatic carcinoma were studied to evaluate the hormonal effects of different doses of estramustine phosphate (Estracyt). The drug was given by mouth in increasing doses; during the first month 70 mg daily, during the second 140 mg, during the third 280 mg and during the fourth and following months 560 mg. The following hormonal parameters were studied before the treatment and then once weekly during a period of four months: testosterone, dihydrotestosterone, androstenedione, cortisol, FSH and LH. The levels of the steroids were also re-assessed one to two years later. The patients were also followed clinically at regular intervals. Initial testosterone levels of approximately 20 nmol/l plasma were reduced to approximately 0.6 nmol/l already by the lowest Estracyt dose of 70 mg/day. No further decrease was obtained by a stepwise increase of doses up to 560 mg/day. The plasma levels of dihydrotestosterone, androstenedione, FSH and LH were also reduced significantly following the administration of the lowest daily Estracyt dose and then remained at that low level. Cortisol levels increased steadily during the four months of the study. After longterm treatment the hormonal indices were by and large the same as during the last initial treatment period. Initially, the clinical effect of the treatment was excellent. In 4 patients, however, the therapy had to be discontinued after some time, because of complicating oedema (2 patients) or refractoriness to therapy (2 patients). Three years after initiating the therapy 6 patients still were on Estracyt treatment. All of them were doing well subjectively. In 5 patients the prostatic cancer was in remission or at least stable. In one patient, however, skeletal metastases were progressing. In conclusion, Estracyt was found to possess a maximal hormonal (oestrogenic) effect already in doses far below those usually recommended.

Topics: Administration, Oral; Aged; Androgens; Clinical Trials as Topic; Dose-Response Relationship, Drug; Estramustine; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Hydrocortisone; Luteinizing Hormone; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Acid Phosphatase; Aged; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone

To clarify the mechanism of action of Estracyt, we performed experiments using 3H-estramustine of high specific activity. 3H-Radioactivity accumulated selectively in the ventral prostate of castrated male rats after the administration of 3H-estramustine. Estramustine and its metabolites were retained in the ventral prostate for long time periods. The uptake of 3H-radioactivity was almost totally localized in the cytosol fraction, but not in a purified receptor fraction. The apparent equilibrium dissociation constant of the estramustine binding protein was 18.9 nM, and the apparent equilibrium Bmax value was 0.76 nmoles/mg of cytosol protein. In addition, we wish to report in this paper the results of clinical trials of Estracyt studied by a cooperative research group in Japan from 1977 to 1979. It was concluded that Estracyt was effective in 89% of previously untreated prostatic cancer patients and in 38% of reactivated cancer patients.

Topics: Animals; Antineoplastic Agents; Carrier Proteins; Castration; Clinical Trials as Topic; Cytosol; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Tissue Distribution; Tritium

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

Topics: Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Nausea; Nitrogen Mustard Compounds; Probability; Prostatic Neoplasms; Vincristine; Vomiting

In a prospective randomized multicenter trial patients with highly or moderately differentiated prostatic carcinoma, previously untreated, were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol. As regards frequency and duration of tumour remission there was no statistical difference between the two groups. Nor did they differ significantly with respect to adverse reactions. This is an interim report and will be followed later on by a final evaluation.

Topics: Bone Neoplasms; Estramustine; Estrogens; Humans; Male; Neoplasm Staging; Nitrogen Mustard Compounds; Phosphoric Monoester Hydrolases; Prostatic Neoplasms; Random Allocation

Two hundred and twelve patients treated for prostatic cancer grade I or II were investigated for cardiovascular complications. The patients were part of a multicentre study in the Stockholm area and had been randomized to treatment with either estramustine phosphate (Estracyt) or polyestradiol phosphate and ethinyl estradiol. Cardiovascular complications categorized as impaired arterial circulation including ischemic heart disease, venous thromboembolism, cardiac incompensation and cerebral depression were found to be equally frequent following the two different forms of treatment. Among the patients getting cardiovascular complications, these occurred within two months after the start of treatment in 50% and within one year in 85% of them. There was a statistically significant correlation between the incidence of cardiovascular complications and a history of previous cardiovascular disease. This criterion was however in retrospect found to predict cardiovascular complications in only 67 of the 126 patients getting one or several of these complications.

Topics: Aged; Cardiovascular Diseases; Estramustine; Estrogens; Follow-Up Studies; Hemodynamics; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

A preliminary report is presented of prospective, randomized study with continuous and intermittent oral Estracyt treatment in patients with prostatic carcinoma. It seems that the therapeutic effect of intermittent treatment is as favorable as continuous therapy. Side effects and costs are lower with intermittent therapy.

Topics: Drug Administration Schedule; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitrogen Mustard Compounds; Prostatic Neoplasms

Two parallel prospective randomized studies have been undertaken by the EORTC Urological Group in previously untreated patients with prostatic cancer in order to compare low dose Stilboestrol versus Cyproterone acetate versus Medroxyprogesterone acetate in the first trial, and Stilboestrol versus Estracyt in the second trial. Although the follow up is still short, no superiority of the other drugs over Stilboestrol had appeared so far with regard to either objective response or significant side effects apart from gynaecomastia. In the third trial, patients with advanced disease no longer responsive to hormonal treatment were randomized to either Adriamycin or Procarbazine. Toxicity and early death were particularly frequent in Procarbazine treated patients, whereas most patients progressed in both treatment groups.

Topics: Cyproterone; Diethylstilbestrol; Doxorubicin; Estramustine; Humans; Male; Medroxyprogesterone; Prostatic Neoplasms

A number of chemotherapeutic agents show moderate promise for the palliative treatment of metastatic prostatic carcinoma. Although patterns of metastatic disease make classic response rates difficult to obtain and interpret, doxorubicin, cyclophosphamide, dacarbazine (DTIC), and cisplatin have activity in patients who have failed conventional hormonal treatment. In most studies, a survival advantage is seen for responders to these and other chemotherapeutic agents, but no survival advantage has been seen for the treatment cohorts when compared to groups not receiving chemotherapy. Therefore, estimates of the usefulness of these agents must be considered tentative. Multiple drug therapy has not yet shown definite superiority to single agent treatment. The uses and limitations of acid phosphatase as a tumor marker, as well as particular difficulties in measuring tumor response in the disease, are detailed herein.

Topics: Acid Phosphatase; Adenocarcinoma; Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Estramustine; Fluorouracil; Humans; Lomustine; Male; Prednimustine; Prostatic Neoplasms

Even though surgery and/or radiation has been the treatment of choice of early carcinoma of the prostate, there is conclusive evidence that tumor may recur in a certain number of patients at the primary site and/or at a distant location. The only way to achieve a complete cure in these patients with localized cancer appears to be by addition of relatively safe, effective chemotherapeutic agents. Estracyt and/or Cytoxan appear to be such agents. These two drugs showed definite activity in the treatment of patients with advanced prostatic carcinoma. Chemotherapeutic agents appear effective as adjuvant in the treatment of other solid tumors. It is worthwhile that this modality of treatment be tried in patients with early, curable prostatic carcinoma.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

The relationship of prior hormonal therapy to subsequent response on estramustine phosphate (Estracyt) was examined in 107 patients with advanced prostatic cancer treated in two different Phase II chemotherapy trials. In both trials patients with the longest prior hormonal treatment were the least likely to respond to estramustine phosphate. Patients in the series from the National Prostatic Cancer Project with a response classification to prior hormonal therapy had only a 26 per cent response to subsequent estramustine phosphate therapy, whereas 40 per cent of those with no prior response to hormonal therapy responded to estramustine phosphate. This latter group had the shortest average disease duration from diagnosis. The sample of prostate cancers studied appeared to include groups that were sensitive to both hormones and cytotoxic activity as well as to either of these two alone. These data support the contention that estramustine phosphate may act both as an estrogenic and a cytotoxic agent.

Topics: Aged; Clinical Trials as Topic; Drug Evaluation; Estramustine; Estrogens; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Patients with poorly differentiated prostatic carcinoma and skeletal metastases were randomized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane (2.6-cis) and estramustine-17-phosphate (estramustine). Parallel with the clinical study a group of non-randomized patients were treated with 2.6-cis. Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group. There were no drug-related changes in blood chemistry, kidney function tests, hematology or liver enzymes. There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group. In both groups follicle-stimulating and luteinizing hormone values were depressed. Testicular and penis atrophy was observed in the 2.6-cis group. Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups. In general, no tumor regression was observed during administration of 300 mg. 2.6-cis daily for at least 3 months. Some tumor regression was noted during 600 mg. estramustine therapy daily.

Topics: Aged; Estramustine; Estrogens, Non-Steroidal; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Silicones; Siloxanes

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9 percent of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.

Topics: Drug Therapy, Combination; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Topics: Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Dacarbazine; Diethylstilbestrol; Drug Evaluation; Drug Therapy, Combination; Estramustine; Fluorouracil; Humans; Hydroxyurea; Male; National Health Programs; Neoplasm Recurrence, Local; Prednisolone; Procarbazine; Prognosis; Prostatic Neoplasms; Streptozocin; Time Factors; United States

Estramustine phosphate (Estracyt) was used in the treatment of 154 patients with carcinoma of the prostate in stage IV. Sixty-three patients were given Estracyt from the outset (primary treatment group) and 91 had previously received some other endocrine therapy (secondary treatment group). All of the patients were observed for more than one year. The drug was given intravenously and/or orally. Objective remissions occurred in 46 (73.0%) of the 63 patients in the primary treatment group and subjective remissions in all the objective responders and in 12 additional patients (92.0%). The corresponding figures for the secondary treatment group were 28 (30.7%) and 52 (57.1%) of 91. The side-effects were negligible, and the drug was well tolerated. No cumulative toxic effect was observed in patients who had been receiving the treatment for more than five years. In our opinion the compound is valuable in the treatment of advanced prostatic carcinoma (stage IV).

Topics: Acid Phosphatase; Administration, Oral; Clinical Trials as Topic; Drug Evaluation; Estramustine; Follow-Up Studies; Humans; Injections, Intravenous; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Remission, Spontaneous

30 patients with oestrogen-escaped carcinoma of the prostate have been treated with estramustine phosphate (Estracyt). 27% showed a partial objective response and 33% had a subjective response. The terms used for defining a response are challenged and it is recommended that comparative controlled trials are necessary to judge the place of this drug in the management of advanced prostatic cancer.

Topics: Clinical Trials as Topic; Drug Evaluation; Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

In Roswell Park Memorial Institute, between 1969 and 1974, a total of 32 patients with widespread metastasized carcinoma of the prostate were treated with oral Estracyt. Objectively demonstrable remissions were achieved in eight patients (8/32 equals 25%). Subjective improvement of their general condition was experienced by 15 patients (15/32 equals 47%). The toxicity of Estracyt manifests itself with gastrointestinal disorders, which in most cases are amenable to anti-emetic treatment.

Topics: Administration, Oral; Aged; Clinical Trials as Topic; Drug Evaluation; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Palliative Care; Prostatic Neoplasms

The experience gained with Estracyt, kindly supplied by AB LEO, Sweden, is reported. On the basis of former data in the literature we only used the drug in estrogen resistant and advanced cases. Estracyt (estramustine phosphate) is a nitrogen mustard derivative of the urethan type, attached to oestradiol-17-phosphate. In histologically verified cases, it was administered in daily doses of 300 mg intravenously for three weeks, followed by maintenance doses of 300 mg a week in tablets for three months. During treatment, liver and bone marrow function was checked systematically. The changes in morphological picture were studied by means of biopsies during and at the end of treatment. In agreement with the data in the literature a favourable effect was observed in estrogen resistant patients, with no toxic effect whatever on the bone marrow. At the same time GOT and GPT and BSP retention examinations demonstrated a hepatotoxic side effect. The pathological values returned to normal after withdrawal of the drug. Histological examinations showed that the tumour cells had changed but failed to disappear after treatment.

Topics: Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Resistance; Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

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 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.. 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.. NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Estramustine; Gonadotropin-Releasing Hormone; Humans; Japan; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies

Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt-estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component.

Topics: Antineoplastic Agents; Cisplatin; Drug Screening Assays, Antitumor; Estramustine; Humans; Male; Prodrugs; Prostatic Neoplasms; Tumor Cells, Cultured

To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP).. Our NCHT protocol involved complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m. In the NCHT group, 10.0% experienced pathologic complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien-Dindo grade III or higher) 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 = 5.251, 95%CI 1.300-21.201; P = .020). In propensity score matching, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = .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 = .027).. 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.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Docetaxel; Estramustine; Follow-Up Studies; Humans; Male; Neoadjuvant Therapy; Propensity Score; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Survival Rate; Treatment Outcome

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.

Topics: Apoptosis; Caspase 3; Down-Regulation; Estramustine; Humans; Male; MicroRNAs; PC-3 Cells; Prostatic Neoplasms

The aim of the present study was to assess the cost-effectiveness of extended pelvic lymph node dissection (ePLND) compared to neoadjuvant chemohormonal therapy using gonadotropin-releasing hormone agonist/antagonist and estramustine. We retrospectively analyzed data within Michinoku Urological Cancer Study Group database containing 2971 PC patients treated with radical prostatectomy (RP) at four institutes between July 1996 and July 2017. We identified 237 and 403 high-risk patients who underwent RP and ePLND (ePLND group), and neoadjuvant chemohormonal therapy followed by RP and limited PLND (neoadjuvant group), respectively. The oncological outcomes and cost-effectiveness were compared between groups. Medical cost calculation focused on PC-related medication and adjuvant radiotherapy. Biochemical recurrence-free and overall survival rates in the neoadjuvant group were significantly higher than those in the ePLND group. Significantly higher number of patients progressed to castration-resistant PC in the ePLND group than in the neoadjuvant group. Background-adjusted multivariate Cox regression analysis using inverse probability of treatment weighting (IPTW) revealed that neoadjuvant chemohormonal therapy independently reduced the risk of biochemical recurrence after RP. The 5-year cost per person was significantly higher in the ePLND group than in the neoadjuvant group. Although the present study was retrospective, neoadjuvant chemohormonal therapy followed by RP as a concurrent strategy has potential to improve oncological outcome and cost-effectiveness.

Topics: Aged; Antineoplastic Agents, Hormonal; Cost-Benefit Analysis; Disease-Free Survival; Estramustine; Gonadotropin-Releasing Hormone; Humans; Lymph Node Excision; Male; Middle Aged; Neoadjuvant Therapy; Proportional Hazards Models; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Retrospective Studies; Treatment Outcome

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. The current guidelines recommend extended pelvic lymph node dissection (e-PLND) for selected intermediate- and high-risk patients treated with RP. However, the indications, optimal extent, and therapeutic benefits of e-PLND remain unclear. The aim of this study was to assess whether e-PLND confers an oncological benefit for high-risk Pca compared to neoadjuvant luteinizing hormone-releasing hormone and estramustine (LHRH + EMP). The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at four 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 outcome measure was BRFS. The 5-year biochemical recurrence-free survival rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9 and 54.7%, respectively (P < 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. Although the present study was not randomized, neoadjuvant LHRH + EMP therapy followed by RP might reduce the risk of biochemical recurrence.

Topics: Aged; Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Estramustine; Gonadotropin-Releasing Hormone; Humans; Lymph Node Excision; Lymph Nodes; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prostatic Neoplasms; Retrospective Studies; Risk Factors

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.

Topics: Academic Medical Centers; Aged; Antineoplastic Agents, Hormonal; Cohort Studies; Disease-Free Survival; Drug Therapy, Combination; Estramustine; Gonadotropin-Releasing Hormone; Humans; Japan; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Oligopeptides; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Rate; Treatment Outcome

Exploring the relationships among adverse events is important because those that arise from a common mechanism are amenable to a common intervention, which can improve symptom management, quality of life, and treatment adherence. To date, symptom cluster studies have used patient-reported data, which are not always available in clinical trials. In this study, we proposed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) to identify adverse event clusters because the CTCAE data are collected as standard practice and can therefore be used when patient-reported outcomes are unavailable.. The CTCAE data from a randomized clinical trial conducted by SWOG that compared docetaxel plus estramustine versus mitoxantrone plus predinsone in patients with advanced prostate cancer were used to identify severe adverse event clusters. A variable based hierarchical cluster analysis was conducted using the CTCAE for the 323 patients who experienced at least one grade 3 or higher adverse event.. A total of 109 adverse event types were captured using the CTCAE. Four clusters had moderate associations: nausea, vomiting, and anorexia (n = 35, r = 0.45); joint/bone(myalgia, arthralgia, and arthritis) and muscle weakness (n = 26, r = 0.29); anemia and transfusion (n = 20, r = 0.38); and neutrophils/granulocytes, febrile neutropenia, and leukocytes/lymphopenia (n = 114, r = 0.29). Two clusters had weak associations: fatigue/malaise/lethargy and dehydration (n = 66, r = 0.12); and constipation, infection without neutropenia, and abdominal pain/cramping (n = 35, r = 0.13).. Several severe adverse event clusters were identified in patients with advanced prostate cancer. Identifying adverse event clusters using CTCAE data from clinical trials is feasible.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Cluster Analysis; Docetaxel; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; National Cancer Institute (U.S.); Prednisone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Taxoids; United States

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 a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca.. The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS.. The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110).. Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

Topics: Aged; Antineoplastic Agents, Hormonal; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Propensity Score; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Analysis

We investigated the clinical significance of chromogranin A (CgA) expression as a neuroendocrine (NE) marker during prostate cancer (PCa) progression, especially as a potential predictor of chemotherapeutic response in castration-resistant PCa (CRPC) patients based on immunohistochemical findings.. Sixteen CRPC patients who underwent combination (docetaxel/estramustine/ carboplatin; DEC) chemotherapy were retrospectively studied. Immunostaining of CgA was performed using prostate biopsy samples obtained at the initial PCa diagnosis, during androgen deprivation therapy, at the time of CRPC diagnosis, and after 2 cycles of DEC therapy. The positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells. Differences in positive rates among the treatment courses were compared using a Mann-Whitney test.. The mean percentage of CgA-positive PCa cells increased in a stepwise manner until CRPC development and then significantly decreased after DEC therapy. Subanalysis of CgA at CRPC diagnosis showed a more evident reduction of CgA expression after DEC therapy in patients who also had a high level of CgA as compared to those with a low CgA level (P = .003). Likewise, longer prostate-specific antigen progression-free survival was related to CRPC and high CgA (P = .028).. NE differentiation of PCa cells is accelerated despite androgen deprivation and reaches a peak at the time of CRPC diagnosis. Although further studies using larger samples are needed, CgA expression in CRPC may be a candidate tissue biomarker to reflect the chemotherapy sensitivity of individual PCa cells.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chromogranin A; Disease Progression; Disease-Free Survival; Docetaxel; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids

Topics: Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Denosumab; Diphosphonates; Docetaxel; Drug Approval; Drugs, Investigational; Estramustine; Goserelin; Humans; Imidazoles; Male; Mitoxantrone; Nitriles; Oligopeptides; Phenylthiohydantoin; Prostatic Neoplasms; Radioisotopes; Radium; Taxoids; Tissue Extracts; United States; United States Food and Drug Administration; Zoledronic Acid

To date, the different treatment modalities for high-risk prostate cancer (Pca) have not been compared in any sufficiently large-scale, prospective, randomized clinical trial. We used propensity-score matching analysis to compare the oncological outcomes of high-risk prostate cancer between patients treated with radical prostatectomy (RP) and those treated with radiation therapy (RT).. We studied 216 patients who received neoadjuvant therapy followed by RP (RP cohort) and 81 patients who received neoadjuvant androgen-deprivation therapy (ADT) followed by RT (RT cohort). The RP cohort received a luteinizing hormone-releasing hormone agonist and estramustine phosphate (280 mg/day) for 6 months prior to RP. The RT cohort received ADT for at least 6 months prior to RT using a 3-dimensional conformal radiotherapy technique. The total radiation dose was 70 to 76 Gy administered at 2 Gy/fraction.. Propensity-score matching identified 78 matched pairs of patients. The 3-year overall survival rates were 98.3% and 92.1% in the RP and RT groups, respectively (P=0.156). The 3-year biochemical recurrence-free survival rates were 86.4% and 89.4% in the RP and RT groups, respectively (P=0.878).. Our study findings may suggest almost identical cancer control of RP and RT with appropriate neoadjuvant therapy in high-risk Pca. Therefore, issues of health-related quality of life may have an important impact on decision making in treatment of high-risk Pca.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Male; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Propensity Score; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy Dosage; Retrospective Studies; Survival Rate

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Goserelin; Humans; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Taxoids; Tosyl Compounds

This retrospective chart review study was conducted to evaluate the efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC) and to determine who would benefit from EMP therapy. EMP was administered at a daily dose of 560 mg to 102 patients as a third-line therapy, who had already received combined androgen blockade (CAB) and subsequent alternative antiandrogen therapy. The responses to EMP after its induction and its toxicity were evaluated. We also analyzed the association between the clinicopathological factors of the patients and their responses to EMP therapy. A reduction in the serum prostate-specific antigen (PSA) 4 weeks after induction was observed in 70 patients (68.6%), while 30 cases (29.4%) achieved more than 50% reduction of PSA. Long-term reduction of PSA from baseline for more than 6 months was observed in 31 patients (30.4%). EMP treatment was discontinued in 11 patients (10.8%) because of side effects (nausea in six patients, gynecomastia in three patients, eruption in one patient, and liver dysfunction in one patient). Multivariate analysis demonstrated that long duration of prior hormonal therapy was an independent favorable factor for reduced PSA levels, long responses, and overall survival. The data suggest that oral EMP administration as a third-line monotherapy is well tolerated and effective to some degree in patients with CRPC who have already received CAB and subsequent alternative antiandrogen therapy. Thus, EMP can be regarded as one treatment option, especially for patients whose prior duration of hormonal therapy was long.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Castration; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

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

Treatment options for patients who progressed to castration-resistant prostate cancer (CRPC) are very limited. The purpose of this study was to assess the efficacy of estramustine phosphate (EMP) in patients with CRPC, grouped according to the risk classification advocated by Armstrong et al. and to identify candidates for EMP treatment. Between March 2003 and July 2010, 82 patients with CRPC were treated with 280 or 560 mg EMP per os daily until disease progression or occurrence of unacceptable adverse events. Prostate-specific antigen (PSA) response and overall survival were evaluated according to risk classification. 52 (67%) patients achieved PSA decline. Rates of PSA decline in the good-, intermediate-, and poor-risk groups were 77, 71, and 25%, respectively, significantly higher in the good- and intermediate-risk groups than the poor-risk group (p=0.03). The median overall survival times in good-, intermediate-, and poor-risk groups were 21, 19, and 9 months, respectively (p=0.005 for good vs intermediate, p=0.001 for intermediate vs poor). When the intermediate-risk group was divided into two subgroups by PSA doubling time (PSADT), men with PSADT≥2 months achieved higher PSA response rate (88%) and longer survival (22 months) than those with PSADT<2 months (53%, 15 months). Patients with good-risk or intermediate-risk with PSA doubling time≥2 months achieved favourable PSA response and survival and may benefit from chemotherapy with EMP.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms

The significance of combination of docetaxel (DTX) with estramustine phosphate (EMP) in castration-resistant prostate cancer (CRPC) patients remains unclear. In this study, we aimed to retrospectively evaluate the efficacy and toxicity of DTX with or without EMP and to elucidate the significance of DTX and EMP combination therapy in Japanese EMP-refractory CRPC patients.. To compare the efficacy and toxicity of DTX and EMP, we divided CRPC patients, who were confirmed to be resistant to EMP, into the following two groups: group D (n = 28), which included patients treated with DTX (60 mg/m2, once in every four weeks) alone, and group DE (n = 33), which included patients treated with a combination of DTX (60 mg/m2, once in every four weeks) and EMP (twice daily oral administration at 280 mg).. Prostate specific antigen (PSA) response (> 50% decline in PSA) was observed in six patients (21%) in group D and eight patients (24%) in group DE. The median time to progression (TTP) was 12.0 months and 6.2 months and the median overall survival (OS) was 26.4 months and 24.3 months in group D and DE, respectively. There was no statistical difference between the two groups in terms of PSA response, TTP, and OS. The incidence of adverse events of grade 3/4 was low in both the groups, and there was no statistical difference between the two groups.. Although treatment with DTX at 60 mg/m2 was effective and highly tolerated in EMP-refractory Japanese CRPC patients, the DTX and EMP combination therapy might not exhibit any survival benefit for CRPC patients.

Topics: Aged; Aged, 80 and over; Biomarkers; Disease-Free Survival; Docetaxel; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids

This article reviews the initial experience with chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) and outlines some of the ongoing clinical trials in this area. In addition, the authors outline current knowledge on outcomes of patients treated with taxane-based chemotherapy on retrospective analysis of randomized trials. These data are intended to provide physicians and patients with a general idea on the outcomes of men with mCRPC that may facilitate clinical decisions as well as the design and evaluation of clinical trials.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Cytotoxins; Disease Progression; Docetaxel; Drug Therapy, Combination; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Prognosis; Prostatic Neoplasms; Taxoids; Treatment Outcome

To assess the impact of continued androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer (CRPC) receiving first-line docetaxel-based chemotherapy.. A retrospective review was performed on 78 patients fulfilling the criteria for CRPC who were treated with docetaxel-based chemotherapy over 5 years.. Thirty-nine patients received concurrent ADT (ADT group), whereas 39 patients discontinued ADT (No-ADT group). PSA response rates were 66.7% for ADT patients and 48.7% for No-ADT patients (P = 0.27). The median progression-free survival and overall survival were 5.0 months and 24.8 months for ADT patients and 4.9 months and 22.1 months for No-ADT patients, respectively (P = 0.57, P = 0.94). Follow-up testosterone levels were available in 13 patients of the No-ADT group and none of them recovered a normal serum testosterone level over a median follow-up duration of 8.3 months from ADT discontinuation. ADT was recommenced in 21 of 39 patients in the No-ADT group and, of these, 6 (29%) achieved a PSA response.. Clinical outcomes were not significantly different when patients with CRPC received concurrent ADT, or were not so treated, when receiving first-line docetaxel-based chemotherapy. Despite ADT withdrawal, serum testosterone level did not recover to the noncastrated level during the period of chemotherapy, and reinduction of hormone sensitivity occurred in about one-quarter of patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Republic of Korea; Retrospective Studies; Survival Analysis; Taxoids; Testosterone

A 66-year-old man was referred to our outpatient clinic for an elevated serum prostatic-specific antigen (PSA 4,319 ng/ mL). Magnetic resonance imaging (MRI) showed multiple metastatic lesions in the bones. The patient had received androgen deprivation therapy, but six months after treatment, he was diagnosed as having prostate cancer refractory to hormones. Combined treatment with docetaxel (DOC 30 mg/m²/week )and estramustine phosphate (EMP 560 mg/day) was initiated as first-line chemotherapy, but the treatment was discontinued because of side effects. Then, treatment with zoledronic acid was started(4 mg/4 weeks)and the PSA level decreased dramatically from 457.2 ng/mL to 5.5 ng/mL. Seven months after the diagnosis of CRPC, MRI showed a decrease ofbone metastases, and the PSA levels continued to decrease, eventually reaching 0.3 ng/mL. Zoledronic acid appears to not only show efficacy in preventing skeletal-related events, but has a potential antitumor effect in patients with metastatic CRPC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Castration; Diphosphonates; Estramustine; Fatal Outcome; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms; Zoledronic Acid

Chemotherapy with docetaxcel (DTX) plus estramustine (EMP) for castration-resistant prostate cancer (CRPC) was started 30 months after the patient, a 65-year-old man, was diagnosed as having advanced prostate cancer cT3aN1M1 (OSS) with an initial PSA of 490 ng/ml. Prostate biopsy specimens revealed moderately differentiated adenocarcinoma, Gleason's sum 4＋5. He was treated with DTX 30 mg/m2 on day 2 and oral EMP 560 mg/day days 1-3 weekly for 3 out of 4 weeks. PSA at start of DTX plus EMP was 81.7 ng/ml, and that after 59 months was 66.6 ng/ml. No objective change in computed tomography and bone scan were observed. He also had no cancer-related symptoms and activity of daily life was good. Chemotherapy was interrupted twice because of pleural effusion and dyspnea by DTX, at 3 and 4 months, respectively, long-term disease stabilization was obtained by this treatment. Other adverse events including interstitial pneumonia, cardiovascular disorders and myelosuppression were not observed. He was maintained on the same chemotherapy. DTX plus EMP chemotherapy is an effective treatment for CRPC patients. Continuing this therapy it is important to survey and control adverse events caused by DTX and EMP carefully.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Taxoids; Treatment Outcome

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Estramustine; Humans; Male; Oxonic Acid; Prostatic Neoplasms; Tegafur; Uracil

In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups.. Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2.. Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2.. Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of patient selection, study 3 has been successfully launched on September 2005 with high drug compliance. Better clinical results are being accumulated.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cause of Death; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms

A 82-year-old man was referred to our hospital for treatment of hormone-refractory prostate cancer with liver metastases. The obstruction of intrahepatic bile ducts due to the rapid growth of liver metastases induced liver dysfunction. We administered 25 mg/m(2) docetaxel on day1 and 280 mg/body estramustine phosphate on day 1 to day 3, every 4 weeks. After two courses of this combined chemothrapy, the liver metastases were markedly reduced in size with the rapid improvement of liver function.

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Liver Diseases; Liver Neoplasms; Male; Prostatic Neoplasms; Taxoids

Chemotherapy is indicated in metastatic castration-refractory prostate cancer. It aims at alleviating symptoms and increasing survival, without impairing quality of life. Docetaxel is considered as the reference treatment in this indication. However, several studies demonstrated the relevance of associating estramustin with docetaxel, due to the synergistic effect of the combination and the action of estramustin on resistance mechanisms. Moreover, the addition of estramustin to chemotherapy demonstrated a survival benefit for patients. Thrombotic events are frequent in patients with advanced prostate cancer and estramustine is known to increase the risk. Optimization of treatment requires a thorough assessment of the individual risk in each patient as well as the prescription of an anti-thrombotic prophylaxis, which should be currently based on low molecular weight heparin.

Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Paclitaxel (PTX) and docetaxel (DTX) have been reported to be effective for treating hormone-refractory prostate cancer (HRPC). The objective of this study was to examine the efficacy of weekly DTX (PTX)-based chemotherapy and compare weekly DTX-based chemotherapy with triweekly (once every 3 weeks) DTX-based chemotherapy. We performed a combination chemotherapy on a weekly cycle with an i.v. PTX 100 mg/m(2) or i.v. DTX 30 mg/m(2) (days 1, 8, 15, and 22), i.v. carboplatin (CBDCA) (day 1, area under the plasma concentration time curve = 6), and oral estramustine phosphate 10 mg/kg daily for 10 HRPC patients. In addition, we investigated the patient characteristics and treatment efficacy and toxicity. Among all cases, serum prostate-specific antigen (PSA) decreased by 50% or more in 90% of patients, by 75% or more in 70%, and 90% or more in 40% after chemotherapy. The effectiveness of weekly DTX-based chemotherapy was comparable with previous reports, and we showed no toxicity serious enough to require cancellation of chemotherapy. In conclusion, weekly DTX-based chemotherapy was no less effective and less toxic than triweekly DTX-based chemotherapy for HRPC patients and therefore can be useful as the first-line chemotherapy regimen for HRPC patients, especially the elderly or those with a poor performance status.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Disease Progression; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

Topics: Adenocarcinoma; Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Precision Medicine; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment

To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone-refractory prostate cancer (HRPC).. A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate-specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed.. A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3-4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4-5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe.. Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Therapy, Combination; Estramustine; Humans; Hydrocortisone; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; Taxoids

The objective of this study was to evaluate the efficacy and safety of low-dose docetaxel, estramustine and dexamethasone combination chemotherapy in patients with hormone-refractory prostate cancer (HRPC). Sixty-nine patients with HRPC were enrolled. Docetaxel was given at a dose of 25 mg/m(2) on days 1 and 8 every 3 weeks, oral estramustine 280 mg twice daily on days 1 to 3 and 8 to 10, and oral dexamethasone 1 mg daily throughout the course. Cycles were repeated every 21 days. Treatment was continued until disease progression or excessive toxicity. Patients were evaluated for response and toxicity. Patients received a median of eleven cycles (range : 1-25). Prostatic-specific antigen (PSA) was decreased greater than 50% in 53 (77%) out of 69 patients and median duration of PSA response was 10.2 months. Median time to progression and overall survival 10.2 and 24 months, respectively. Grade 1-2 fatigue was the most common toxicity observed in 10 (15%) patients. Grade 3-4 toxicities were observed in five (7%) patients (2 thrombosis, 2 bilirubin elevation, and 1 aspartate transaminase/alanine transaminase elevation). Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy is an effective and well tolerated treatment for Japanese HRPC patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Dexamethasone; Docetaxel; Drug Administration Schedule; Estramustine; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids

Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to maximal androgen blockade (MAB) but later showing PSA relapse and treated with estrogen.. In prostate cancer patients newly diagnosed from January 1992 to December 2008 at our institution, there were 85 patients in that the PSA level dropped below 10 ng/ml by MAB, but showed PSA relapse thereafter and treated with estrogen. We investigated the relationship between age at diagnosis, clinical stage, pathological differentiation, initial PSA, the value of PSA nadir, duration between diagnosis and initiation of estrogen therapy, duration between PSA failure and initiation of estrogen therapy, the value of PSA at estrogen therapy, PSA doubling time (PSA-DT) at estrogen therapy, PSA response three months after initiation of estrogen therapy, use of diethylstilbestrol diphosphate (DES-P) at the initial stage of therapy, local radiotherapy to prostate, type of estrogen and prognosis after estrogen therapy.. In Kaplan-Meier method, factors which showed poorer prognosis were stage B and D, poorly differentiated, PSA 11.9 ng/ml or higher at estrogen therapy, PSA-DT shorter than 2.3 months before estrogen therapy and PSA response without CR three months after initiation of estrogen therapy. In multivariate analysis, the factor that most significantly affected prognosis after estrogen therapy was PSA response three months after initiation of estrogen therapy (hazard ratio: 12.61), followed by PSA-DT at estrogen therapy (hazard ratio: 2.59).. We investigated the prognostic factors refractory to MAB and treated with estrogen. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to families and patients.

Topics: Aged; Androgen Antagonists; Combined Modality Therapy; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Estrogens; Ethinyl Estradiol; Humans; Kaplan-Meier Estimate; Male; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; Prostatic Neoplasms; Survival Rate; Time Factors

Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in-vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel-resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P<0.05) with no significantly different overall survival of mice treated by docetaxel and estramustine since day 1 or since the onset of resistance to docetaxel. Among the six human androgen-independent tumors treated with estramustine alone, two highly sensitive models, two intermediate responding tumors, and two resistant models were observed. Altogether, these results suggest that estramustine should be combined with docetaxel in PC patients, but the use of this treatment could be limited, particularly in elderly patients, to docetaxel-resistant cases.

Topics: Aged; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Comorbidity; Docetaxel; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Estramustine; Gastrointestinal Diseases; Humans; Male; Mice; Mice, Nude; Neoplasms, Hormone-Dependent; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Vascular Diseases; Venous Thrombosis; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Clinical Trials as Topic; Docetaxel; Drug Approval; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Quality of Life; Taxoids; Tissue Extracts

An 81-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone as an outpatient. After 4 courses of chemotherapy, he was admitted to our hospital in December 2007 because of general fatigue, appetite loss and erythema of the back of hands and face. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. An 80-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone without admission. After 8 courses of the chemotherapy, appetite loss appeared. In January 2008, medical examinations revealed nails peeling off, facial erythema and erosion of the back of his hands. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. Pellagra, a nicotinic acid deficiency disease, is rarely observed clinically nowadays. However, it may occur in the patients, undergoing chemotherapy without admission.

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Docetaxel; Estramustine; Humans; Male; Pellagra; Prostatic Neoplasms; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Taxoids

We evaluated the efficacy and toxicity of intermittent docetaxel (DCT) with estramustine (EM) for hormone-refractory prostate cancer (HRPC).. Fifteen patients were enrolled. They received injected DCT (70 mg/m2 body surface) on day 1 in association with oral EM 560 mg/day (days 1-5). Treatments were repeated every 3 weeks. Serum prostate-specific antigen (PSA) levels were categorized based on the first three courses. Patients exhibiting either a response or stable disease (SD) could have a holiday from treatment (intermittent schedule). The holiday continued until elevation of the PSA level from the nadir baseline level occurred three times. All patients were evaluated for toxicity and quality of life (QOL). Survival curves were established using Kaplan-Meier graphs.. The median number of courses of DCT/EM therapy was five (range, 3-12 courses). The response rate of the first cycle was 53%: 3 patients with complete response (CR), 5 patients with partial response (PR), 4 patients with SD, and 3 patients with disease progression. Eight patients were able to begin the second re-entry cycle. No patients showed a CR, 2 patients exhibited PR, 4 patients had SD, and the overall response rate was 25%. The survival rates were 93% at 1 year, and 26.1% at 2 years Grade 3-4 anemia was observed in 2 patients (13.3%), neutropenia in 11 (73.3%), and thrombocytopenia in 2 (13.3%). The QOL scale showed good QOL after 6 months, with improvement in the score for nausea and vomiting.. Intermittent DCT/EM therapy was well tolerated, and has the potential to prolong survival, with a high QOL, in patients with HRPC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Quality of Life; Taxoids

Management of castration-resistant prostate cancer after docetaxel has become an unmet need for which various agents have been investigated. We report our experience with a paclitaxel-based regimen.. From February 2004 to November 2007, 15 patients (PTS) received paclitaxel 80 mg/m(2) weekly on day 1, carboplatin (AUC = 6) on day 1 every 21 days and estramustine 140 mg on days -1, 0 and 1 every week.. Patient characteristics are: median age 67 years (range 44-81), median performance status (Eastern Cooperative Oncology Group) 1 (range 0-2) and median prostate-specific antigen 67.5 ng/ml (range 1.5-480). All PTS had soft-tissue and 12 (80%) also had osseous disease. A >50% decrease in prostate-specific antigen levels occurred in 9 PTS (60%, 95% CI 32-84). Responses included a partial response in 6 (40%, 95% CI 16-68) and stable disease in 5 PTS (33%). Median duration of progression-free survival was 4.0 months (range 1.1-13) and median survival was 14.6 months. After a median of 4 cycles (range 1-7), significant toxicity included fatigue grade 3 in 2 PTS (13%), neuropathy grade 2 and grade 4 in 1 patient each, and a single episode of grade 3 edema. Myelosuppression was mild. Two PTS (13%) had urinary tract infection and 1 patient neutropenic fever. One patient died due to brain hemorrhage.. Administration of second-line paclitaxel-based chemotherapy after docetaxel therapy is active in PTS with castration-resistant prostate cancer. This regimen is too toxic for palliative therapy. Careful patient selection is needed when this regimen is considered for therapy in these PTS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Taxoids; Time Factors; Treatment Outcome

To evaluate the prostate-specific antigen (PSA) 'flare' phenomenon in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel, as flare is a known effect of androgen-deprivation therapy in hormone-dependent prostate cancer.. The charts of 56 patients who received docetaxel-based chemotherapy in three different centres from August 1999 to August 2007 were reviewed retrospectively. The biochemical response was characterized according to the Bubley criteria. There was an immediate PSA response (PSA decline >or= 50%) in 23 (41%) patients, PSA stabilization (PSA decline < 50%) in 16 (29%) and PSA progression in nine (16%). There was also a fourth response, i.e. PSA flare, defined as an increase in PSA level with no symptomatic progression, after starting docetaxel-based chemotherapy administered every 3 weeks.. Eight (14%) patients with PSA flare were identified; all had osseous disease and five had additional soft-tissue disease. The PSA flare lasted a median (range) of 21 (21-42) days and it spread over a median of 1 (1-2) cycles. The temporary PSA surge exceeded baseline values by a median (range) of 61.5 (12-404)%. There was a subsequent PSA response in six of the eight patients and PSA stabilized in the remaining two. Patients with flare received a median of 8.5 (5-12) treatment cycles, vs a median of 8 (2-12) in the immediate PSA response group (P = 0.103, Student's t-test). The Response Evaluation Criteria in Solid Tumors criteria evaluation showed one patient with a partial response and six with stable disease. The median survival of patients with PSA flare was 12.5 months, while that of the immediate PSA responders was 20.1 months (not statistically significant, P = 0.168, log-rank test).. Of patients with AIPC, 14% had an initial PSA flare after starting docetaxel-based chemotherapy. The occurrence of PSA flare had no effect on treatment duration or outcome. With lack of clinical progression, docetaxel-based chemotherapy should be administered for at least two 3-week cycles before further decisions are made about efficacy.

Topics: Aged; Aged, 80 and over; Androgens; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids

Topics: Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Docetaxel; Estramustine; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

Topics: Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Docetaxel; Estramustine; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy.. This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m(2) (day 2) and estramustine 140 mg three dimes daily (days 1-3).. Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p=0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p=0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p=0.007).. Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy.

Topics: Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Docetaxel; Estramustine; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

The intention of this study is to describe the impact and underlying potential basis of the prostate-specific antigen (PSA) flare-up phenomenon in patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel-based chemotherapy.. We retrospectively identified 74 consecutive patients who received docetaxel/estramustine-based chemotherapy at our institution. Patients were evaluated based on modified criteria from the Prostate-Specific Antigen Working Group regarding survival and toxicity. Additionally, two androgen receptor mutations derived from patients with advanced disease were analyzed for promiscuous transactivation activity.. The 74 patients were stratified into four groups: response, partial response, flare-up-initial PSA elevation, and progression. Median survival in the flare-up group (n=8) was 20 months and did not differ from the response group (p=0.564). The flare-up group showed a maximum PSA elevation from baseline between 3.4 and 28.3% (between three and six weeks) followed by PSA decline >or=50% from the baseline level in seven of the eight patients. The androgen receptor mutations AR(877) and AR(715) displayed a 37.5- and 5.2-fold increase in transactivation activity by progesterone and a 12.6- and 5.4-fold increase by estrogen compared to the AR(WT), respectively.. A considerable portion of HRPC patients experience an initial PSA flare-up under systemic chemotherapy. In this study, occurrence of flare-up phenomenon did not impact survival. Chemotherapy should be continued a minimum of six weeks before removing patients from a docetaxel-based regimen. We showed evidence that co-medication with dexamethasone/prednisolone and/or estramustine itself can induce an initial PSA flare-up via androgen receptor mutations.

Topics: Adenocarcinoma; Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Kaplan-Meier Estimate; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Retrospective Studies; Survival Rate; Taxoids; 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

To investigate how thalidomide confers its survival benefit in prostate cancer, by assessing its effect on circulating endothelial cells (CECs) and progenitors (CEPs) in a combined therapy of thalidomide and chemotherapy drugs in a human prostate cancer xenograft model, as in clinical trials patients treated with both thalidomide and docetaxel had a >50% decrease in prostate-specific antigen (PSA) levels and longer median overall survival than those treated with docetaxel monotherapy.. A human prostate cancer xenograft model was used to evaluate the effect of either thalidomide, docetaxel or a combination of the two drugs on circulating ECs. Drug treatment was continued for 17 days, and tumours were measured two or three times a week. Blood samples were taken at three different time points: before the treatments, 4 days and 17 days into the treatments, and CECs and CEPs were measured by flow cytometry analysis.. There was an increased level of apoptotic/dead CECs shortly after the intravenous injection of docetaxel, and the addition of thalidomide further increased the apoptotic/dead CEC level, showing that thalidomide enhances the cytotoxicity of docetaxel against tumour vascular ECs.. Thalidomide increased the apoptotic/dead CEC level and enhanced the cytotoxicity of docetaxel against tumour vascular ECs, confirming its antiangiogenic property in vivo in combined anticancer treatments. In addition, there was a correlation between the increased apoptotic/dead CEC levels early in the treatment and antitumour efficacy later, suggesting that the apoptotic/dead CEC level could be used as a marker, at an early stage, to predict tumour response to antiangiogenic therapies.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Docetaxel; Drug Synergism; Endothelial Cells; Estramustine; Humans; Male; Mice; Mice, SCID; Neoplasm Transplantation; Prostatic Neoplasms; Random Allocation; Stem Cells; Taxoids; Thalidomide; Transplantation, Heterologous

Metastatic prostate cancer (PC) is incurable by androgen deprivation therapy alone, due to the presence of androgen-independent/supersensitive cells in hormone-naive PC. A 67-year-old man was diagnosed with PC (Gleason score, 5 + 4) with multiple bone metastases. He was treated by chemohormonal therapy with cisplatin and estramustine phosphate (EMP) followed by maximal androgen blockade, and showed a complete response. As of the time of writing, no clinical or prostate-specific antigen recurrence has been observed for over 15 years, despite cessation of the treatment. This is the first report to indicate a possible cure of metastatic PC by chemohormonal therapy combined with appropriate anti-tumor drugs targeted to both androgen-independent and -dependent clones before the hormone-refractory state.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Estramustine; Humans; Male; Prostatic Neoplasms

To evaluate the efficacy of docetaxel/carboplatin (DC)-based chemotherapy as first- and second-line chemotherapy for patients with hormone-refractory prostate cancer (HRPC).. We retrospectively identified all patients with HRPC treated with DC-based chemotherapy at the Dana-Farber Cancer Institute. Regimens either included estramustine (EDC) or not (DC). We identified patients who received EDC as first-line chemotherapy and patients who received DC as second-line or subsequent chemotherapy. Patients treated with EDC received 20-70 mg/m(2) docetaxel every 1-4 weeks, estramustine 140 mg three times daily and carboplatin (area under the curve, AUC), (4-6) every 3-4 weeks. Patients treated with DC received docetaxel 50-70 mg/m(2) and carboplatin AUC (4-6) every 3-4 weeks.. In all, the study included 54 patients; 24 received EDC and 30 DC (median age 62.8 and 66.9 years, respectively); their prostate-specific antigen (PSA) level at the start of chemotherapy was 112.7 and 213.3 ng/mL, respectively. There were declines of >or=50% in PSA level in 88% and 20% in the two groups, respectively. The median overall survival was 17.7 and 14.9 months in the EDC and DC groups, respectively. The most common reversible grade 4 toxicity with either regimen was neutropenia (4% and 7% in EDC and DC, respectively).. DC-based chemotherapy is well tolerated and active in HRPC. Adding carboplatin to docetaxel provides an additional activity in 20% of patients as a second-line or subsequent chemotherapy.

Topics: Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Docetaxel; Estramustine; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome

Chemotherapy has emerged as a standard treatment in patients with castration-refractory prostate cancer (CRPC). Consensus criteria are available to define response in CRPC as at least a 50% decline in serum prostate-specific antigen (PSA) confirmed 4 weeks later. The objective of this work was to study early serum PSA changes in patients under chemotherapy and to correlate these changes with subsequent response assessment.. Serum PSA levels were monitored every 3 weeks in 79 patients with CRPC treated with chemotherapy and a time course of serum PSA levels was obtained. Correlation with response was studied.. According to consensus criteria, 21 (40%) and 20 (38%) patients achieved a PSA response and stabilization, respectively, after first-line chemotherapy. Among patients who achieved either a response or a stabilization, 8 of 41 (20%) had a serum PSA rise during the first 8 weeks of chemotherapy, followed by a subsequent decline in serum PSA. The same observation was made in patients receiving second-line chemotherapy: 6 of 20 patients achieving a response or stabilization had an initial serum PSA rise. The postchemotherapy increase in serum PSA could reach more than twice the baseline value. The duration of the PSA surge ranged from 1 to 8 weeks. When considering responders only, 6 of 30 (20%) had a postchemotherapy serum PSA surge, followed by a drop.. Postchemotherapy PSA surges occur not infrequently in patients with CRPC who respond to chemotherapy. Physicians should be aware of this effect to avoid inadequate early discontinuation of chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Estramustine; Gonadotropin-Releasing Hormone; Humans; Kinetics; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Sesquiterpenes; Syndrome; Taxoids; Treatment Outcome

We report a case of endobronchial metastasis from prostate adenocarcinoma. A patient with a history of prostate cancer under complete androgen blockade presented to the respiratory department complaining of dyspnea and dry coughing. Flexible bronchoscopy showed multiple polypoid lesions in the tracheobronchial tree and the immunohistochemical studies on the biopsy specimen determined the diagnosis. The patient was treated with paclitaxel, estramustine phosphate and carboplatine, and experienced symptoms suppression. To our knowledge, this is the first case of endobronchial metastasis of a patient with androgen refractory prostate cancer without any evidence of extrathoracic metastasis. The current report also emphasises the need for a multidisciplinary approach for cases of endobronchial metastases, with the collaboration of pneumologists, urologists, pathologists and oncologists.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bronchial Neoplasms; Bronchoscopy; Carboplatin; Estramustine; Humans; Male; Middle Aged; Paclitaxel; Prostatic Neoplasms; Tomography, X-Ray Computed

Topics: Androgens; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Selection Bias; Survival Analysis; Taxoids; Treatment Outcome

Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor Ro 28-2653 has been shown in various models of different tumor entities. We hypothesized that the inhibitor effect of Ro 28-2653 on the tumor growth could be improved by combination with chemotherapeutic drugs and examined therefore the effect of Ro 28-2653 alone and in combination with etoposide or estramustine in the MatLyLu Dunning R-3327 rat tumor model characteristic for the androgen-independent prostate cancer (PCa).. In vitro effects were estimated measuring the proliferation of MatLyLu cells incubated with the three agents alone or in combination using the XTT test. The in vivo effects of the agents alone or in combination were examined by measuring the tumor weight 18 days after tumor cell injection.. The proliferation rate was only inhibited by etoposide while that effect was increased in combination with Ro 28-2653 and estramustine. Ro 28-2653 reduced the tumor weight by 86%. That effect was significantly increased in combination with etoposide to 92%.. The inhibitory effect of the MMP inhibitor Ro 28-2653 on the tumor growth in the Dunning PCa model is enhanced by the standard chemotherapeutic drug etoposide. A combined application of both agents could be considered as potential tool to improve the therapy of patients with advanced PCa after failure of hormonal treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Estramustine; Etoposide; Humans; Injections, Intraperitoneal; Male; Neoplasm Invasiveness; Neoplasm Transplantation; Piperazines; Prostatic Neoplasms; Pyrimidines; Rats; Time Factors; Tissue Inhibitor of Metalloproteinases

This case report demonstrates the effect of zoledronic acid (ZA) on a patient with bone metastatic hormone-refractory prostate cancer (HRPC) resistant to taxane, estramustine phosphate, carboplatin, and dexamethasone. The pathogenesis, diagnosis, and management of bone metastasis on HRPC are also reviewed.

Topics: Aged; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Bone Neoplasms; Bridged-Ring Compounds; Carboplatin; Dexamethasone; Diphosphonates; Drug Resistance, Neoplasm; Estramustine; Humans; Imidazoles; Male; Prostatic Neoplasms; Taxoids; Zoledronic Acid

Topics: Antineoplastic Agents; Bone Neoplasms; Carboplatin; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Male; Prostatic Neoplasms; Taxoids; Zoledronic Acid

A total of 42 patients with hormone-refractory prostate cancer received E-E therapy. Oral estramustine phosphate (EMP) was administered twice daily for a total daily dose of 560 mg every day and oral etoposide (E-E therapy, 50 mg/body/day) was given on days 1-21 and stopped on days 22-35. Treatment was continued until the disease progression was confirmed radiographically or PSA had increased from base line of at least 25%. The median follow-up period after E-E therapy was 77.4 months (range : 12.5 to 122.3). Nineteen patients (43%) achieved a PSA decrease of 50% or greater. The median survival time of the patients who had a decrease of 50% or greater in the PSA value (PSA responder) was 29.3 months and the patients who did not (PSA non-responder) was 14.1 months (p = 0.01). There were no significant differences between PSA responders and non-responders when taking into account variables. Excluding those patients with only PSA elevation, the survival time was 14.9 months with no significant difference between PSA responders and non-responders. The toxicities (grade 3 or more) were identified as anemia, leukocytopenia thrombocytopenia, cardiovascular events, and gastrointestinal and hepatic disorders, which occurred in 0, 5, 2, 2, 14, and 2% of the patients, respectively. E-E therapy was considered to be an active oral regimen and well-tolerated for outpatients with hormone-refractory prostate cancer in Japanese patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Etoposide; Humans; Leukopenia; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Thrombocytopenia

To assess the clinical pattern of progression and prostate-specific antigen doubling time (PSA-DT) after exposure to docetaxel-based chemotherapy in patients with androgen-independent prostate cancer (AIPC).. Fifty-five patients received docetaxel-based chemotherapy; data were collected retrospectively from three different departments. Progression was known in 44 (79%) and the PSA-DT was available in 33 patients.. Of the 29 patients with soft-tissue and soft-tissue plus bone metastases, 22 (76%) developed soft-tissue progression. Among the 35 patients with bone and bone plus soft-tissue metastases, 27 (77%) had osseous progression. There was no difference between the PSA-DT at progression before and after docetaxel-based therapy (mean 3.1 vs 2.7 months, P = 0.592, Student's t-test.). However, the median (range) PSA-DT at progression after docetaxel-based therapy was 0.84 (0.3-4) months in patients with a PSA response, significantly shorter than the median of 3.1 (0.3-12) months of patients with no biochemical response (P = 0.002, Student's t-test). The PSA-DT dynamics at progression had no effect on survival (P = 0.63, log-rank test).. The pattern of progression after docetaxel-based chemotherapy is predominantly osseous in patient with bone metastases and mostly soft-tissue in those with soft-tissue disease. Progression after docetaxel-based chemotherapy in AIPC does not modify the PSA-DT before docetaxel. Evaluation of a larger population is needed to assess the clinical relevance of PSA dynamics after docetaxel therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Soft Tissue Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

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

Prostate carcinoma is one of the most frecuent cancers in men. Significant numbers of patients have regional lymph node and bone metastases during the course of the disease. Mediastinal lymphadenopathy and cutaneous metastases are uncommon and signify well-advanced disease. We report the case of a patient with prostate cancer who develops mediastinal lymphadenopathy, pulmonary nodules and cutaneous metastases 8 years after the diagnosis.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cyproterone; Diphosphonates; Estramustine; Fatal Outcome; Flutamide; Humans; Imidazoles; Ketoconazole; Lung Neoplasms; Lymphatic Metastasis; Male; Mediastinum; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Radionuclide Imaging; Skin Neoplasms; Triptorelin Pamoate; Zoledronic Acid

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Risk Assessment; Survival Rate; Taxoids

The prostate specific antigen (PSA) level usually is lowered in response to initial endocrine therapy even in advanced cases of prostate cancer, but in some cases, it is not. We examined the cases in which the PSA level was not sufficiently lowered by initial endocrine therapy with maximal androgen blockade (MAB) or estrogenic drugs.. The subjects were 20 patients with prostate cancer diagnosed between January 1992 and December 2005 whose PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs. We investigated the frequency of cases, pretreatment PSA levels, PSA nadir levels after initial endocrine therapy and throughout the therapy, PSA response to second line therapy, and the prognosis.. The PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs in 4.9% of the cases. Cancer-specific survival rates in all cases were extremely poor, 75.0% at 1 year and 14.7% at 3 years. Prognosis tended to be worse in patients with a higher PSA nadir level throughout the therapy and on whom second therapy was not effective, although the difference was not statistically significant.. The patients whose PSA levels were not lowered sufficiently by MAB or estrogenic drugs had an extremely poor prognosis. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and their families.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Drug Therapy, Combination; Estramustine; Ethinyl Estradiol; Humans; Male; Middle Aged; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Docetaxel; Estramustine; Humans; Male; Meta-Analysis as Topic; Mitoxantrone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids

Epothilones and taxanes interfere with microtubule function. Ixabepilone, which is an epothilone-B analog, has activity against taxane-resistant cell lines and as first-line therapy for men with hormone-refractory prostate carcinoma (HRPC). Clinical cross-resistance of ixabepilone and taxanes in HRPC is unknown.. Records were evaluated retrospectively from patients with HRPC who were treated on a randomized Phase II trial of ixabepilone with or without estramustine and who subsequently received taxane chemotherapy. Posttherapy declines in prostate-specific antigen (PSA) levels and time to PSA progression were defined by consensus criteria. The median survival was evaluated by using the Kaplan-Meier method.. Forty-nine patients who received ixabepilone with estramustine (28 patients) or without estramustine (21 patients) subsequently received second-line taxane therapy. Second-line PSA declines > or = 50% were achieved by 51% of patients (95% confidence interval [95% CI], 33-66%). Second-line PSA declines > or = 50% were achieved by 61% of patients (95% CI, 42-78%) who achieved a first-line PSA decline > or = 50% with ixabepilone, compared with 33% of patients (95% CI, 13-59%) who did not (P = 0.08). Patients who discontinued first-line ixabepilone treatment for disease progression were less likely to achieve a PSA decline > or = 50% in response to second-line, taxane-based therapy compared with patients who discontinued for toxicity or patient preference (36% vs. 71%; P = 0.01).. Second-line taxane chemotherapy after ixabepilone resulted in a substantial frequency of PSA declines. Although patients with ixabepilone-refractory disease were less likely to respond to second-line taxane chemotherapy, 36% did achieve a PSA response. These findings were consistent with incomplete clinical cross-resistance between the taxanes and the epothilones.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome

(1) The standard treatment for metastatic prostate cancer is hormone therapy, based on medical castration (with an LH-RH agonist) or surgical castration (pulpectomy), possibly combined with an androgen antagonist. For patients with hormone-resistant disease the only cytotoxic agents approved in France, estramustine and mitoxantrone, have no proven impact on survival. (2) Docetaxel is now approved in Europe for the treatment of hormone-resistant metastatic prostate cancer, in combination with a steroid. (3) In an open-label comparative trial involving 1006 patients, docetaxel infusion at a dose of 75 mg/m2 every 3 weeks, in combination with prednisone (or prednisolone), significantly extended the median survival time by about 2.5 months as compared with a mitoxantrone-prednisone combination (18.9 versus 16.5 months). In another open-label comparative trial involving 674 patients, a combination of docetaxel + estramustine was significantly more effective than a mitoxantrone + prednisone combination in extending median survival time (17.5 versus 15.6 months). (4) The adverse effects of docetaxel + prednisone were the same as those seen with other indications (hair loss, nausea and vomiting, diarrhea, neutropenia, nail disorders, neuropathies), and were severe in 25% of patients. (5) In France the cost of docetaxel therapy for hormone-resistant metastatic prostate cancer is more than 1000 euros every three weeks. (6) In practice, docetaxel is the first cytotoxic agent shown to prolong survival in men with hormone-resistant metastatic prostate cancer. The benefit is limited, however, especially given the potentially severe adverse effects of docetaxel, which must be disclosed to patients.

Topics: Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug Approval; Drug Therapy, Combination; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Taxoids; Treatment Outcome

The focus of this study was to evaluate the therapeutic benefit of combined gastrin-releasing peptide (GRP) receptor-targeted radiotherapy (TRT) with chemotherapy, using the PC-3 xenograft severe combined immunodeficiency (SCID) mouse model. (177)Lu-DOTA-8-AOC-BBN(7-14)NH(2) is a radiotherapeutic peptide that specifically targets the gastrin-releasing peptide receptor overexpressed on primary and metastatic prostate cancer. The chemotherapeutic agents, docetaxel and estramustine, were administered as single agents or in combination with the receptor-targeted radiotherapeutic agent. Combination receptor TRT/chemotherapy studies were begun 21 days postxenografting and were conducted as multiple-dose trials. The GRP receptor TRT agent was administered every 14 days, and single and combination chemotherapy dose regimens were given weekly. Tumor size, body weight, and body condition score were evaluated twice-weekly and a hematology profile once-weekly. Therapy study tumor volumes were evaluated by way of a repeated measures analysis of variance (ANOVA). Tumor volume measurements at 12 days postdose administration demonstrated a statistically significant (two-tailed P-value <0.05) tumor growth suppression in all experimental groups receiving GRP receptor-targeted radiotherapy, when compared to the control group. The two combined GRP receptor TRT/chemotherapy treatment groups demonstrated the greatest tumor growth suppression of all treatment groups. In comparing the two combined GRP receptor TRT/chemotherapy groups to the GRP receptor TRT alone group, a statistically significant difference was demonstrated for the combined groups by day 30, postdose administration. These data demonstrate that GRP receptor-targeted radiation therapy, using (177)Lu-DOTA-8-AOC-BBN(7-14)NH(2), used either alone or in combination with conventional chemotherapy, can suppress the growth of androgen- independent prostate cancer (AIPC).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blood Chemical Analysis; Bombesin; Docetaxel; Estramustine; Female; Lutetium; Male; Mice; Mice, SCID; Models, Molecular; Peptide Fragments; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Receptors, Bombesin; Taxoids; Tumor Protein, Translationally-Controlled 1; Xenograft Model Antitumor Assays

Prostate-specific antigen (PSA) decline after discontinuation of estramustine phosphate (EMP) is extremely rare. We report a case with dramatic PSA decline after withdrawal of EMP. A patient with prostate cancer had been treated with luteinizing hormone-releasing hormone and EMP. After refractory, EMP was withdrawn. After withdrawal of EMP, PSA dramatically decreased from 214 ng/mL to 3.71 ng/mL (98.5% decline) and remained low for more than 17 months. In association with PSA decline, lumbago and metastatic lesions improved. We should be aware of this phenomenon and the discontinuation of EMP is recommended in patients with rising PSA after an initial response to EMP.

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Estramustine; Follow-Up Studies; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Refusal

The introduction of PSA screening has led to confirming a shift towards an earlier pathological stage in the diagnosis of prostate cancer. Consequently, the proportion of detecting early stage prostate cancer has clearly been increasing. On the other hand, progressive cancers in the form of distant metastases and locally advanced ones that have been confirmed at the initial diagnosis exhibit a constant rate. In addition, there have been a lot of cases where hormonal resistance was acquired during hormonal therapy which resulted in advanced metastases of the prostate. Prostate cancer has a tendency to be metastatic to bones. Combining the fact that the survival period of patients undergoing treatment is prolonged after metastases, the length of suffering caused by complications, such as ostealgia, pathological fracture and myelopathy, becomes an issue in which QOL and ADL of the patient are sacrificed for a long time. As for treatment of prostate cancer with metastases, a palliative treatment is common in the clinical scene. However, we can extend a life prognosis with use of radiotherapy and surgical treatment in addition to the palliative treatment at an appropriate time. It appears that a combination of new chemotherapy and hormonal therapy will be promising. In the future, we believe that the appearance of new anticancer drugs, endocrine therapies, bisphosphonates and strontium treatment could be used as a part of the treatment strategy for prostate cancer with bone metastases.

Topics: Activities of Daily Living; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Bone and Bones; Bone Neoplasms; Combined Modality Therapy; Diphosphonates; Estramustine; Humans; Male; Prostatic Neoplasms; Quality of Life; Radiography; Radionuclide Imaging

The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145.. The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram.. Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells.. The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Cyclophosphamide; Docetaxel; Drug Synergism; Estramustine; Etoposide; Humans; Imatinib Mesylate; Immunohistochemistry; In Vitro Techniques; Male; Piperazines; Prostatic Neoplasms; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Docetaxel; Estramustine; Humans; Male; Prostatic Neoplasms; Survival Analysis; Taxoids

Docetaxel is an effective agent for the treatment of androgen-independent prostate cancer (AIPC). Its combination with estramustine phosphate (EMP) has shown promising results in AIPC but the toxicity remains considerable. In an effort to minimize toxicity, we designed an every-2-week docetaxel administration regimen with a 3-day low-dose EMP regimen. Patients with bone metastases also received zoledronic acid.. A total of 54 patients with AIPC received docetaxel at 45 mg/m2 and EMP (140 mg orally every 8 hours for nine doses) every 2 weeks. Zoledronic acid was administered at 4 mg every 28 days.. Of the 49 assessable patients, 22 (45%, 95% confidence interval [CI] 31% to 60%) had a prostate-specific antigen response. Of 24 patients with measurable disease, 9 (38%, 95% CI 19% to 59%) had a response to therapy (one complete response and eight partial responses). The median time to progression was 4.4 months (95% CI 2.7 to 6), and overall survival was 13.3 months (95% CI 9 to 17.6). Toxicity was mild, with only 5 cases of grade 3 or 4 toxicity. The pain score improved by 1 point in 21 (54%) of 39 symptomatic patients, and 14 (40%) of 38 patients who used analgesics discontinued analgesic consumption by the end of treatment.. The combination of an every-2-week regimen of docetaxel, EMP, and zoledronic acid is an effective, well-tolerated regimen that results in symptomatic improvement in a significant proportion of patients with AIPC.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alopecia; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Diphosphonates; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Estramustine; Humans; Imidazoles; Life Tables; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Neutropenia; Orchiectomy; Pain; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, High-Energy; Remission Induction; Survival Analysis; Taxoids; Treatment Outcome; Zoledronic Acid

Estramustine phosphate sodium (EMP) frequently causes side-effects such as gastrointestinal discomfort, nausea, and edema in extremities. We analyzed single nucleotide polymorphisms (SNP) in the 17beta-hydroxysteroid dehydrogenase (HSD17B) genes, which are involved in the metabolism of EMP, to predict the risk of EMP side-effects in prostate cancer patients.. We performed genotyping of SNP in the HSD17B genes of 44 Japanese patients with newly diagnosed prostate cancer. The association of SNP and individual EMP side-effects was evaluated.. Peripheral edema occurred more frequently in patients with C/C genotype of IMS-JST123219 than in those with C/G genotype (OR: 5.47, 95% CI: 1.27-23.64). Haplotype analysis showed that appetite loss was associated with the G allele of IMS-JST123219 and the T allele of IMS-JST123218 (OR: 9.13, 95% CI: 1.15-72.76).. These preliminary data demonstrated that analyses of SNP in the HSD17B genes might predict the occurrence of side-effects from EMP.

Topics: 17-Hydroxysteroid Dehydrogenases; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Appetite; Edema; Estramustine; Gene Frequency; Genotype; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Risk Factors

Both docetaxel and estramustine are antimicrotubule agents with antitumor activity in various cancers including prostate cancer. Clinical trials for docetaxel and estramustine combination treatment have suggested improved antitumor activity in hormone-refractory prostate cancer. However, the molecular mechanisms involved in the combination treatment with docetaxel and estramustine have not been fully elucidated. In order to establish such molecular mechanisms in both hormone insensitive (PC-3) and sensitive (LNCaP) prostate cancer cells, gene expression profiles of docetaxel- and estramustine-treated prostate cancer cells were obtained by using Affymetrix Human Genome U133A Array. Total RNA from PC-3 and LNCaP cells untreated and treated with 2 nmol/L docetaxel, 4 micromol/L estramustine, or 1 nmol/L docetaxel plus 2 micromol/L estramustine for 6, 36, and 72 hours was subjected to microarray analysis. Real-time PCR and Western blot analysis were conducted to confirm the microarray data. Clustering analysis based on biological function showed that docetaxel and estramustine combination treatment down-regulated some genes that are known to regulate cell proliferation, transcription, translation, and oncogenesis. In contrast, docetaxel and estramustine combination treatment up-regulated some genes related to induction of apoptosis, cell cycle arrest, and tumor suppression. Docetaxel and estramustine also showed differential effects on gene expression between mono- and combination treatment. Combination treatment with docetaxel and estramustine caused alternations of a large number of genes, many of which may contribute to the molecular mechanisms by which docetaxel and estramustine inhibit the growth of prostate cancer cells. These results provide novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Cell Line, Tumor; Cluster Analysis; DNA, Complementary; Docetaxel; Down-Regulation; Drug Screening Assays, Antitumor; Estramustine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Models, Biological; Oligonucleotide Array Sequence Analysis; Prostatic Neoplasms; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Taxoids; Time Factors; Transcription, Genetic

To evaluate the therapeutic effect of high-intensity focused ultrasound (HIFU) combined with chemotherapy (paclitaxel + estramustine) on AT2 Dunning adenocarcinoma, as no satisfactory treatment for localized prostate cancer is available for patients with a poor prognosis, e.g. stage T3, a high Gleason score, or a prostate-specific antigen level of >15 ng/mL.. Forty-one Dunning AT2 tumour-bearing Copenhagen rats were divided into four groups, i.e. control, chemotherapy, HIFU, and chemotherapy + HIFU (the last three treated for 1 week). The growth in tumour volume was recorded for 3 weeks, the point at which tumour volume was considered to have doubled (doubling time). The growth curves of each group were plotted and evaluated statistically.. At 30 days of follow-up the distributions of tumour volume with treatment group were significantly different (P < 0.001); volumes were significantly greater in the control than in the chemotherapy-only or in the HIFU-only group (both P = 0.006). The greatest difference was between the chemotherapy + HIFU and the control group. The tumour doubling times were 13.2 days for HIFU-only, 31.2 days for chemotherapy + HIFU and 7.7 days for the controls.. These results suggest that this combined therapy could be useful for treating patients with high-risk prostate cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Estramustine; Male; Paclitaxel; Prostatic Neoplasms; Rats; Ultrasound, High-Intensity Focused, Transrectal

Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint.. After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared.. Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029).. Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgens; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Disease Progression; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor, Ro 28-2653 (5-biphenyl-4-yl-5-[4-(-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione), has been shown in various models of different tumor entities. The tumor growth-reducing effect has been demonstrated in the orthotopic rat prostate Dunning model (subline MatLyLu). Based on these results we investigated Ro 28-2653 in combination with estramustine on the G subline of the Dunning tumor. This subline is characterized by a low metastatic ability and androgen sensitivity. Efficacy was determined by recording tumor growth in vivo by magnetic resonance imaging (MRI). Tumor cells were injected into the prostates of 81 Copenhagen rats. MRI was performed at day 100 and at day 126 after tumor cell injection. The duration of therapy was 17 days with daily oral application of Ro 28-2653 (100 mg/kg) and four i.p. injections of estramustine (7.5 mg/kg). Histological evaluations were conducted to provide further information about the effects on tumor morphology. Orthotopic tumor induction was successful in 100% of the animals. Tumor volume calculations with MRI showed a significant difference between the control groups, the animals treated with Ro 28-2653, and the animals treated with the combination of Ro 28-2653 and estramustine. The new MMP inhibitor Ro 28-2653 reduces tumor growth and provides a compatible therapeutic alternative for patients with prostate cancer.

Topics: Animals; Antineoplastic Agents, Hormonal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Estramustine; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms, Hormone-Dependent; Piperazines; Prostatic Neoplasms; Pyrimidines; Rats; Rats, Inbred Strains; Survival Rate; Time Factors; Tumor Cells, Cultured

Estramustine administered orally as estramustine phosphate (EMP) remains a major tool in hormone refractory prostate cancer chemotherapy. The presence of estramustine binding protein, prostatin, in prostate tissue may be a determinant of response to treatment. Lipophilins are secretory proteins with homology to prostatin. Reverse transcription-polymerase chain reaction was performed to estimate expression patterns of lipophilins A to C in human biopsies and cell lines resistant to estramustine. Although lipophilin A was not expressed in prostate tissue, both lipophilins B and C were expressed in normal and tumor prostate without significant differences. For lipophilin C, a somatic mutation (T to C transition at positions 409 and 412) was found in human tumor samples and absent in normal prostate tissue. No consistent response to EMP was observed in enhanced green fluorescent protein (EGFP)-tagged lipophilin C-transfected PC3 cells compared with parental controls. Among these EGFP-lipophilin C clones, no direct correlation between response to EMP treatment (IC50 values) and EGFP expression was observed (p = 0.73). Lipophilin C mRNA levels did not vary significantly between wild-type and estramustine-resistant cells in prostate (DU145 and PC3) and ovarian (SKOV3) cancer cell lines. Overall, these results suggest that lipophilins are not specific determinants of estramustine efficacy.

Topics: Antineoplastic Agents, Hormonal; Biopsy; Blotting, Western; Cell Line, Tumor; Cell Survival; Clone Cells; Estramustine; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Male; Mutation; Neoplasm Proteins; Prostatic Neoplasms; Recombinant Fusion Proteins; RNA, Messenger

The aim of our study is to find out the good responders for estramustine phosphate (EMP) therapy in patients with prostate cancer. We have focused on the metabolism of EMP and studied the association between a functional single-nucleotide polymorphism in the catechol-O-methyltransferase gene (Val158Met of COMT) and PSA-progression-free survival in Japanese patients with prostate cancer treated by EMP.. Seventy-two Japanese patients with previously untreated prostate cancer who were found to be eligible for low-dose EMP therapy were enrolled in the study. Genotyping of the Val158Met polymorphism of COMT was conducted by both the polymerase chain reaction-based restriction fragment length polymorphism method and TaqMan assay.. Patients with the Val/Val genotype of COMT had a significantly higher PSA-progression-free rate as compared to those with the Val/Met or Met/Met genotype (p=0.027). The adjusted hazard ratio of biochemical PSA failure for the Val158Met genotype of COMT was 2.164 (95% CI, 1.111 to 5.525).. The Val158Met polymorphism of COMT is associated with the PSA-progression-free rate of EMP-treated patients in prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Catechol O-Methyltransferase; Disease Progression; Disease-Free Survival; Estramustine; Genetic Predisposition to Disease; Genotype; Humans; Male; Methionine; Middle Aged; Polymorphism, Genetic; Prodrugs; Prostate-Specific Antigen; Prostatic Neoplasms; Valine

Hormone-refractory prostate cancer (HRPC) has modest response rates to second-line estrogenic agents such as diethylstilbestrol and the herbal product PC SPES. Estramustine phosphate (EMP) is a microtubule inhibitory agent with estrogenic properties commonly used in patients with metastatic HRPC. To determine whether previous response to second-line estrogen therapy would predict subsequent response to EMP-based chemotherapy, a retrospective study was conducted.. Patients with HRPC previously treated with second-line estrogenic therapy who subsequently received EMP-based chemotherapy were enrolled in a retrospective analysis. The progression of disease or response to treatment was determined with use of standard prostate-specific antigen (PSA) criteria and Response Evaluation Criteria in Solid Tumors.. Seventy-eight patients were included in the analysis. Twenty-five patients with disease progression after receiving estrogen therapy received subsequent EMP-based chemotherapy. Overall, initial PSA response to any estrogen therapy was 54%. The overall PSA response to EMP-based chemotherapy was 60%, and the objective response was 36%. The PSA response to subsequent EMP-based chemotherapy was independent of patients having a previous response to estrogen therapy (70% vs. 53%; P = 0.68). The median overall survival for patients receiving estrogenic therapy and subsequent EMP-based chemotherapy was 12.7 months.. Previous response to second-line hormonal maneuvers with estrogen therapy does not predict subsequent response to EMP-based chemotherapy.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Diethylstilbestrol; Disease Progression; Drugs, Chinese Herbal; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms

A 77-year-old man presented with complaints of dysuria, nocturia and painless nodule on his penis. Laboratory examination revealed elevated serum prostate-specific antigen (PSA) and CA19-9. Pathological examinations on prostate and penile biopsy specimens revealed prostate adenocarcinoma with penile metastasis. The patient was diagnosed as having prostate cancer stage D2 (T4N1M1) with bone, lymph node and penile metastases. There was no response to initial hormonal therapy with the surgical castration and diethylstilbestrol. However, decrease of the tumor size, as well as PSA and CA19-9 values were achieved after the combined chemotherapy with Estramustine, Paclitaxel and Carboplatin.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Carboplatin; Combined Modality Therapy; Estramustine; Humans; Male; Orchiectomy; Paclitaxel; Penile Neoplasms; Prostate-Specific Antigen; Prostatic Neoplasms

Although treatment of hormone-refractory prostate cancer (HRPC) is difficult, a single-agent weekly dose of docetaxel has been reported as a promising regimen for patients with HRPC. The purpose of this study was the investigation of the efficacy of docetaxel for Japanese patients with HRPC.. Ten patients with HRPC were treated with weekly docetaxel at Tsukuba University Hospital and were evaluated for the responses with respect to serum prostate-specific antigen (PSA), tumor size and survival. Considering the ethnic balance, the dose of docetaxel was reduced to 30 mg/m(2) weekly compared with 36 mg/m(2) in the study reported previously.. A biochemical response (>50% decrease in PSA) was observed in five patients (56%; 5/9) with an average time to progression of 4.5 months. In two partial responders as determined by PSA, respective metastatic lesions in bone and soft tissue were also improved. The estimated median survival duration was 6 months. Most of these responses were accompanied by a significant reduction in the requirement for analgesic agents. No severe toxicity of this regimen was observed, except for gastric ulcer in one patient who was excluded from the evaluation.. Weekly administration of docetaxel as a single agent was associated with a high rate of PSA reduction. This treatment is feasible for patients with HRPC, even those who have a poor performance status and extensive prior treatments.

Topics: Aged; Alopecia; Anorexia; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Estramustine; Feasibility Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Soft Tissue Neoplasms; Taxoids

The human ABCA2 transporter is a member of a large family of ATP-binding proteins that transport a variety of molecules across biological membranes. Using RNA ligation-mediated PCR (RLM-PCR), we have identified a novel first exon, which we designate 1B that is located 699 bp upstream of the previously characterized first exon, which we designate 1A. These first exons are alternatively spliced to the second exon of the ABCA2 transcript resulting in a protein that has a unique amino terminus. For exon 1B, the new amino terminus encoded by the first exon is 52 amino acids and for exon 1A, 22 amino acids. We observed that among adult tissues examined, the highest expression of the 1B isoform was in peripheral blood leukocytes (PBL). Laser scanning confocal microscopy revealed that the 1A isoform and the 1B isoform co-localize with lysosome-associated membrane proteins-1 and -2 (LAMP-1 and -2). Cytotoxicity assays suggested a role for ABCA2 in estramustine and estradiol resistance, and overexpression of ABCA2 is seen in an estramustine-resistant prostate carcinoma line. Since both isoforms of the ABCA2 transporter have identical subcellular localization and both are overexpressed in a resistant cell line, we propose that they are also functionally redundant. It is likely that expression of ABCA2 by two independent promoters constitutes locus of regulation controlling expression of the protein to meet requirements in different tissues.

Topics: Alternative Splicing; Animals; ATP-Binding Cassette Transporters; Base Sequence; CHO Cells; Cricetinae; Cricetulus; Drug Resistance; Estradiol; Estramustine; Exons; Humans; Male; Molecular Sequence Data; Prostatic Neoplasms; Transfection; Tumor Cells, Cultured

To demonstrate a synergistic action between high intensity focal ultrasound (HIFU) and combination chemotherapy with paclitaxel and estramustine phosphate (EMP) on a prostate cancer model.. The animal model used in this study was the Copenhagen rat and the tumour model is a Dunning R 3327-AT 2 hormone-independent prostatic adenocarcinoma cell line. Chemotherapy was administered once a week for 4 weeks according to 2 modalities: low-dose with paclitaxel 2 mg/kg/day, 1 day per week and EMP 50 mg/kg/day, 3 days per week; or high-dose with paclitaxel 3 mg/kg/day, 1 day per week and EMP 75 mg/kg/day, 3 days per week. Treatment with HIFU was performed at the second week and only 55% of the tumour volume was treated. The study was conducted on 42 rats divided into 6 arms: Control, HIFU, low-dose paclitaxel-EMP, high-dose paclitaxel-EMP, HIFU + low-dose paclitaxel-EMP and HIFU + high-dose paclitaxel-EMP. Study endpoints were the course of tumour volume and animal survival.. After two weeks of treatment, a statistically significant difference for tumour volume was observed between the various arms of the study (p < 0.0001). The HIFU-chemotherapy arm and, to a lesser degree, the chemotherapy only arm, presented the lowest tumour progression.. The combination of HIFU + paclitaxel-EMP is more effective than treatment with HIFU alone or paclitaxel-EMP alone on growth of the Dunning tumour, right from the first weeks of treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Combined Modality Therapy; Disease Models, Animal; Estramustine; Male; Paclitaxel; Prostatic Neoplasms; Rats; Ultrasonic Therapy

Only very limited data are available on the presence of circulating tumor cells during cytotoxic chemotherapy for hormone-refractory prostate cancer. We analyzed 241 blood samples from 32 patients with hormone-refractory PCa under a chemotherapy schedule. The etoposide, estramustine phosphate and paclitaxel scheme as well as the mitoxantrone and prednisone schedule were used to treat patients with advanced prostate cancer. The pre-therapy serum PSA values were in the range from 1.4 ng/ml to 2,870.9 ng/ml (median 74.5 ng/ml). We isolated the CD45-negative cell population by immunomagnetic depletion from 16 ml of peripheral blood samples. These cells were stained for pan-cytokeratin and evaluated. Patients were observed for an average of 67 weeks (range 16-120). In 77 (32%) samples originating from 27 (84%) patients, tumor cells were detected at least once. Twenty of these patients had shown an initial response to therapy as indicated by a >/=50% decrease of the pre-therapy PSA value. Of these, 14 patients experienced a biochemical and/or a clinical progression. For 13 (93%) of them, circulating tumor cells were detectable during the time of PSA response, i.e. during the PSA decline and before a biochemical or clinical progression. However, we could not correlate the amount of circulating tumor cells with the observed PSA levels. This study demonstrates that circulating tumor cells are detectable during chemotherapy for hormone-refractory prostate cancer regardless of the degree of PSA response.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Humans; Immunomagnetic Separation; Keratins; Leukocyte Common Antigens; Male; Middle Aged; Mitoxantrone; Neoplasms, Hormone-Dependent; Neoplastic Cells, Circulating; Paclitaxel; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Tumor Cells, Cultured

Estramustine phosphate (EMP) is a compound widely used for the treatment of hormone-refractory prostate cancer. In order to better understand the precise molecular mechanism(s) by which EMP exerts its effects on hormone-resistant PC3 prostate cancer cells, we have utilized microarray to interrogate 22,215 known genes to determine the gene expression profiles altered by EMP treatment. The purpose of this investigation was to identify gene expression profile first and then in future studies determine the specific role of these genes in EMP-induced apoptosis in prostate cancer cells. We found a total of 726 genes which showed >2 fold change after EMP treatment. Clustering analysis showed 12 different types of expression alteration. These genes were also subjected to cluster analysis according to their biological functions. We found that EMP regulated the expression of genes, which are critically involved in the regulation of cell growth, cell cycle, apoptosis, iron homeostasis, cytoskeleton and cell signaling transduction. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of microarray, and the results of real-time quantitative RT-PCR were consistent with the microarray data. From these results, we conclude that EMP caused changes in the expression of a large number of genes that are related to the control of cell survival and physiological behaviors. The gene expression profiles may provide comprehensive molecular mechanism(s) by which EMP exerts its pleiotropic effects on prostate cancer cells. EMP-induced regulation of these genes may be further exploited for devising therapeutic strategies for prostate cancer.

Topics: Estramustine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

To assess the effectiveness and tolerability of estramustine sodium phosphate in men with hot flushes during combined androgen blockade (CAB) therapy for prostate cancer.. Seven men with moderate to severe hot flushes were received estramustine sodium phosphate. Treatment response was assessed by hot flush score.. A significant reduction in the hot flush score was seen with all patients. No thromboembolic complications occurred in any patients.. Estramustine sodium phosphate appears to be a promising, well-tolerated and useful therapy for men with hot flushes during CAB treatment for prostate cancer.

Topics: Aged; Androgen Antagonists; Estramustine; Hot Flashes; Humans; Male; Prostatic Neoplasms; Treatment Outcome

We report on a patient with androgen ablation-refractory prostate adenocarcinoma who had an objective response for longer than 24 months using a combination of estramustine and lanreotide. At baseline from our combination therapy, his prostate-specific antigen level was 21.30 ng/mL and serum chromogranin A level was 816 ng/mL. The patient discontinued complete androgen deprivation therapy and underwent combination therapy with oral estramustine 420 mg/day plus lanreotide acetate 73.9 mg intramuscularly every 4 weeks. After 33 months of follow-up, the patient was alive without clinical disease progression, and his prostate-specific antigen and chromogranin A level was 0.10 and 12 ng/mL, respectively.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chromogranin A; Chromogranins; Estramustine; Humans; Male; Peptides, Cyclic; Prostate-Specific Antigen; Prostatic Neoplasms; Somatostatin

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Bone Neoplasms; Diphosphonates; Drug Resistance, Neoplasm; Drug Therapy, Combination; Estramustine; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms

Prostate cancer is known to be refractory to chemotherapy with only mitoxantrone showing some benefit. Recent clinical data indicate the antitumoral efficacy of taxanes alone or combined with estramustine phosphate. We compared the response to these treatments of hormone dependent and independent human prostate cancer xenografts.. PAC120, an androgen dependent human prostate cancer xenograft, and several HIDs, which are androgen independent variants, were established in nude mice. Human gene expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Androgen deprivation was achieved by surgical castration. Tumor bearing mice received 20 mg./kg. docetaxel on day 2, 1 mg./kg. hydrocortisone on days 1 to 3, 4 mg./kg. estramustine phosphate on days 1 to 4 or 1 mg./kg. mitoxantrone on day 1 by the intraperitoneal route for 3-week cycles. Relative tumor volume and growth delay were evaluated. Histological examination of tumors was done before and after treatment.. Mitoxantrone transiently decreased the growth rate of HID xenografts but did not affect that of PAC120. Estramustine phosphate alone inhibited the growth of PAC120 but not that of HID variants. Docetaxel inhibited the growth of all prostate cancer xenografts (PAC120 and HIDs) and increased survival. PAC120 showed distinct response patterns during prolonged treatment. Efficacy was significantly decreased by splitting docetaxel into 2 doses given at a 7-day interval (p = 0.01). The docetaxel effect was potentiated by estramustine phosphate in 1 of the 2 HID variants tested. In castrated mice docetaxel induced a greater growth delay than in intact male mice (p = 0.01). High Her2/neu and beta2-tubulin transcripts were detected in all samples. Prostate specific antigen, androgen receptor and multidrug related protein-1 mRNA did not correlate with the drug response, while CYP3A4 mRNA inversely correlated with the response. Docetaxel treated tumors had an increased number of mitotic cells with centrosome alterations and multinuclei, an increased number of Ki67 labeled cells and a strong decrease in beta-tubulin without evidence of apoptosis.. Docetaxel showed a significant antitumoral effect on hormone dependent and tumors, which was largely superior to that of mitoxantrone. Estramustine phosphate alone had a modest effect. The drug response was associated with high Her2/neu expression, low CYP3A4 expression and the induction of numerous mitotic abnormalities.

Topics: Androgens; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Humans; Male; Mice; Mice, Nude; Middle Aged; Mitoxantrone; Neoplasm Transplantation; Paclitaxel; Prostatic Neoplasms; Taxoids

A 62-year-old patient was referred with the suspected diagnosis of Peyronie disease. The patient showed the clinical picture of a beginning malignant priapism with hematogenous metastases from an recurrent prostatic carcinoma. The penile metastases were misdiagnosed as Peyronie disease. Although both clinical pictures show some superficial similarity, Peyronie disease usually fulfills classical criteria which help to clearly distinguish it from neoplastic diseases.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Drug Therapy, Combination; Epirubicin; Estramustine; Flutamide; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Orchiectomy; Palliative Care; Penile Induration; Penile Neoplasms; Priapism; Prostatic Neoplasms; Time Factors

Prostatic carcinoma is exceptional in young adults before the age of 30. It is often diagnosed at a late, clinically advanced stage with a poorly differentiated histological type. Treatment is usually palliative and the prognosis is very poor with a mean survival of 6 months. The authors report a new case in a 25-year-old patient with locally advanced poorly differentiated prostatic carcinoma and a Gleason score of 10 treated by endocrine therapy, radiotherapy and chemotherapy with a good clinical and radiological course with a follow-up of two years.

Topics: Adenocarcinoma; Adult; Androgen Antagonists; Combined Modality Therapy; Estramustine; Humans; Male; Prostatic Neoplasms; Radiotherapy Dosage; Treatment Outcome

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Resistance, Neoplasm; Estramustine; Etoposide; Humans; Male; Paclitaxel; Prostatic Neoplasms; Treatment Outcome

Estramustine phosphate is associated with estrogenic complications. However, hypertriglyceridemia has not yet been associated with estramustine phosphate. We describe a patient in whom severe hypertriglyceridemia and pancreatitis developed after treatment with estramustine phosphate. A 59-year-old man with hormone-refractory prostate cancer was treated with estramustine phosphate, docetaxel, and carboplatin. After three cycles, the patient was admitted with triglyceride levels of 12,210 mg/dl and pancreatitis. After resolution of hypertriglyceridemia and pancreatitis, chemotherapy with docetaxel and carboplatin was continued without recurrence of hypertriglyceridemia. We conclude that estramustine phosphate has the potential to cause hypertriglyceridemia in susceptible individuals.

Topics: Antineoplastic Agents; Estramustine; Humans; Hypertriglyceridemia; Male; Middle Aged; Pancreatitis; Prostatic Neoplasms

The role of age as a prognostic factor for survival remains debatable in patients with prostate carcinoma.. The authors conducted a retrospective study of the significance of age as a prognostic factor for survival and progression free survival in 386 patients who underwent orchidectomy for locally advanced or metastatic prostate carcinoma, 75% of whom had T0-T4, M1 disease. After undergoing orchidectomy, 192 patients received no further therapeutic intervention, whereas 194 patients received additional treatment with estramustine phosphate (EMP) as first-line therapy.. The findings confirmed that age was a significant prognostic factor for survival and progression free survival in patients with prostate carcinoma as well as a predictor of response to chemotherapy. The data also showed that, although combining orchidectomy with EMP appeared to be beneficial in younger patients, using this relatively more aggressive therapeutic approach as first-line therapy in older patients (age > or = 80 years) may shorten their survival.. The current findings call for caution with the additional use of EMP as first-line therapy in older patient with prostate carcinoma.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Prognosis; Prostatic Neoplasms; Retrospective Studies; Survival Rate

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Therapy, Combination; Estramustine; Humans; Male; Prostatic Neoplasms; Taxoids

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Estramustine; Forecasting; Humans; Male; Neoadjuvant Therapy; Paclitaxel; Prostatic Neoplasms; Taxoids; Vinblastine

The subjects for the present study were 270 patients with prostate cancer who underwent initial treatment at our hospital over the 14 years from 1986 to 1999. They were investigated to assess the relationship between their treatment and metachronous tumors. Sixteen patients (5.9%) developed cancer of other organs after starting treatment for prostate cancer. These metachronous tumors included gastric cancer in six patients as well as lung cancer, esophageal cancer, colorectal cancer, liver cancer, renal cancer, bladder cancer, skin cancer, leukemia, and mediastinal adenocarcinoma. Treatment for prostate cancer other than surgery included radiotherapy in eight patients, administration of estramustine phosphate sodium in nine patients, and LH-RH analogues in six patients. The chi-square test showed no significant difference in the incidence of metachronous cancer in relation to the presence/absence of these three therapies. The present study therefore ruled out the possible induction of other tumors by treatment for prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estramustine; Gonadotropin-Releasing Hormone; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms, Second Primary; Prostatic Neoplasms; Stomach Neoplasms

Chemotherapeutic drug resistance remains a significant obstacle in the control of prostate cancer. The influence of p53 and androgen status on the drug response of new cell lines from normal, benign and primary tumour epithelium was investigated. The prostate cell lines 1542-NPTX, BPH-1, 1542-CP(3)TX, 1532-CP(2)TX, 1535-CP(1)TX and LNCaP were exposed to TD(50) doses of etoposide, vinblastine and estramustine for a period of 24 h and re-incubated for a further 4 days before measuring the cell viability by crystal violet vital dye staining assay. The virus-transformed cell lines were found to be approximately ten times more sensitive to etoposide and vinblastine than the non virus-transformed LNCaP cell line. Estramustine proved to be the least toxic drug. The LNCaP cell line emerged as DHT-sensitive against nanomolar concentrations of 5alpha-dihydrotestosterone in charcoal-stripped growth medium. The virus-transformed cell lines were DHT-insensitive. Induction of p21 by (60)Co gamma-irradiation was used to assess the functionality of the p53 gene. p21 induction in the LNCaP cell line reached a peak 7.5 h post-irradiation. No significant p21 induction occurred in the virus-transformed cell lines. We show that the androgen-independent tumour cell lines are more sensitive to etoposide and vinblastine than the androgen dependent cell line, LNCaP. Except for LNCaP cells, etoposide and vinblastine were found to be three- to ten-fold more effective than estramustine. In the benign hyperplasia cell line, BPH-1, only etoposide is highly effective. Etoposide and vinblastine were found to effectively inactivate the androgen-independent cell lines, in which p53 is dysfunctional.

Topics: Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Estramustine; Etoposide; Gene Expression Regulation; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Vinblastine

Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment.

Topics: Estramustine; Humans; Male; Mutation; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Transcription, Genetic

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Estramustine; Humans; Male; Mitoxantrone; Paclitaxel; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms

Prostatic carcinoma metastasizing to the penis is rare. A case of adenocarcinoma of the prostate with metastases to the penile shaft and glans penis is presented.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Estramustine; Humans; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Orchiectomy; Penile Neoplasms; Prostate-Specific Antigen; Prostatic Neoplasms

The aim of this study was to investigate whether there is an association between the presence of neuroendocrine elements in relapsed prostate cancer and sensitivity to estramustine/etoposide and carboplatin or cisplatin. Thirty patients with progressive metastatic castrate prostate cancer were selected on the basis of clinical criteria for treatment with cytotoxic chemotherapy. The criteria included a tumor biopsy specimen taken during relapse showing neuroendocrine features based on morphology alone (carcinoid elements, small cell tumor) or by immunohistochemistry (detection of chromogranin A, neuron-specific enolase or synaptophysin). Patients were treated with cis- or carboplatin, estramustine (orally) and etoposide (orally or intravenously). Remission of radiographically visualized lesions, decline of prostate-specific antigen (PSA) or death owing to any cause constituted (separately reported) the endpoints. Tumor remission was found in about half of the patients, determined either by changes in measurable lesions or by a 50% decline in serum PSA. Neuroendocrine elements--irrespective of how they were identified--were not predictive of tumor remission or survival. Regression of measurable lesions by > 50% was seen in 4/9 (44%) cases of small cell carcinoma, 6/13 (46%) of poorly differentiated carcinoma, 7/13 (54%) of tumors with one marker immunohistochemically detected and 3/7 (43%) of tumors without any staining. It is concluded that response to chemotherapy was not predicted solely on the basis of the presence or absence of neuroendocrine elements in a relapsed tumor specimen. The results support the use of cytotoxic drugs in the relapsed setting and definitive trials are ongoing to prove any benefit to survival.

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Neuroendocrine; Cisplatin; Estramustine; Etoposide; Humans; Male; Middle Aged; Prostatic Neoplasms; Remission Induction

A flare in serum alkaline phosphatase (ALP) activity post-orchidectomy has been shown to be of negative prognostic value for progression-free survival (PFS) in patients with prostate cancer. The aim of this study was to investigate whether a flare in ALP may help identify patients in whom prognosis could be positively influenced by early chemotherapy.. A retrospective analysis of the database of a Dutch multicenter study was conducted to evaluate the prognostic value of the flare in ALP post-orchidectomy for survival and PFS in 112 patients treated with orchidectomy (previously reported) compared to 121 age- and stage-matched patients additionally treated with estramustine-phosphate (EMP) as first line therapy.. There was no overall difference in PFS and survival between the two treatment regimen. Subgroup analysis of patients demonstrating a greater than 50% increase in ALP post-orchidectomy showed, however, a significant increase in PFS in patients additionally treated with EMP.. Our data suggest that the simple measurement of ALP activity within 4 weeks of castration represents a useful adjunct in assessing which patients with prostate cancer undergoing androgen ablation may benefit from additional early chemotherapy.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Disease-Free Survival; Estramustine; Humans; Male; Middle Aged; Orchiectomy; Predictive Value of Tests; Prognosis; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

Topics: Aged; Aged, 80 and over; Estramustine; Humans; Hypocalcemia; Male; Parathyroid Hormone; Prostatic Neoplasms; Vitamin D; Vitamin D Deficiency

The antimicrotubule drug estramustine phosphate (EMP) has been shown to sensitize prostate carcinoma cells to radiation via synchronization at the G2/M phase of the cell cycle. This synchronization may also render cells more sensitive to hyperthermia, providing a rationale for multimodal treatment approaches. We have investigated the effects of EMP and hyperthermia, as well as the regulation of heat shock proteins (HSP) in the PC-3 prostatic carcinoma cell line. Cells were incubated with four doses of EMP for 48 h followed by a 1-h hyperthermia treatment ranging from 41 degrees C to 44 degrees C. Cell cycle distribution at the end of the EMP incubation was investigated by flow cytometry. Cytotoxicity was assessed by colony formation assays. HSP accumulation was investigated by Western immunoblotting. Doses of 1, 5, 10 and 15 microM EMP synchronized 27, 28, 46, and 68% of PC-3 cells at G2/M. With 5, 10 and 15 microM, a sensitizing effect of EMP was assessed at hyperthermic temperatures of 42, 43 and 44 degrees C. EMP did not alter the expression of HSP72, but substantially induced the synthesis of HSP27 in PC-3 cells. Our data show that EMP sensitizes PC-3 cells to hyperthermia induced cytotoxicity. This observation supports the rationale for multimodal treatment approaches in locally advanced prostate cancer.

Topics: Antineoplastic Agents; Carcinoma; Cell Cycle; Estramustine; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Humans; Hyperthermia, Induced; Male; Molecular Chaperones; Neoplasm Proteins; Prostatic Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

Current therapy for locally advanced prostate cancer is suboptimal. A treatment regimen was designed to improve systemic control by neoadjuvant targeting of hormone-sensitive and -insensitive micrometastatic disease and to improve local control by escalating the biologic effective dose to the prostate using estramustine (EMP) concurrently with radiotherapy.. Eighteen patients with locally advanced prostate cancer (Stages T3/T4 or T1c/T2b/T2c with a Gleason score of > or =7 and a serum PSA >15 ng/ml) were entered onto this trial. Therapy consisted of two 21-day cycles of oral estramustine (10 mg/kg/day) in three divided doses and oral etoposide (50 mg/m(2)/day, in two divided doses), followed by concurrent estramustine (10 mg/kg/day, PO) and three-dimensional conformal radiotherapy.. Two patients required discontinuation of chemotherapy due to development of Grade 3 and 4 toxicity. All others completed both components of therapy per protocol guidelines. Minor toxicities included alopecia (100% of patients), anemia (69%), leukopenia (37%), thrombocytopenia (19%), and nausea (6%) but did not require dose modifications. There were no fatalities. Actuarial 3-year overall survival and disease-free survival (DFS) were 88% and 73%, respectively. Local control rate, assessed by repeated prostate biopsies at 18 months post completion of therapy, was 71%.. The described regimen is well tolerated, and preliminary efficacy data are encouraging. The underlying concepts of early targeting of both hormone-sensitive and -insensitive micrometastatic clones, in combination with aggressive local therapy, warrant further investigation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Estramustine; Etoposide; Feasibility Studies; Humans; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation-Protective Agents; Radiotherapy, Conformal; Survival Analysis

Topics: Administration, Oral; Aged; Estramustine; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neoplasms, Second Primary; Prostatic Neoplasms; Radiotherapy

We describe a patient with androgen-independent prostate cancer in whom hypocalcemia developed during treatment with estramustine. The patient's total serum calcium level before and after the initiation of estramustine was 8.3 and 4.3 mg/dL, respectively (normal range 8.4 to 10.2). This finding prompted us to review the calcium levels in 135 consecutive patients who were also undergoing treatment with a similar estramustine-containing regimen. We found that hypocalcemia had developed in 20% of these patients during treatment. We speculate that estramustine may cause hypocalcemia by inhibiting the mobilization of calcium and the action of the parathyroid hormone in the skeleton.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Bone Neoplasms; Estramustine; Humans; Hypocalcemia; Incidence; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

Topics: Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Docetaxel; Estramustine; Humans; Hydrocortisone; Male; Paclitaxel; Prostatic Neoplasms; Taxoids

Increases of individual beta tubulin isotypes in antimicrotubule drug resistant cell lines have been reported by several laboratories. We have previously described elevations in beta(III)and beta(IVa)isotypes in estramustine and paclitaxel resistant human prostate carcinoma cells. To investigate further the function of beta tubulin isotypes in antimicrotubule drug response, human prostate carcinoma cells that normally have very low to undetectable levels of beta(III)were stably transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin (HA) epitope tag was added at the 3' end prior to cloning into the vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids and selected in the presence of Zeocin. Immunofluorescent staining of the transfectant cells have shown significant expression and incorporation of HA-tagged beta(III)tubulin into cellular microtubules. Quantitation of Western blots revealed the HA-tagged beta(III)levels to be approximately 7-fold higher than the vector control cells. RT-PCR analysis confirmed the increase at the transcript level and also revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell viability assays indicated that sensitivity of beta(III)transfected cells to various antimicrotubule agents was similar to vector transfected cells: IC50 values for estramustine, paclitaxel, colchicine and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for both cell lines. Thus, overexpression of beta(III)isotype in human prostate carcinoma cells by stable transfection failed to confer antimicrotubule drug resistance to these cells. Counterregulatory increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these beta(III)transfected cells may be a compensatory mechanism used by the cells to overcome the effects of elevated beta(III)levels on the cellular microtubules. These results highlight the difficulty in isolating the contribution of single tubulin isotypes in drug response studies.

Topics: Antineoplastic Agents; Colchicine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estramustine; Genetic Vectors; Humans; Male; Microtubules; Neoplasm Proteins; Paclitaxel; Prostatic Neoplasms; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tubulin; Tumor Cells, Cultured; Vinblastine

An 82-year old man received total androgen blockade therapy (bilateral orchiectomy and 375 mg/day flutamide) for the treatment of stage C prostate cancer. Serum PSA levels were undetectable for 13 months and thereafter increased gradually. We administered estramustine phosphate sodium (EPS) instead of flutamide under the diagnosis of hormone refractory prostate cancer. EPS therapy was discontinued after 9 months because serum PSA levels increased again. Then, the patient complained of bilateral breast nodules and pain. Bilateral mammectomies were performed due to bilateral breast cancers which had been diagnosed by aspiration biopsies and radiographic examinations, but he died four months after the operations. Final pathological diagnosis was ductal adenocarcinoma of the breasts. Immunohistochemical study revealed expressions of PSA in the breast cancers. We diagnosed double cancers of the prostate and the breast because of the different expression patterns of progesterone receptor between them. We review the literatures and discuss the differential diagnosis of prostate cancer and PSA-producing breast cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms, Male; Carcinoma, Ductal, Breast; Estramustine; Humans; Male; Prostatic Neoplasms; Receptors, Progesterone

Topics: Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Pain; Prostate-Specific Antigen; Prostatic Neoplasms

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colitis; Diarrhea; Docetaxel; Estramustine; Female; Humans; Male; Paclitaxel; Prostatic Neoplasms; Taxoids; Vinblastine; Vinorelbine

Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer.. Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low- and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14.. The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs.. These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Estramustine; Humans; Inhibitory Concentration 50; Male; Microtubules; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Paclitaxel; Prostatic Neoplasms; Rats; Taxoids; Tumor Cells, Cultured

3 weeks after commencing treatment with estramustine phosphate, typical manifestations of hemolytic-uremic syndrome occurred in a 66-year-old patient with prostate cancer. Urinary tract obstructions were excluded and no renal damage could be identified. An improvement in renal function was achieved by stopping estramustine phosphate and infusing adequate amounts of fluids and electrolytes. Anemia and thrombocytopenia also progressively improved after the discontinuation of chemotherapy. Nausea and vomiting, hepatotoxicity, impotence, reduced libido and hypercalcemia are major side effects of estramustine phosphate, and would be difficult to explain our observations without considering the role played by estramustine phosphate. Our observations suggest that estramustine phosphate might play either a direct role or produce a side effect within the context of latent paraneoplastic syndrome. The improvement in renal function which occurred when treatment stopped might confirm our hypothesis.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Estramustine; Hemolytic-Uremic Syndrome; Humans; Male; Prostatic Neoplasms

Osteoblasts and osteoblast-derived survival growth factors, such as insulin-like growth factor I (IGF I), inhibit chemotherapy apoptosis of prostate cancer cells, thereby producing cytotoxic drug-resistant tumor growth, in vitro.. We tested a novel therapeutic approach, referred to as antisurvival factor (AFS) therapy, that aimed at reduction of osteoblast-derived IGFs, using dexamethasone (4 mg per os, qD) and growth hormone (GH)-dependent liver-derived IGFs, using a somatostatin-analog (lanreotide, 30 mg, intramuscularly (i.m.), q14D) in combination with triptorelin (3.75 mg, intramuscularly, q28D) to produce a clinical response in 4 patients with progressing hormone-refractory prostate cancer.. The patients given ASF therapy exhibited an excellent improvement of clinical performance and a decline of prostate-specific antigen (PSA) within 2 months of ASF therapy. One of them experienced excellent clinical response (normalization of PSA), two experienced good clinical response (decline of PSA of more than 50%), and one experienced stabilization (decline of PSA of less than 50%).. We conclude that this novel concept of combination therapy, using ASF with hormone ablation, is a promising salvage therapy that should be further assessed with a randomized clinical trial.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Dexamethasone; Doxorubicin; Estramustine; Humans; Male; Middle Aged; Peptides, Cyclic; Prostatic Neoplasms; Somatostatin; Triptorelin Pamoate

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

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Routes; Estramustine; Follow-Up Studies; Humans; Hydrocortisone; Male; Paclitaxel; Prostatic Neoplasms; Taxoids; Treatment Outcome

Topics: Aged; Antineoplastic Agents, Hormonal; Estramustine; Humans; Male; Pain; Prostate-Specific Antigen; Prostatic Neoplasms; Substance Withdrawal Syndrome

Following hormonal therapy, few treatment regimens have activity in metastatic prostate cancer. Cytotoxic agents have minimal activity in this disease. However, combinations of cytotoxic agents may be beneficial. The activity of estramustine, vinblastine, etoposide, and suramin on cell growth was evaluated. Prostate specific antigen (PSA) is routinely used as a surrogate marker for disease progression. Many pharmacological agents alter PSA levels independently of their effect on tumor growth, the effect of these agents on PSA secretion was determined. Each agent was evaluated alone and in combination with the other drugs in two prostate cancer cell lines. In LNCaP cells, estramustine and suramin were cytostatic, while vinblastine and etoposide were cytotoxic. Estramustine down-regulated etoposide PSA secretion, while suramin had no effect. The effects of etoposide and vinblastine on PSA secretion were not evaluable. In PC-3 cells, only etoposide was cytotoxic. Tandem combinations were more cytotoxic than single agents in both cell lines. The addition of a third agent to the tandem combination produced less cytotoxicity. In our hands, the best combinations were estramustine/vinblastine, suramin/vinblastine, and suramin/etoposide. These combinations yielded 20-60% higher cytotoxicity than any of the drugs alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Division; Dose-Response Relationship, Drug; Drug Synergism; Estramustine; Etoposide; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Suramin; Tumor Cells, Cultured; Vinblastine

Hormone-refractory prostate cancer is the terminal step in the natural history of prostate cancer. To date, no chemotherapeutic agents have been shown to impact clinical outcome at this stage. Recently, the Food and Drug Administration approved the combination of mitoxantrone and prednisone based solely on its superior palliative effects as compared to steroids alone in 2 randomized trials. Progress in biologically driven drug development has led to the identification of several estramustine-based regimens that, although based on single institution experience, appear to have at least a comparable but very promising level of activity in hormone-refractory prostate cancer patients. One such combination, estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), is particularly attractive because of its convenient schedule and side effect profile. To objectively assess the therapeutic benefit of this combination, the Southwest Oncology Group is initiating a randomized phase III trial comparing estramustine and docetaxel with the standard arm of mitoxantrone and prednisone using time to progression and survival as the primary end points. Secondary end points will include toxicity profiles, assessments of quality of life parameters, and magnitude of decline of prostate-specific antigen levels between the two treatment arms.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Docetaxel; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Paclitaxel; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Antimicrotubule drugs are used as chemotherapeutic agents due to their effects on essential cellular functions such as mitosis, organelle transport and maintenance of cell shape. When used in combination, paclitaxel with estramustine or vinblastine has demonstrated activity against hormone refractory prostate cancer. To understand the mechanism of resistance that develops in patients as a result of antimicrotubule drug therapy, we exposed human prostate carcinoma cells to IC20 and IC40 doses of estramustine, paclitaxel or vinblastine for 48 h and examined the beta-tubulin (the cellular target) isotype composition. The results revealed an increase in the betaIII-tubulin isotype as a result of drug treatment both at protein and message levels. In addition, examination of human brain cell lines with different intrinsic levels of betaIII showed that cell lines with higher betaIII levels were more resistant to paclitaxel. These results are in agreement with our previous findings in human prostate carcinoma cell lines that were made resistant to estramustine or paclitaxel and suggest an important function for betaIII in antimicrotubule drug resistance. Also, the complete coding sequence of human betaIII tubulin reported here will provide molecular tools for future investigations.

Topics: Amino Acid Sequence; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Base Sequence; Cloning, Molecular; DNA, Complementary; Drug Resistance; Estramustine; Humans; Male; Microtubules; Molecular Sequence Data; Paclitaxel; Prostatic Neoplasms; Sequence Analysis, DNA; Tubulin; Tumor Cells, Cultured; Vinblastine

Estramustine (EM) is an antimicrotubule drug used in the treatment of hormone refractory advanced prostate cancer. To investigate the mechanism of resistance to EM, we compared its effects on human prostate cancer cells (DU145) and an estramustine-resistant derived cell line (E4). Immunofluorescence demonstrated that EM caused depolymerization of microtubules and blocked cells in mitosis in DU145 cells, with less effect in E4 cells. Using tubulin isotype-specific antibodies, a threefold increase in betaIII and approximately twofold increase in betaI + II isotype in E4 cells compared to DU145 cells were observed. A most interesting observation concerned an increase in the posttranslational modification of alpha-tubulin of both polyglutamylation and acetylation in the E4 cells. Significant to this observation, using direct EM photoaffinity labeling of tubulin, drug binding to the most acidic posttranslationally modified forms of alpha-tubulin was shown to be minimal. Taken together, these results indicate that the modification of the tubulin expression pattern may be responsible for estramustine resistance by both lowering the amount of drug bound to microtubules and inducing more stable microtubules.

Topics: Animals; Antineoplastic Agents, Hormonal; Cattle; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Microscopy, Fluorescence; Photoaffinity Labels; Prostatic Neoplasms; Tubulin; Tumor Cells, Cultured

Estramustine (EM) is an anti-microtubule drug used in the treatment of hormone-refractory advanced prostate cancer. Since microtubules are the targets for EM cytotoxicity, we investigated the effects of EM on the microtubule-associated protein tau to determine what role it may play in drug resistance. We have compared tau expression in human prostate cancer cells (DU145) and an EM-resistant derived cell line (E4). Reverse transcriptase polymerase chain reaction has established that tau is expressed in both cell lines but increased 1.9-fold in E4 compared with DU145 cells. This result was confirmed at the protein level by Western blotting. Tau is a phosphoprotein, most of its reported phosphorylation sites being serine or threonine residues. We have shown, however, that tau is also phosphorylated at tyrosine residues in DU145 cells and that the phosphotyrosine level of tau is significantly increased in E4 cells. Moreover, DU145 cells exposed to short term micromolar drug concentrations enter a phase of microtubule depolymerization, display an increased level of tau phosphorylation and follow a pattern similar to that observed in EM-resistant E4 cells. EM is therefore able to induce a very rapid change in the posttranslational state of tau. Our results show that the acquisition of EM resistance in E4 cells, which is accompanied by changes at the tubulin level, is also associated with important changes in tau expression and phosphorylation.

Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Neoplasm Proteins; Prostate; Prostatic Neoplasms; tau Proteins; Tumor Cells, Cultured

Estracyt (EMP) has been used for the treatment of hormone refractory prostate cancer for many years. Recently, new data from combination studies have given rise to new interest in this old drug. Explanations for the synergy found in the clinic are many, but one major factor may be the previous indication that the drug accumulates in the prostate tumor. We have, therefore, examined the level of the four metabolites, estromustine (EoM), estramustine (EaM), estrone, and estradiol in the tumor and serum of 14 patients with T2 and T3 prostate cancer receiving a single i.v. dose of 600 mg of EMP, about 12 h before radical prostatectomy. Because it has been suggested that the uptake into the prostate tumor is due to binding to the estramustine binding protein (EMBP), we have in addition measured the level of EMBP in the prostate tumor tissue. The main serum and tissue metabolite in all patients was EoM followed by EaM, estrone, and estradiol. The levels for EoM ranged from 63.8-162.8 ng/ml in the serum and from 64.8-1209 ng/ml in the prostate tumor, resulting in a mean ratio for serum to tumor of 1:5. The levels for EaM ranged from 8.3-51.4 ng/ml in the serum and 73.9-563.4 ng/ml in the tumor, giving a mean ratio for serum to tumor of 1:13. The levels of EMBP were higher in T3 tumors than in T2 tumors, 54.1 and 40.7 ng/g tissue, respectively. A significant correlation was found between the levels of EaM (r = 0.60) and the levels of EMBP in the tumor. These data demonstrate that 12 h after a single i.v. dose of 600 mg of EMP the levels of the cytotoxic metabolites EoM and EaM are substantially higher in the tumor than in the serum of the same patient and that a correlation exists between the levels of EaM in the tumor and the levels of EMBP. Thus, this supports the hypothesis that the EMBP is responsible for the retention of EoM and EaM in the prostate tumor.

Topics: Aged; Antineoplastic Agents, Hormonal; Carrier Proteins; Estradiol; Estramustine; Estrone; Humans; Male; Middle Aged; Phosphates; Prostatectomy; Prostatic Neoplasms; Prostatic Secretory Proteins

Carcinoma of the prostate gland is the second most frequent malignancy in males, accounting for 17% of cancer in men; between a third and one-half of these patients will have distant metastases at onset, but rarely cutaneous. We now report a case of prostatic adenocarcinoma with such metastases involving the right nipple and periareolar skin, overlying an area of hormone-induced gynaecomastia.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Estramustine; Fatal Outcome; Gynecomastia; Humans; Male; Prostatic Neoplasms; Skin Neoplasms

Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect

Topics: Androgen Antagonists; Antineoplastic Agents, Alkylating; Binding, Competitive; Estramustine; Estrogens; Estrone; Genes, Reporter; HeLa Cells; Humans; Kinetics; Luciferases; Male; Metribolone; Mutagenesis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Receptors, Androgen; Recombinant Proteins; Transcriptional Activation; Transfection; Triamcinolone Acetonide; Tumor Cells, Cultured

The interaction of the antimitotic agent estramustine with bovine microtubule proteins and purified tubulin was investigated. Direct photoaffinity labeling of microtubule protein with [14C]estramustine resulted in the labeling of both alpha- and beta-tubulin, and this was inhibited with unlabeled estramustine in a dose-dependent manner. [14C]Estramustine was incorporated into both the soluble and polymerized forms of tubulin. The affinity constant for estramustine binding to tubulin was determined by equilibrium dialysis to be 23 +/- 5 mM. Estramustine did not affect [3H]vinblastine binding, and vinblastine had no effect on direct labeling with [14C]estramustine. Both rhizoxin and paclitaxel decreased the covalent labeling of tubulin with [14C]estramustine in a dose-dependent fashion and were noncompetitive inhibitors of the binding of estramustine to tubulin. The binding of colchicine to tubulin was not inhibited by estramustine as detected by fluorescence and DEAE filter assays. The estramustine binding site on tubulin is therefore distinct from that of colchicine and vinblastine and may at least partially overlap with the binding site for paclitaxel. In both bovine brain microtubules and cytoskeletal proteins from human prostatic carcinoma cells, the incorporation of [14C]estramustine into the beta III isotype of tubulin was found to occur with a reduced efficiency compared to that of the other beta-tubulin isotypes and alpha-tubulin. Since this isotype is overexpressed in estramustine resistant human prostate carcinoma cells, these results indicate that beta III-tubulin may play a role in the response to the effects of estramustine.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Binding Sites; Brain; Cattle; Colchicine; Estramustine; Guanosine Diphosphate; Guanosine Triphosphate; Humans; In Vitro Techniques; Male; Microtubule Proteins; Mitosis; Paclitaxel; Prostatic Neoplasms; Tubulin; Vinca Alkaloids

To evaluate combinations of anti-tumour agents in tissue cultures using three established cell lines derived from patients with prostate cancer to obtain potential candidates for therapeutic testing in patients with prostate cancer.. Seventeen anti-tumour agents were tested for synergism or antagonism in combination studies in DU 145, PC 3 and LnCaP cell lines. After determining the dose required for 50% inhibition of growth in each, combinations were screened using the median-effect plot and combination-index isobolograms.. Estramustine (the primary product of dephosphorylation of estramustine phosphate) showed strong synergism in all three cell lines with hydroxyflutamide, the non-immunosuppressive cyclosporin analogue PSC 833, and Liarozole. In the hormone-sensitive cell line LnCaP alone, synergism was also observed with vinblastine, paclitaxel, docetaxel, bicalutamide, ketoconazole and all-trans-retinoic acid. Other synergistic combinations of two agents were: Liarozole plus docetaxel in LnCaP, PSC 833 plus bicalutamide in DU 145 and PC 3, dexamethasone plus docetaxel in LnCaP, and finasteride plus hydroxyflutamide. Synergistic combinations of three agents were: estramustine plus PSC 833 and Liarozole and schedule-dependent combinations of estramustine, PSC 833, and all-trans-retinoic acid.. Some of the synergistic combinations have shown clinical effects in patients with hormone-refractory prostate cancer. Based on these findings, new combinations, e.g. estramustine with either PSC 833 or Liarozole, need to be clinically evaluated.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Estramustine; Humans; Male; Prostatic Neoplasms; Tumor Cells, Cultured

Clinical effects of estramustine phosphate (EMT) on hormone refractory prostate cancer were studied. Prostate cancer relapsed in 70 of the 259 patients with stage C and D diseases who had initially responded to endocrine therapy. After cancer relapse, endocrine therapy was changed to oral administration of EMT in 21 patients, while initial endocrine therapy was continued in 14 and additional radiation therapy was given in 35. A partial response or no change was observed in 11 of the 21 patients (52%) given EMT therapy, the mean duration of the response being 14.2 months. The 21 patients given EMT therapy survived significantly longer than the 14 patients with continued on endocrine therapy, and those responding to EMT therapy tended to have a better survival than those unresponsive. Side effects of EMT included loss of appetite in 2 patients and edema of the lower limb in 1, but they were not severe enough to require discontinuation of the drug. EMT may be a useful drug for patients with advanced prostate cancer with relapse after endocrine therapy.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Hormonal; Bone Neoplasms; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms; Survival Rate

In order to develop a hormone-resistant analog to the hormone sensitive cell-line LNCaP, different methods were tried.. After almost one year of continuous culture in RPMI-1640, containing a low concentration of androgens, the hormone sensitive cell-line LNCaP became hormone resistant and was named LNCaP-r.. We used the LNCaP/LNCaP-r model system in order to study methods for the parenteral treatment of prostate carcinoma with estrogens, to study the mechanism of action of estramustine, and to identify markers useful as predictive tests for prostate carcinoma.. A model system made up of the hormone sensitive prostate LNCaP cell-line and the hormone resistant LNCaP-r subline was developed and characterized. This system is, despite a number of limitations, easy to use as a first step to test different hypotheses that can be studied further in later clinical trials.

Topics: Androgens; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Cell Division; Drug Resistance; Estramustine; Estrogens; Hormones; Humans; Lymphatic Metastasis; Male; Prostatic Neoplasms; Research; Tumor Cells, Cultured

Thirty-three patients with prostatic carcinoma were treated with either estramustine phosphate, orchidectomy or high dose medroxyprogesterone acetate. Therapy response was evaluated by cytological examination of fine needle aspiration biopsies performed before and after 6 weeks treatment. At follow-up, 11 of 14 patients treated with estramustine phosphate had regressive and/or degenerative changes, in 2 patients there were no prostatic carcinoma cells in the smears and in one there was a marked reduction of the number of tumour cells. In 7 of 10 patients treated with orchidectomy there was a marked reduction of the percentage of malignant cells while smears from 3 patients were unchanged. In the 8 patients treated with high dose medroxyprogesterone acetate the cell patterns were unmodified compared with before treatment. We conclude that, in contrast to the lack of effect of treatment with medroxyprogesterone acetate, treatment with orchidectomy and especially estramustine phosphate caused morphologic cellular changes in prostatic carcinoma.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biopsy, Needle; Cell Survival; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Humans; Male; Medroxyprogesterone Acetate; Middle Aged; Orchiectomy; Prostate; Prostatic Neoplasms

Procollagen 1 carboxyterminal peptide (P1CP) is thought to be an indicator of new bone formation. The present report demonstrates that effective endocrine therapy induced an initial increase followed by a delayed decrease in serum levels of P1CP and alkaline phosphatase in spite of an immediate decrease in serum PSA and PAP and improvement of clinical symptoms in prostate cancer patients with bone metastases. The transient increase in P1CP and alkaline phosphatase is a healing reaction and is followed by apparent improvement. Short-term effects of endocrine therapy on prostate cancer patients with bone metastases should be comprehensively evaluated based upon the entire spectrum of clinical and laboratory findings including serial changes of serum prostate markers and bone markers as well.

Topics: Adenocarcinoma; Aged; Alkaline Phosphatase; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Bone Neoplasms; Diethylstilbestrol; Estramustine; Gonadotropin-Releasing Hormone; Humans; Male; Peptide Fragments; Procollagen; Prostatic Neoplasms

bcl-xL is an antiapoptotic protein that shares sequence homology with bcl-2 and seems to convey chemoresistance in many human tumor cell lines. bcl-xL protein is expressed at a 3-fold higher level in PC-3 cells than it is in LNCaP cells. Taxol causes apoptosis in both these cell lines, as measured by the formation of DNA ladders and by the observation of typical cellular morphological changes (chromatin condensation and nuclear fragmentation) after 4', 6-diamidino-2-phenylindole staining. Overexpression of bcl-2 in LNCaP cells did not prevent Taxol-induced apoptosis. Treatment of LNCaP cells with 10 nm Taxol led, after 24 h, to relatively specific and almost total down-regulation of bcl-xL protein in the absence of alteration of bax, bak, or bcl-2 levels. This change was paralleled by a similar decrease in the level of bcl-xL mRNA, as demonstrated by reverse transcription-PCR. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA was not changed. In PC-3 cells, 48 h were required for both maximal bcl-xL protein down-regulation and cellular apoptosis. In contrast, treatment of LNCaP cells with estramustine induced apoptosis, but this was not associated with any change in the intracellular level of bcl-xL or bax protein. Instead, relatively specific 2-fold up-regulation of the proapoptotic protein bak was observed. In PC-3 cells, cellular apoptosis induced by estramustine was bak independent. These results augment our understanding of the importance of bcl-xL in prostate cancer and suggest that appropriate manipulation of cytotoxic chemotherapeutic agents may favorably alter the balance between pro- and antiapoptotic proteins in this tumor.

Topics: Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-X Protein; Estramustine; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Kinetics; Male; Membrane Proteins; Paclitaxel; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured

Immunotherapy with subcutaneous rIL-2 and alpha IFN was administered to stage D3 prostate cancer patients after failure of secondary treatment with oral estramustine phosphate. Of a total of 15 patients, 2 are in partial response, with estramustine maintained after 44+ and 36+ weeks, respectively. Response to estramustine was observed initially in 7 of 13 patients, with a median duration of 12 weeks (range 8-20). No response to estramustine was observed in the remaining 6 patients. After the failure of estramustine, 13 patients were treated with immunotherapy. After the first cycle, progression of disease no therapy was given to those patients. A reduction of PSA levels was observed during the first cycle in 2 patients (15.3%); levels subsequently increased during the second cycle of treatment. A partial response was observed in 4 patients (30.7%), with a reduction of PSA levels in 3. The duration of response was 28 and 32 weeks in 2 patients who survived after failure for 18 and 21 weeks, respectively. Two patients are still alive, with continued partial response at 62+ and 42+ weeks. Side effects were represented mainly by a flu-like syndrome, associated with fever and nausea in all patients. The serum concentration of IL-10 was measured in 8 patients under study and in 11 matched controls. Levels higher than mean + 2D of controls before, during, or after immunotherapy were correlated with treatment failure, whereas levels below 6 ng/ml were encountered among the patients who showed a clinical response and a reduction of PSA during treatment. Within the limitations of this pilot study, it appears difficult to distinguish between a spontaneously slowly progressing disease and a true response to therapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estramustine; Humans; Immunotherapy; Injections, Subcutaneous; Interferon-alpha; Interleukin-10; Interleukin-2; Male; Middle Aged; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Recombinant Proteins; Salvage Therapy; Treatment Outcome

The time from first diagnosis of primary multiple metastatic prostate carcinoma until progression and until death in patients less than 60 years old under two different therapeutic regimens was evaluated.. In the group with pure androgen deprivation (n = 21), the mean time until progression was 11.3 (6-55) months, the mean survival time being 21.4 (11-75) months. In the group with androgen deprivation plus cytostatic therapy (n = 10), progression was noted after 26.7 (15-77) months with a medium survival time of 26.2 (16-82) months.. The data argue in favor of changing the usual treatment strategy to combination therapy in "young' patients with primary metastatic prostatic cancer.

Topics: Adult; Androgens; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Castration; Cisplatin; Combined Modality Therapy; Doxorubicin; Estramustine; Gonadotropin-Releasing Hormone; Guidelines as Topic; Humans; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; World Health Organization

Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with beta-tubulin isotype-specific antibodies showed an approximately 6-fold increase in the beta(III)-tubulin levels and moderate increase in overall beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of beta(III) isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using beta-tubulin isotype-specific primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific beta-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.

Topics: Antineoplastic Agents; Base Sequence; DNA Primers; Drug Resistance; Estramustine; Fluorescent Antibody Technique, Indirect; Gene Expression; Humans; Male; Molecular Sequence Data; Prostatic Neoplasms; RNA, Messenger; Tubulin; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Cell Division; Cell Survival; Cells, Cultured; Estramustine; Etoposide; Humans; Male; Paclitaxel; Prostatic Neoplasms; Rats

Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that interact with the nuclear matrix have been demonstrated to have activity against hormone-refractory prostate cancer. It was the aim of this study to assess the activity of estramustine, an estradiol-nitrogen mustard conjugate, and 9-aminocamptothecin (9-AC), a topoisomerase I inhibitor, in a preclinical model of hormone-refractory prostate cancer.. We used the Dunning rat prostatic adenocarcinoma model to demonstrate that the combination of estramustine and 9-AC interacts at the level of the nuclear matrix to inhibit the growth of prostate cancer cells.. We demonstrate that the combination of these two agents at pharmacologically achievable doses are cytotoxic to rat and human prostate cancer cells in vitro and in vivo in the rat.. The combination of the two drugs was significantly more cytotoxic than either drug alone. We have instituted a Phase II clinical trial in patients with hormone-refractory prostate cancer using 9-AC based on these preclinical findings.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Division; Estramustine; Humans; Male; Prostatic Neoplasms; Rats

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Leukemia, Myeloid, Acute; Male; Neoplasms, Second Primary; Prostatic Neoplasms

For the purpose of elucidating whether the biological characteristics of estramustine-binding protein (EMBP) are different in benign prostatic hypertrophy (BPH) and prostatic carcinoma (PC) and also to determine the clinical value of EMBP in the tissue, the EMBP concentration in 19 patients with BPH and 26 with untreated PC was measured by means of radioimmunoassay (RIA) using an antibody raised against EMBP obtained from the rat ventral prostate and compared simultaneously with the dihydrotestosterone (DHT) level in the same tissue. The level of serum prostate-specific antigen (PSA) was also measured in these patients. The EMBP concentration was significantly correlated with the tissue DHT level in BPH and well-differentiated PC (r = 0.745, p < 0.0001), whereas it did not correlate in moderately and poorly differentiated PC (r = -0.159, p = 0.542). By comparing well-differentiated PC with moderately and poorly differentiated PC, the EMBP concentration was significantly lower in the former than in the latter two conditions (p < 0.005) in spite of the highest tissue DHT level in well-differentiated PC. The ratio of the EMBP concentration to the DHT level in moderately and poorly differentiated PC was significantly higher when compared with that observed in either BPH or well-differentiated PC (p < 0.005, respectively). However, the level of serum PSA did not reflect the histological differentiation of PC. These results suggest that: (i) the correlation of the EMBP concentration to the DHT level changed with the progression of the histological grade, and (ii) the ratio of the EMBP concentration to the DHT level in the tissue is clinically valuable in elucidating the biological potential of individual tumors.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carrier Proteins; Dihydrotestosterone; Estramustine; Humans; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay

The binding of vinblastine (VLB) and estramustine (EM) to plasma membranes isolated from human prostate, prostatic tumors as well as from Dunning rat prostatic AT-1 tumors was studied. In addition, the uptake of these drugs in AT-1 tumor cells in culture was examined. Binding of VLB was six-fold lower than that of EM in membrane preparations from all three sources. The uptake of VLB in the intact AT-1 cells was nearly five-fold lower than that of EM. At concentrations comparable to those achieved clinically the binding of EM was 100-fold higher than that of VLB. The data suggest that, owing to a very high membrane concentration of EM relative to that of VLB, the active efflux VLB in drug resistant cells would be impeded. This in turn would lead to a higher accumulation of VLB in cells that actively transport cytotoxic drugs.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Cell Membrane; Estramustine; Humans; Male; Prostate; Prostatic Neoplasms; Rats; Tumor Cells, Cultured; Vinblastine

We evaluated the effectiveness of combination chemotherapy using estramustine and velban for metastatic prostate cancer. Patients with progressive metasatatic prostate cancer and rising prostate-specific antigen (PSA) values were evaluated between 1992 and 1994. All treatment was given on an outpatient basis. Vinblastine, 4 mg/m2 i.v., was given weekly for 6 weeks with a 2-week rest period. Estramustine, 10 mg/kg orally, was given in three divided doses for 6 weeks with a 2-week rest period between cycles. Of 15 patients, six (40%) had a response, in which a 25% decrease in PSA was associated with subjective improvement. There were no complete responses. Five partial responders had less pain. Median duration of response or time to progression was 9 months. Survival was 11.7 months for responders, 13.2 months for nonresponders. The combination of estramustine and velban is an effective therapy in progressive metastatic prostate cancer as measured by a decrease in PSA and improvement of symptoms.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Drug Administration Schedule; Estramustine; Humans; Lymphatic Metastasis; Male; Middle Aged; Pain; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Survival Rate; Vinblastine

The effects of combining estramustine (EM) with vinblastine (VLB) or doxorubicin (DOX) on cellular uptake, cellular retention and cell survival were investigated in Dunning hormone-insensitive rat prostate AT-1 tumor cells and DU-145 human prostatic tumor cells. Accumulation of VLB and DOX by AT-1 cells was less than one-half of that in DU-145 cells. Inclusion of EM or estromustine considerably increased uptake of both VLB and DOX in AT-1 cells but not in DU-145 cells. Verapamil and tamoxifen also potentiated VLB uptake in AT-1 cells. A combination of VLB and EM resulted in a considerable synergistic effect on both cytotoxicity and cellular retention of VLB. The presence of P-glycoprotein (Pgp) in AT-1 cells could be demonstrated by both Western blots and immunocytochemical detection. Photoaffinity labeling of Pgp by [3H]-azidopine was clearly inhibited by VLB, verapamil and EM. Our data strongly support the argument for a combination of EM with not only VLB but also DOX to improve the therapeutic index in patients with prostate cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Synergism; Estramustine; Humans; Male; Prostatic Neoplasms; Rats; Tumor Cells, Cultured; Vinblastine

An 89-year-old man with bilateral leg edema and a huge abdominal mass was admitted for further evaluation. CT scan showed a hugh prostatic mass which occupied the whole pelvis cavity accompanying multiple pelvic bone metastases. Suprapubic needle biopsy revealed that the mass was well differentiated adenocarcinoma of prostate origin. The treatment was initiated by 500 mg per day of estramustine phosphate combined with injectable LH-RH analogue 2 months later. The serum levels of tumor markers were markedly elevated at the first visit; PSA 210ng/ml, PAP 110ng/ml, gamma-Sm 800ng/ml. They became normalized 3 months after the initiation of the treatment, and the mass was reduced to 11.5% of the initial size, which lead to removal of indwelling urethral catheter. The patient and his family, however, refused further treatment and the patient died of disseminated disease 8 months later.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Estramustine; Humans; Leuprolide; Male; Prostatic Neoplasms

The usefulness of estramustine phosphate (ECT) for preventing flare-up in goserelin acetate depot therapy for advanced prostate cancer was studied. Pretreatment with ECT 560 mg daily for 3 weeks almost completely prevented the rise in testosterone level seen in goserelin acetate depot therapy and no signs or symptoms of tumor flare were observed. Long-term ECT completely blocked the rise in luteinizing hormone and testosterone level, but ECT at this dosage was likely to cause complications. The administration of ECT 560 mg daily for 3 weeks prior to goserelin acetate depot therapy was considered sufficient to prevent tumor flare, and its effect was considered to be more marked than that of short-term treatment with antiandrogens.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Drug Therapy, Combination; Estramustine; Goserelin; Humans; Injections, Subcutaneous; Luteinizing Hormone; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

This study describes our experience in the treatment of disseminated prostatic cancer with stramustine phosphate.. We reviewed our series of 41 patients with disseminated prostatic cancer; of these, 6 were treated with stramustine phosphate. Patient age, clinical features, tumor stage and diagnostic methods utilized were analyzed. All patients received 600 mg/day oral stramustine in two doses.. All 6 patients treated with stramustine phosphate showed clinical improvement, the levels of tumor markers returned to normal and bone metastasis disappeared. Moreover, no side effects were observed.. Further research is necessary on the effective use of stramustine phosphate and at the appropriate time in order to obtain the best results as there is no other alternative except radical surgery and at an early stage.

Topics: Aged; Combined Modality Therapy; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Remission Induction; Time Factors

Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that inhibit microtubule function have been found to be cytotoxic to prostate cancer cells in preclinical and clinical settings. It was the aim of this study to assess the activity of estramustine and colchicine, two microtubule inhibitors, in hormone-refractory prostate cancer. In clinically achievable concentrations, the combination of estramustine and colchicine was cytotoxic to both the Dunning rat prostate adenocarcinoma cell line MAT-LyLu (MLL) and human prostate cancer cells (PC-3). Microtubule function was assessed in vitro to evaluate possible mechanisms of action. In motility and cell cycle analysis assays, estramustine and colchicine inhibited cellular motility but not cell cycle transit. In vivo, these two agents both inhibited the growth of implanted Dunning rat prostate adenocarcinoma MLL cells but did not appear to have additive effects. The use of oral colchicine in the treatment of hormone-refractory prostate cancer requires further investigation.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colchicine; Dose-Response Relationship, Drug; Estramustine; Humans; Male; Prostatic Neoplasms; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Flutamide; Humans; Male; Prostatic Neoplasms

The expression of estramustine-binding protein (EMBP) was studied immunohistochemically in whole-mount prostate sections. Specimens were taken from the prostates of 15 patients who had undergone total prostatectomy due to localized (TOd-T2 NO MO) prostatic cancer (PC). Almost all the examined whole-mount sections displayed areas with prostatic intraepithelial neoplasia (PIN). PIN is regarded as the main precursor of invasive PC. High- and low-grade PIN expressed EMBP. The average positively stained areas accounted for averages of 69.2% and 48.7%, respectively. High-grade PIN contained the highest EMBP levels of all the investigated (benign and malignant) epithelia, followed by moderately differentiated PC. With regard to areas with PC, the highest levels of EMBP expression (61.3%) were observed in moderately differentiated PC; poorly differentiated PC came second. Of all the examined epithelia, EMBP levels were lowest in well-differentiated PC (25.8%). Normal prostatic epithelia and hyperplasia were characterized by low EMBP expression, although somewhat higher than well-differentiated PC. A moderate expression (45%) was observed in the seminal vesicles. According to these results, EMBP was expressed mainly in the diseased peripheral zone (PZ), where PIN and prostatic cancer have their highest prevalence.

Topics: Aged; Carrier Proteins; Epithelium; Estramustine; Humans; Immunoenzyme Techniques; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Seminal Vesicles

Estramustine phosphate (EMP) and flutamide (FL) were used as reversible preoperative hormonal drugs in the surgical treatment of patients with localized prostate cancer.. The authors descriptive and quantitatively examined the morphologic and immunohistochemical changes in 40 of 200 step-sectioned radical prostatectomies, obtained after treatment with EMP (25 patients) and with FL (15 patients). Of these, 28 pretreatment needlecore biopsies were available.. Every specimen contained adenocarcinoma. Understaging was found in 50% of the cases and a higher Gleason score in 70%. Benign glands underwent atrophy and squamous metaplasia. Treated tumors showed cytoplasmic vacuolization, nuclear pyknosis, fibrosis and lymphocytic infiltrates. The EMP group had an 84% (P < 0.05) higher mean total regression score than the FL group. Estramustine phosphate induced a 56% (P < 0.05) and a 34% decrease in tumoral prostate specific antigen and prostate specific acid phosphatase intensity scores, respectively, versus 29% and 32% after FL. The mean proliferating cell nuclear antigen (PCNA) labeling index and the mean mitotic index of the EMP group were 52% (P < 0.05) and 70% (P < 0.05) lower than those measured in the FL group. Each FL-treated tumor and 92% of EMP-treated tumors expressed chromogranin A (ChrA); ChrA labeling correlated significantly with PCNA labeling. Seventy-six percent of EMP-treated specimens revealed venous thrombosis.. Estramustine phosphate induces important morphologic and immunohistochemical changes in prostate cancer with an apparent decrease of secretory and proliferative activity when compared with FL-treated tumors. These changes represent pitfalls in the diagnosis and grading of treated carcinomas. Nearly every treated adenocarcinoma of the prostate has neuroendocrine differentiation, showing increasing ChrA labeling with higher tumor stage. A significant correlation between tumor proliferation and neuroendocrine differentiation was noticed in this small cohort of patients. There was a high incidence of periprostatic venous thrombosis after EMP treatment.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Chemotherapy, Adjuvant; Chromogranin A; Chromogranins; Estramustine; Flutamide; Humans; Immunohistochemistry; Male; Mitosis; Neoplasm Staging; Premedication; Proliferating Cell Nuclear Antigen; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

We report a case of advanced prostate cancer in which an initial response to hormonal therapy with surgical castration and estramustine phosphate (EMP) was followed by disease progression, as shown by sequential elevations in serum prostate specific antigen (PSA) and prostate acid phosphatase (PAP) and the development of new symptoms, during maintenance endocrine and anti-cancer chemotherapy. Discontinuation of EMP resulted in sustained reductions in serum PSA and PAP levels and a sustained improvement in symptoms.

Topics: Acid Phosphatase; Adenocarcinoma; Biomarkers, Tumor; Bone Neoplasms; Castration; Estramustine; Humans; Lung Neoplasms; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

Clinically-used drugs such as furosemide, bumetanide and cardiac glycosides, are modulators of transmembrane fluxes of cations. Recently, it has been suggested that the regulation of intracellular cation concentrations could be a primary target for anti-neoplastic drugs, and that the cytotoxic activity may be altered by inhibitors of cation fluxes at the level of the plasma membrane. Therefore, we investigated the mechanisms by which cations are translocated across the plasma membrane of malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines. The interactions between cation flux inhibitors and the cytotoxicity of estramustine were also evaluated. Ouabain, the classical inhibitor of Na+, K+ATPase, markedly reduced 86Rb (K+) influx in all three lines, indicating that this ion transport system is present in the cells. Furosemide and especially bumetanide inhibited the 86Rb influx, indicating the presence of the Na+, K+, Cl- co-transport system. The potassium channel blocker, tetraethylammonium, but not apamin reduced the influx of 86Rb showing that high conductance K+ channels are present, but that channels of low conductance probably do not exist in these cell lines. The Na+, K+, Cl- co-transport inhibitors furosemide and bumetanide significantly reduced cytotoxicity of estramustine in P31 cells, whereas no interaction between other K+ flux inhibitors and the anti-neoplastic drugs were detected in any of the cell lines investigated. Thus, the data show that Na+, K+, ATPase and NA+, K+, Cl- co-transport systems and K+ channels of high conductance are present in malignant glioma (U251 MG), prostatic carcinoma (PC3) and pulmonary carcinoma (P31) cell lines, and that inhibition of the Na+, K+, Cl- co-transport system in P31 is associated with reduced cytotoxicity of estramustine. The results justify further studies evaluating the role of these cation flux pathways in terms of targets for anti-neoplastic therapy.

Topics: Bumetanide; Cell Division; Estramustine; Furosemide; Glioma; Humans; Ion Transport; Lung Neoplasms; Male; Ouabain; Potassium; Potassium Channels; Prostatic Neoplasms; Rubidium Radioisotopes; Sodium-Potassium-Exchanging ATPase; Tumor Cells, Cultured

Estramustine (EM), an antimicrotubule agent, binds microtubule-associated proteins, causes spindle disassembly, and arrests cells at the late G2/M phase of the cell cycle. Since cells in the G2/M phase are the most radiosensitive and some human cancer cells contain high level of EM-binding protein, experiments were carried out to determine whether radiation sensitization could be obtained in human carcinoma cells.. Cells containing a high level of EM-binding protein such as prostate carcinoma (DU-145), breast carcinoma (MCF-7), and malignant glioma (U-251) were used to demonstrate radiosensitization. Cervical carcinoma (HeLa-S3) and colon carcinoma (HT-29) cells which are not known to contain EM-binding protein were also employed. Cell survival was assayed by the colony forming ability of single plated cells in culture to obtain dose-survival curves.. Pretreatment of DU-145, MCF-7, and U-251 cells to a nontoxic concentration (5 microM) of EM for more than one cell cycle time, substantially enhanced the radiation-induced cytotoxicity. The sensitizer enhancement ratio of these cells ranged from 1.35-1.52. The magnitude of the enhancement was dependent on the drug concentration and exposure time. The rate of cell accumulation in G2/M phase, as determined by flow cytometry, increased with longer treatment time in the cell lines which showed radiosensitization. Other antimicrotubule agents such as taxol and vinblastine caused minimal or no radiosensitization at nontoxic concentrations.. The data provide a radiobiological basis for using EM as a novel radiation enhancer, with the property of tissue selectivity.

Topics: Breast Neoplasms; Cell Cycle; Cell Survival; Colonic Neoplasms; Combined Modality Therapy; Estramustine; Female; Flow Cytometry; Glioma; HeLa Cells; Humans; Male; Microtubules; Neoplasms; Paclitaxel; Prostatic Neoplasms; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Vinblastine

Topics: Antineoplastic Combined Chemotherapy Protocols; Estramustine; Etoposide; Humans; Male; Prostatic Neoplasms

To identify specific drug targets of the antimitotic drug estramustine, a photoaffinity analogue, 17-O-[[2-[3-(4-azido-3-[125I] iodophenyl)propionamido]ethyl]carbamyl]estradiol-3-N-bis(2- chloroethyl)carbamate, was synthesized and reacted in competition assays with cytoskeletal protein preparations. By attaching the photoaffinity ligand to the 17 beta-position of the steroid D-ring, the cytotoxic properties of the drug were maintained. In cytoskeletal protein preparations from human prostate carcinoma cells (DU 145) or a clonally selected, estramustine-resistant cell line (E4), the major microtubule-associated protein (MAP) present was MAP4. In both cytoskeletal fractions and reconstituted microtubules, 17-O-[[2-[3-(4-azido-3-[125I]iodophenyl)propionamido] ethyl]carbamyl]estradiol-3-N-bis(2-chloroethyl)carbamate bound to both MAP4 and tubulin. From competition assays, the apparent binding constant for MAP4 from DU 145 cells was 15 microM. Similar calculations for tubulin gave values of 13 microM (bovine brain), 19 microM (DU 145 wild-type cells), and 25 microM (E4 cells). The identification of these cytoskeletal proteins as specific drug targets provides a direct explanation for the antimicrotubule and antimitotic effects of estramustine.

Topics: Affinity Labels; Animals; Azides; Cattle; Drug Resistance; Estramustine; Humans; Male; Microtubule Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Photochemistry; Prostatic Neoplasms; Protein Binding; Tubulin; Tumor Cells, Cultured

For the purpose of elucidating the clinical significance of estramustine binding protein (EMBP), EMBP concentration in human prostatic carcinoma (PC) tissue was measured by radioimmunoassay (RIA) using an antibody raised against rat EMBP and was compared with dihydrotestosterone (DHT) level and histological differentiation in the same tissue. The mean concentrations of EMBP in 20 untreated and 6 hormonally refractory PC were 112.6 +/- 120.7 and 218.0 +/- 102.3 ng/g tissue, respectively. In the 20 untreated PC, the EMBP concentration was not significantly different between the high and low tissue DHT groups. On the other hand, the EMBP concentration was significantly higher in moderately and poorly differentiated PCs as compared with well-differentiated PC, whereas the DHT level was highest in well-differentiated and lowest in poorly differentiated PC. Furthermore, in the 6 hormonally refractory PC, the EMBP concentration was higher in spite of a lower tissue DHT level in comparison with untreated PC. These results suggest that the EMBP concentration does not reflect androgen status in PC tissue but might reflect the malignant potential of the tumor.

Topics: Aged; Carrier Proteins; Combined Modality Therapy; Dihydrotestosterone; Estramustine; Humans; Male; Prostate; Prostatectomy; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay

In this study, we have investigated the combined effect of estramustine treatment and external beam radiation on human prostatic cancer tumor cells (DU 145) transplanted in nude mice. The treatment was given according to two different schedules. In the first treatment regimen, estramustine was administered intraperitoneally (i.p.) intermittently for 20 days. The radiation therapy, which was started on day 9, was given with 6 Gy fractions during an 11-day-long period to a total dose of 36 Gy. The combination treatment (estramustine + radiation) resulted in a significant tumor growth retardation as compared to the control group. This pronounced effect was seen neither with radiation alone nor with estramustine alone. In order to further extend the radiation treatment time, a second therapy regimen was employed. In this part of the study, estramustine was administered i.p. intermittently for 26 days. The radiation therapy, which was started on day 6, was given with 4 Gy fractions during a 21-day-long period to a total dose of 40 Gy. Under these conditions, a significant tumor growth retardation was disclosed, when comparing the combination treatment (estramustine + radiation) with radiation alone. The tumors were analyzed for content of necrosis and proliferative activity. The largest proportion of necrosis was seen in the combination (estramustine + radiation) treatment group. Also, the tumors from this group expressed a decreased proliferative activity. The data indicate that estramustine acts as a radiosensitizing agent in human prostatic cancer cells in vivo. The radiosensitizing properties of the drug encourage further studies with respect to clinical application.

Topics: Animals; Cell Division; Combined Modality Therapy; Drug Synergism; Estramustine; Humans; Ki-67 Antigen; Male; Mice; Mice, Nude; Necrosis; Neoplasm Proteins; Neoplasm Transplantation; Nuclear Proteins; Prostatic Neoplasms; Radiation-Sensitizing Agents; Tumor Cells, Cultured

The present study was designed to determine if estramustine phosphate (EMP) could potentiate the effects of irradiation on the Dunning (R3327) prostatic adenocarcinoma in rats. Two groups of male Copenhagen x Fisher F1 rats carrying bilateral tumors in the flank were used. Irradiation was given with a linear accelerator 6 MV, in a dose of 6 Gy/day for 4 days to the tumor on one side while the tumor on the other side served as control. EMP (360 micrograms/24 hours) was administered with osmotic pumps to one group of rats for 2 weeks, starting 1 week before irradiation. Tumor growth was calculated by measuring tumor volume, and tumor blood flow was measured 8 weeks after treatment. Irradiation alone effectively delayed tumor growth and EMP enhanced these effects. Tumor blood flow was stimulated by EMP treatment irrespective of radiotherapy. Volume density of tumor epithelium was effectively decreased by irradiation but no significant effects could be seen after EMP. In conclusion, the present study shows that EMP potentiates irradiation on rat prostatic adenocarcinoma, and further evaluation of this therapeutic approach in the clinical treatment of prostatic carcinoma is thus justified.

Topics: Adenocarcinoma; Animals; Blood Pressure; Body Weight; Chemotherapy, Adjuvant; Epididymis; Estramustine; Male; Organ Size; Prostate; Prostatic Neoplasms; Rats; Regional Blood Flow; Testis; Testosterone

Early diagnosis and monitoring of progression for relapsed prostatic carcinoma after primary treatment is necessary, and early intervention recommended. This has now been made possible with rising prostate-specific antigen levels as an indication of the endpoint of treatment failure. Patients with relapsed disease can be divided into three groups: those relapsing following curative treatment with surgery or radiotherapy with local or distant metastases; patients who have been treated with primary hormonal palliative therapy or combination hormonal-chemotherapy relapsing after the first palliative treatment, and patients relapsing after all acceptable therapies for the treatment of prostate cancer. The management of these groups of patients is discussed.

Topics: Androgen Antagonists; Antineoplastic Agents; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Palliative Care; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

To investigate the mechanism of action of the antineoplastic drug estramustine, we compared its effects on human prostate cancer cells with those of vinblastine. At their respective concentrations that result in 50% inhibition of clonogenic growth, both drugs caused an accumulation of cells blocked at mitosis and similar dose- and time-dependent depolymerization of interphase microtubules. Also, colcemid-resistant and colcemid-hypersensitive Chinese hamster ovary cells with tubulin mutations were collaterally cross-resistant or -sensitive to estramustine. Thus, the cytotoxicity of estramustine is due to its microtubule depolymerization properties. This could be caused by interaction with tubulin and/or with microtubule-associated proteins (MAPs). Previous investigations have shown that high concentrations of estramustine phosphate can inhibit microtubule polymerization in vitro by binding to MAPs. However, estramustine phosphate is the clinical prodrug to estramustine, the intracellular active compound. In this study, we investigated the effects of estramustine on the binding of MAPs to taxol-stabilized microtubules in vivo. In contrast to previous reports, no effect of estramustine on the binding of MAPs to microtubules was found. Furthermore, we found that polymerization of purified tubulin could be inhibited by estramustine in vitro. Taken together, these results demonstrate that estramustine causes depolymerization of microtubules by direct interaction with tubulin.

Topics: Adenocarcinoma; Animals; Brain Neoplasms; Cattle; Cell Survival; CHO Cells; Clone Cells; Cricetinae; Estramustine; Fluorescent Antibody Technique; Humans; Kinetics; Male; Microtubules; Mitotic Index; Mutation; Prostatic Neoplasms; Protein Binding; Tubulin; Tumor Cells, Cultured; Vinblastine

Metastatic prostate cancer which is refractory to hormone therapy remains an incurable disease for which there is no effective therapy. We have begun to investigate the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated that estramustine phosphate (EMP), an estradiol-nitrogen mustard conjugate that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the level of the nuclear matrix. In a nascent DNA synthesis assay, EMP and etoposide interact to selectively inhibit new DNA synthesis on the nuclear matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarcinoma cell line Mat-LyLu as well as the metastatic human prostate adenocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prostate adenocarcinoma growth in the Dunning Copenhagen rat model. These data have formed the basis of a Phase I/II clinical trial to examine the effect of EMP and etoposide in patients with stage D hormone-refractory prostate cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; DNA, Neoplasm; Drug Screening Assays, Antitumor; Estramustine; Etoposide; In Vitro Techniques; Male; Nuclear Matrix; Prostate; Prostatic Neoplasms; Rats; Tumor Cells, Cultured

Analysis of the clinical progression of 61 patients with prostate cancer undergoing hormone therapy. PSA allowed early detection in 86.9% cases. In 25 patients no rescue treatment was instituted, and 36 patients were treated with estramustine phosphate resulting in decreased PSA levels in 58% and objective response in 36%. Of these, 82% showed decreased PSA levels for over six months. Survival rate was higher in respondent, treated patients and comparable in non-respondents, treated versus non treated patients.

Topics: Acid Phosphatase; Actuarial Analysis; Androgen Antagonists; Biomarkers, Tumor; Diethylstilbestrol; Estramustine; Humans; Male; Orchiectomy; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

This report provides new morphological insights, based on diagnostic methods, into metastases to the bone in prostate cancer patients. Lumbar CT examination is available to evaluate whether metastases are truly present or not, especially in aged patients with positive bone scans. The evaluation of response is clearer on CT. Furthermore, CT is useful not only in estimating the presence of metastases, CT also provides definite details on the extent of the metastatic condition.

Topics: Aged; Aged, 80 and over; Bone Neoplasms; Carcinoma; Chlormadinone Acetate; Diagnosis, Differential; Estramustine; False Positive Reactions; Follow-Up Studies; Humans; Male; Middle Aged; Osteolysis; Prostatic Neoplasms; Radionuclide Imaging; Spinal Diseases; Spinal Neoplasms; Tomography, X-Ray Computed

Estramustine (EM) and taxol, two antimicrotubule agents with distinct and apparently opposing mechanisms of action, were found to be effective in combination in the preclinical treatment of EM-resistant and sensitive, wild-type human prostatic carcinoma cell lines. Estramustine combined with 1 nM taxol (concentration 100-fold less than that measured in plasma of patients treated with taxol) produced greater than additive effects on the inhibition of cell survival of both wild-type and EM-resistant cells. When taxol was used with another microtubule-destabilizing drug, vinblastine, no significantly increased cytotoxicity was observed. Other effects on wild-type and EM-resistant cells produced by the combination of EM and taxol included (a) an increased proportion of the cells in the S phase of the cell cycle; (b) no mitotic block; and (c) an increase in the percentage of micronucleated cells from a control value of less than 1% to greater than 20% after drug treatment. Immunofluorescent microscopic analysis of the effect of this drug combination on the mitotic spindle apparatus revealed specific examples of aberrant mitotic figures, including multiple asters, cells with two distinct spindles, and tripolar spindles able to traverse mitosis and complete cytokinesis. These data provide supportive preclinical evidence for the potential development of an EM/taxol combination clinical regimen either for prostate or other cancers.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Cycle; Drug Screening Assays, Antitumor; Estramustine; Flow Cytometry; Humans; Male; Micronucleus Tests; Microtubules; Paclitaxel; Prostatic Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

Natural killer (NK) cell activity was studied together with tumor marker serotests (PSA, PAP) and blood testosterone, estradiol, cortisol, and prolactin concentrations in treated prostate cancer patients. NK cell activity data were correlated with tumor stage (stage D0 + D1 versus stage D2) and showed statistically insignificant differences. Both tumor progression and stabilization of metastatic disease, triggered by the application of more appropriate therapy in progressive subjects, yielded low NK activity data. By contrast, normal NK activity was found during both partial remission of stage D2 tumor and stabilization of the same disease, after an initial period of tumor remission. Differences between NK activity data from the aforementioned two groups are statistically significant (P less than 0.01). In subjects examined, the application of NK activity assay to those with advanced disease reflected changes in the outcome of the treatment more closely than it did routine tumor marker assessment. The activity of NK cells seems unaffected by changes in basal blood estradiol, cortisol, testosterone, and prolactin concentrations that occur during therapy with pharmacological agents (estradiol, cyproterone acetate, diethylstilbestrol, and flutamide) and during surgical castration. The reported NK activity recordings in treated prostate cancer patients might be indicative of the presence of tumor cells in the circulation. If this holds true, the measurement of NK activity would appear to furnish urological oncology with a new tool for early, rapid recognition of progressive metastatic tumors.

Topics: Acid Phosphatase; Antineoplastic Agents; Biomarkers, Tumor; Cyproterone Acetate; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Diethylstilbestrol; Estradiol; Estramustine; Flutamide; Hormones; Humans; Hydrocortisone; Killer Cells, Natural; Male; Orchiectomy; Prolactin; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunoassay; Testosterone

In low-stage prostatic carcinoma, local cure can be obtained with radiation therapy alone, while in locally advanced disease the chances for cure are less. In this study, we have addressed the question of whether estramustine (EM), the main cytostatic metabolite of estramustine phosphate (Estracyt), may act as a radiosensitizing agent. This drug accumulates in prostatic cancer and has also been shown to arrest cancer cells at metaphase both in vitro and in vivo. The human prostatic cancer cell line DU 145 was grown as cultures monolayer and incubated with EM in concentrations varying from 1 to 20 micrograms/ml. External beam irradiation was performed with doses ranging from 0 to 8 Gy using gamma rays from a 60Co source. Clonogenic cell survival (CS) was used to analyse the radiation sensitizing effect of EM. The radiation dose modifying factor (DMF) at the survival level 0.1 was found to be 0.77 in the presence of EM (5 micrograms/ml), i.e., 23% sensitization was obtained. When irradiating cells at the standard fraction dose of 2 Gy in the absence of EM, 22% of the cells lost their clonogenic ability. In presence of EM (5 micrograms/ml), 2 Gy caused 40% of the cells to lose their clonogenic ability. Thus a radiation sensitizing effect of EM was established in the CS assay. It was also of interest to determine if the radiosensitizing effect of EM could be confirmed in a rapid assay. The rapid fluorescence assay was used to observe early damage of the cells. Results showed that by 2 days after exposure to irradiation a weak tendency towards sensitization was seen, while a clear sensitization was obtained after 4 days. This indicates that the rapid assay might be developed to a predictive assay for detection of the response of primary prostate tumor cells to the radiation sensitizing effect of EM.

Topics: Cell Survival; Estramustine; Humans; Male; Prostatic Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tumor Cells, Cultured

The usefulness of serum acid phosphatase (SAP) in monitoring patients with advanced prostate carcinoma has been questioned. We reviewed a series of 59 patients with stage D2 prostate carcinoma. All patients had extended follow-up through at least one clinical relapse, or death. Responses to a variety of therapies were characterized as absent, subjective, or objective. All patients with an elevated pre-treatment SAP that fell to normal following therapy had prolonged survivals and improved prognoses. Conversely, all patients with an elevated SAP which did not normalize following therapy had poorer survivals. Among 36 objective responses to therapy, the SAP was elevated prior to or simultaneous with disease progression in 33 (93% sensitivity). In each ease where the pretreatment SAP normalized following therapy, any subsequent elevation in SAP above normal was always associated with clinical evidence of disease progression (100% specificity). Changes in SAP following therapy correlate well with both disease regression and disease progression in patients with advanced prostatic carcinoma.

Topics: Alkaline Phosphatase; Biomarkers, Tumor; Bone Neoplasms; Carcinoma; Cyclophosphamide; Estramustine; Estrogens; Flutamide; Follow-Up Studies; Humans; Male; Neoplasm Proteins; Neoplasm Staging; Orchiectomy; Predictive Value of Tests; Prostatic Neoplasms; Treatment Outcome

Sixty-eight patients who underwent radical prostatectomy without or after neo-adjuvant hormonotherapy for B2 or C stage prostate cancer were evaluated as concerned to the ease of the surgical procedure. Although it is difficult to assess this parameter, we experienced more difficulties and blood loss was higher in patients who had preoperative hormonal deprivation. Ongoing randomized trials could demonstrate an oncological benefit of neo-adjuvant hormonotherapy before radical prostatectomy. This eventual benefit will have to be balanced against an increased surgical difficulty.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Chemotherapy, Adjuvant; Cyproterone; Estramustine; Flutamide; Humans; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms

The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.

Topics: Adenocarcinoma; Adrenal Glands; Animals; Aromatase Inhibitors; Body Weight; Chlorobenzenes; Estradiol; Estramustine; Hypophysectomy; Male; Neoplasm Metastasis; Neoplasms, Experimental; Orchiectomy; Organ Size; Prostatic Neoplasms; Pyrimidines; Pyrrolidines; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis; Thiophenes

Estramustine is one of the main metabolites of estramustine phosphate (EstracytR), a drug used in the treatment of advanced prostatic cancer. In the present study the hormone independent human prostatic carcinoma cell line DU 145 implanted subcutaneously in nude mice (NMRI) was used to investigate the mode of action of estramustine in vivo. Metaphase arrest was found in mice treated with estramustine intraperitoneally, 200 and 400 micrograms daily for 2 weeks, 5 days a week. A significant dose dependent decrease in the number of anaphase figures was found. A 7 to 8 fold increase in the number of abnormal metaphases, i.e., highly contracted and unaligned chromosomes, was found. Uptake and retention of 3H-estramustine was found in tumour tissue. No increase in the mitotic index or the number of abnormal metaphases was found in animals treated with polyestradiol phosphate (EstradurinR). This is the first time evidence has been presented demonstrating the anti-mitotic effect of estramustine in vivo.

Topics: Animals; Carcinoma; Estramustine; Humans; Male; Mice; Mice, Nude; Mitotic Index; Neoplasm Transplantation; Prostatic Neoplasms; Tumor Cells, Cultured

A quadruple tumor marker serotest assay (neurone-specific enolase, NSE, prostate-specific antigen, PSA, prostatic acid phosphatase, PAP, and carcino-embryonic antigen, CEA) was performed on sera from both 63 patients with untreated prostate cancer and 135 patients treated with orchiectomy, flutamide, diethylstilbestrol (DES), cyproterone acetate (CPA), and Estracyt. In untreated patients with local tumor elevated blood NSE concentrations were found more frequently (10/35, 28.6%) than in untreated subjects with disseminated disease (3/28, 10.7%). Elevated NSE values were measured more frequently in nonresponders to therapy 10/46 (21.7%), than in responders during prostate cancer partial remission (2/89, 2.2%). In none of NSE-positive neoplasms a small cell prostate cancer has been histologically detected. Many of NSE-positive tumors are also closely associated with elevated blood CEA values. The applied anticancer drugs were inefficient in the normalization of neither one from the pair of elevated NSE and CEA concentrations (regardless of the numerical values of the other two markers, PSA and PAP), but their values were found to decline occasionally only after surgical treatment. In patients with raised PSA, PAP, and CEA levels but with a normal NSE value, the application of the same treatment strategies was in the most of subjects sufficient to provoke either temporary or even lasting tumor response to therapy. Hence, it appears that the assessment of the NSE serotest, despite its minimal value in the overall tumor staging and monitoring, might furnish the decision-making step related to the treatment of aggressive prostate cancer with an additional and powerful tool.

Topics: Acid Phosphatase; Antigens, Neoplasm; Antineoplastic Agents; APUD Cells; Biomarkers, Tumor; Carcinoembryonic Antigen; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Flutamide; Humans; Male; Orchiectomy; Phosphopyruvate Hydratase; Prostate-Specific Antigen; Prostatic Neoplasms

Efficacy of orchiectomy and intravenous administration of diethylstilbestrol diphosphate (DESP) for the treatment of prostatic carcinoma was evaluated on 184 patients treated between 1975 to 1989. The patients were between 49 to 88 years old with a mean age of 73.4 +/- 8.3 years. Clinical stage was A in 9.8%, B in 12%, C in 26.6% and D in 51.6%. The histologically well, moderately and poorly differentiated adenocarcinoma were observed in 20.9, 29.4 and 49.7%, respectively. The 5-year survival rate of stage A, B, C and D calculated with the Kaplan-Meier method were 90, 49, 60 and 34%, respectively. The 5- and 10-year survival rate of the patients who had received orchiectomy was 53 and 24%, respectively, while that of the patients without orchiectomy was 38 and 14%, respectively. The 5 and 7-year survival rate of the patients treated with intravenous administration of DESP was 54 and 34%, respectively while that of the patients without DESP was 46 and 31%, respectively. These findings suggest that orchiectomy and intravenous administration of DESP in any form prolonged patient survival compared with only oral administration of estrogens or antiandrogens. Reactivation was seen in 24 (40%) of the 60 patients under sufficient observation. Clinical relapse occurred within an average of 32.3 +/- 26.4 months after primary hormonal manipulation. The average time to relapse in stage D was shorter than that in stage B and C. Reactivation was observed in the patients on interrupted treatment earlier than in the patients on continuous administration of drugs. Cardiovascular death followed by endocrine therapy was 7.4% in this study.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Chlormadinone Acetate; Combined Modality Therapy; Diethylstilbestrol; Drug Administration Schedule; Estramustine; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasm Staging; Orchiectomy; Prostatic Neoplasms; Survival Rate

We describe a 62-year-old male with brain metastasis from prostatic carcinoma, which regressed with medical and surgical endocrine therapies. The patient's presenting complaints were left periocular and deep ocular pain and a defect of the left visual field. During treatment of the above symptoms, macrohematuria, dysuria and pollakiuria occurred. Pathological examination of a transrectal needle biopsy disclosed moderately differentiated adenocarcinoma of the prostate. Computerized tomographic scan (CT) and magnetic resonance imaging demonstrated a brain tumor at the frontal skull base and the region of the frontal lobe suspected to be a metastasis of the prostatic carcinoma. One week after a period of daily administration of estramustine phosphate sodium, the prostate was observed to be softened and slightly decreased in size. The visual field defect and disturbance of urination gradually improved. The prostate decreased to normal size and no tumor mass could be detected on the brain CT after 3 months of treatment.

Topics: Adenocarcinoma; Biopsy, Needle; Brain Neoplasms; Combined Modality Therapy; Estramustine; Frontal Lobe; Humans; Male; Middle Aged; Orchiectomy; Pain; Prostatic Neoplasms; Tomography, X-Ray Computed; Ultrasonography; Vision Disorders

The chemotherapeutic drug, estramustine, has been shown to cause the disassembly of microtubules via binding to microtubule-associated proteins. In this report, estramustine is shown to be a potent inhibitor of mitotic progression in the human prostatic carcinoma cell line, DU 145. Examination of individual living cells via video-enhanced differential interference contrast (DIC) optics shows that the drug delays the onset of anaphase, reduces anaphase spindle-pole elongation (anaphase B), and delays cytokinesis. In addition, immunofluorescent studies demonstrate that estramustine causes a rapid disorganization of the mitotic apparatus at significantly lower concentrations than those reported previously. Electron microscopic studies show that microtubule bundles are present in drug-treated mitotic cells in association with kinetochores and centrioles.

Topics: Anaphase; Cell Division; Estramustine; Humans; Male; Metaphase; Microscopy, Electron; Microscopy, Fluorescence; Microtubule-Associated Proteins; Microtubules; Prostatic Neoplasms; Spindle Apparatus; Tumor Cells, Cultured

Following EMS mutagenesis, three estramustine (EM) resistant DU 145 human prostatic carcinoma cell lines were clonally selected by exposure to incrementally increasing concentrations of the drug. Although only low levels of resistance (approximately 3-fold) were attainable, this resistance was stable in the absence of continuous drug exposure. These EM-resistant clones (EMR 4,9,12) did not exhibit cross resistance to vinblastine, taxol, or adriamycin, and had collateral sensitivity to cytochalasin B. None of the lines had elevated expression of P-glycoprotein mRNA or glutathione S-transferase activity, suggesting a phenotype distinct from the classic multi-drug resistance phenotype. This conclusion was supported further by the observation that two MDR cell lines (FLC mouse erythroleukaemic and SKOV3 human ovarian carcinoma cells) showed sensitivity to EM. Fluorescent activated cell sorting analysis of the effects of EM on cell cycle traverse revealed that at EM concentrations up to 20 microM an increasing percentage of wild type cells were blocked in G2/M; no such effect occurred in EMR lines. Differential interference contrast microscopy was employed to study EM's effect on mitosis. EMR lines were able to form functional, albeit smaller, spindles at EM concentrations that resulted in chromosomal disorganisation and inhibition of mitotic progression in wild type cells. EMR lines were able to progress through mitosis and cytokinesis at the same rate as untreated cells. Tritiated EM was used to evaluate potential drug uptake/efflux mutations in ERM clones. EMR 4 and 9 incorporate less EM than wild type cells; however, they have significantly decreased cellular volumes. The initial efflux rate constants for EMR clones were greater than for wild type cells. Within 5 min greater than 70% of the drug was lost from resistant cells compared to a 50% loss by the wild type. Although the specific mechanisms of resistance have yet to be defined, the lack of collateral resistance to other MDR/anti-microtubule agents could serve as the basis for the clinical use of EM in combination chemotherapy.

Topics: Anti-Bacterial Agents; Cell Cycle; Drug Resistance; Estramustine; Flow Cytometry; Humans; Male; Mutagenesis; Prostatic Neoplasms; Tumor Cells, Cultured

A high dose-rate (60Co) afterloading technique was evaluated in a series of 73 patients with prostatic carcinoma stages I-IV. The intraurethral irradiation was combined with external pelvic radiotherapy. A minimum total dose of 78 Gy was delivered to the target volume. In a subgroup of patients estramustine (Estracyt) was given as adjuvant chemohormonal therapy during irradiation. The median follow-up for the whole group was 63 months. The crude 5-year survival rate was 60% and the corrected survival rate 90%. Survival was related to the tumor grade. Local pelvic recurrences were recorded in 17.8%. 'Viable cells' in posttherapy aspiration biopsy were not associated with tumor recurrences or survival. Four patients (5%) had grade 3 late radiation reactions with urethral stricture or bladder fibrosis. Urinary tract infections and prior transurethral resections were not associated with a higher frequency of reactions. Concurrent estramustine therapy seemed to increase the frequency of both acute and chronic radiation reactions. Local control, recurrence, and survival were not affected by chemohormonal therapy. The use of tomography, magnetic resonance, and ultrasound as aids to computerized dosimetry may improve local dose distribution and reduce the irradiated volume.

Topics: Brachytherapy; Cobalt Radioisotopes; Combined Modality Therapy; Estramustine; Evaluation Studies as Topic; Humans; Male; Prostatic Neoplasms; Radiotherapy, High-Energy

We analysed ploidy and S-phase fraction (SPF) from 78 paraffin-embedded primary prostatic carcinomas by DNA flow cytometry. DNA aneuploidy and above median (4.2%) SPF were both associated with high tumour grade, large size of prostate and presence of distant metastases. Both aneuploidy and high SPF (greater than 4.2%) indicated short 10-year progression-free (P = 0.01 for ploidy and P = 0.0002 for SPF), overall (P = 0.004 and P less than 0.0001) as well as prostate cancer survival (P = 0.002 and P less than 0.0001). Ten-year overall survival rate was 45% in cases with SPF below 4.2% and 0% in those with higher values, whereas the corresponding prostate cancer-specific survival rates were 80% and 11%, respectively. None of the seven tumours with SPF above 12% showed an objective response to endocrine therapy, whereas 26/49 (52%) of those with lower SPF values responded (P = 0.01). DNA ploidy, tumour grade, T-stage or M-stage did not significantly correlate with endocrine responsiveness. SPF was also the best predictor of progression free survival in patients treated hormonally. In conclusion, detection of high SPF in prostate cancer may indicate lack of hormonal responsiveness and poor prognosis.

Topics: Aged; Aneuploidy; Diploidy; DNA, Neoplasm; Estramustine; Estrogens; Flow Cytometry; Follow-Up Studies; Humans; Male; Middle Aged; Ploidies; Prognosis; Prostatectomy; Prostatic Neoplasms; S Phase

The clinical effect of Estracyt on untreated prostatic carcinoma was evaluated. The subjects consisted of 51 of 71 patients with prostatic carcinoma who were observed for 6 months or more after oral administration of 560 mg of estramustine phosphate. This drug was effective in all patients: markedly effective in 34 (66.6%), moderately effective in 13 (25.5%), and slightly effective in 4 (7.8%). During the observation period varying from 6 months to 2 years and 6 months, 7 patients had recurrence of progression. The interval between the drug administration and recurrence of progression varied from 6 months to 1 year and 10 months (mean, 15.8 months). Prostate acid phosphatase and gamma-seminoprotein remained normal between 3 and 15 months after the administration but became elevated due to recurrence of progression after 18 months or more in some patients. Blood testosterone, luteinizing hormone, and follicle stimulating hormone decreased while blood cortisol increased. Therefore, estrogen was acting effectively. Side effects were observed in 56.9% of the patients, the most frequent being mazoplasia in 33 patients (45.8%), and cardiovascular complications and apoplexy in 11 patients (15.3%). Estracyt was effective for untreated prostatic carcinoma but the problems such as recurrence of progression and side effects require further examination.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Capsules; Drug Evaluation; Estramustine; Humans; Hydrocortisone; Male; Middle Aged; Prostatic Neoplasms; Testosterone

Expression of estramustine-binding protein (EMBP) was determined in eight variants of the Dunning R3327 rat prostate adenocarcinoma. This secretory protein was previously isolated from the normal rat prostate and binds estramustine and estromustine, the metabolites exerting anti-mitotic and anti-proliferative activity of the anticancer agent estramustine phosphate (EstracytR). EMBP was found in relatively high amounts only in the androgen-responsive G and H tumors from intact hosts, whereas low (AT-1, HI-F) or nondetectable levels (HI-S, AT-3, MAT-LyLu, MAT-Lu) were obtained in the androgen-independent tumors. Castration decreased EMBP expression in both G and H tumors, as did estradiol and estramustine when given separately to intact rats. Supplementation of castrates with exogenous androgen stimulated EMBP expression above the pre-castration level and was further enhanced when combined with estradiol and in particular estramustine. Partial physicochemical characterization of EMBP in G and H tumors was performed by using ligand-based and immunoblotting techniques. [3H]Estromustine was bound to cytosols and salt extracts from tumors with the same affinity and displayed similar surface-charge distribution, sedimentation behavior, and subunit composition as found for ventral and dorsolateral prostatic tissue from tumor-bearing rats. This study indicates that the synthesis of EMBP is under androgenic control and that its expression may be correlated to androgen responsiveness, metastatic potential, and androgen receptor content but not to growth rate and morphology of the tumors. EMBP may therefore provide a mechanism for concentration of cytotoxic activity at the target site in EMBP-positive tumors and help in the evaluation of antitumor effects obtained when administering estramustine.

Topics: Adenocarcinoma; Animals; Carrier Proteins; Estradiol; Estramustine; Gonadal Steroid Hormones; Immunoblotting; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Tumor Cells, Cultured

The expression of the proliferation-associated antigen Ki-67 was studied in human prostatic cancer. The antigen was analyzed with an immuno-histochemical technique in TUR specimens. A correlation was seen between Ki-67 positivity and differentiation grade. All TUR specimens (15/15) with poorly differentiated carcinomas expressed the antigen. Moderately differentiated carcinomas constituted an intermediate group and slightly less than half of the cancers (12/27) were positive for the antigen. Only one of the highly differentiated carcinomas (1/12) expressed the antigen. All TUR specimens from patients with benign prostatic hyperplasia (8/8) were negative. The effect on Ki-67 positivity was also investigated in a human prostatic cancer heterotransplanted to nude mice and subjected to ionizing irradiation with or without concomitant estramustine treatment. The antigen expression was compared with that seen in tumour tissues from untreated mice and from mice treated with estramustine alone. A pronounced effect was seen in the combination treatment group with an approximately 50% reduction of the Ki-67 positive cells. The results are discussed in relation to prognosis and follow-up after radiation therapy and the possible use of estramustine in combination with radiation therapy.

Topics: Animals; Carcinoma; Combined Modality Therapy; Estramustine; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Male; Mice; Mice, Nude; Neoplasm Transplantation; Nuclear Proteins; Prostatic Neoplasms; Tumor Cells, Cultured

In this study, we have investigated the model DNA values and the expression of estramustine-binding protein (EMBP) in formalin-fixed and paraffin-embedded TUR specimens from 76 untreated patients with prostatic cancer. In addition, specimens from 13 patients were analyzed for tumour EMBP expression only. Ploidy was measured as diploid, tetraploid and non-tetraploid aneuploid or aneuploid in the near-diploid region. All patients had been referred during 1978-1981, and were subjected to TUR due to urinary obstruction. Survival data were obtained for all patients through March 1988. Statistical analyses were performed using a Cox's regression model with respect to survival and cause specific survival and correlated to the DNA pattern and the expression of EMBP. The existence of a near-diploid aneuploid cell population as well as poor differentiation grade were both statistically significantly correlated with poor survival. Near-diploid aneuploid cell lines were seen in 9/76 (12%) of the patients and were also seen in well differentiated cancers (4/17). The expression of EMBP was most abundant in the moderately differentiated cancers. However, all prostatic cancer specimens investigated were positive for the antigen. Patients with poorly differentiated carcinomas and high EMBP expression showed a tendency towards better prognosis than those with poorly differentiated carcinomas and low EMBP expression. The present patient material was, however, too small to show a statistically significant correlation between EMBP and survival.

Topics: Aged; Aged, 80 and over; Aneuploidy; Biomarkers, Tumor; Carrier Proteins; Diploidy; DNA, Neoplasm; Estramustine; Flow Cytometry; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Prostatic Neoplasms; Prostatic Secretory Proteins

Incubation with estramustine phosphate for 24 h inhibited DNA, RNA and protein synthesis in primary cultures of human kidney, mammary, prostatic, cervical and endometrial carcinoma. Not only the presence, but also the concentration of oestrogen receptors correlated with estramustine phosphate effects on tumour cell proliferation.

Topics: Cell Division; Cytosol; DNA, Neoplasm; Dose-Response Relationship, Drug; Estramustine; Female; Humans; Kidney Neoplasms; Leucine; Male; Prostatic Neoplasms; Protein Biosynthesis; Receptors, Estrogen; RNA, Neoplasm; Thymidine; Tumor Cells, Cultured; Uridine; Uterine Cervical Neoplasms; Uterine Neoplasms

Total serum testosterone, serum testosterone binding globulin and free androgen index were determined before and during treatment in 14 patients with previously untreated disseminated prostatic cancer. Six patients received estramustine phosphate and six other patients underwent orchiectomy. Two further patients received estramustine phosphate because of tumor progression one and two years after orchiectomy. The result of the study indicates that estramustine phosphate is significantly more effective than orchiectomy in eliciting low levels of free androgens. This complete androgen ablation is produced by a depression of total testosterone and a concomitant increase of total serum testosterone binding globulin which yields a free androgen index an average 4.6 times lower in estramustine phosphate treated patients than in patients who underwent orchiectomy.

Topics: Androgens; Drug Administration Schedule; Estramustine; Humans; Male; Orchiectomy; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Testosterone

Estramustine phosphate disodium (Estracyt) was used in the treatment of 38 patients with prostatic carcinoma for at least 1 year. Of these patients 37 patients were treated with Estracyt as primary treatment and 1 patient had been treated with another antiandrogenic therapy before the Estracyt treatment. Estracyt was given orally in a dose of 560 mg/day in divided oral doses. The clinical evaluation was done for the change of PAP, the relapse rate, the survival rate and the side effect. Among 22 cases which had shown abnormally high PAP values before the treatment started, the values decreased or normalized in 21 cases (95.5%) in the first year of administration of Estracyt. In 6 cases, however, the values increased again in the second year or later. Relapse was observed in 10 (26.3%) out of 38 cases. Relapse rate was 2.6%, 51.7%, and 51.7%, at the first, third, and fifth year, respectively. Survival rate was 97.4% at the first year, 88.5% at the third year, and 68.8% at the fifth year for the follow-up study. Side effects were observed in 14 (36.8%) out of 38 cases. The main side effect was gynecomastia. Gastro-intestinal disturbance and edema were also observed. However, there were only 2 cases (5.2%) in which administration of Estracyt had to be discontinued.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Drug Administration Schedule; Drug Evaluation; Estramustine; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms; Survival Rate

In this retrospective study, 71 patients with secondary hormone-refractory prostatic carcinomas were treated with estramustine phosphate (EMP), at three different dosages (280, 560, 840 mg orally). All patients were completely followed up until cancer-induced death. In 12 cases of further progression polychemotherapy was administered. As this was not a randomized study, an analysis of statistical significance was not performed. The higher dosages of EMP caused an extended progression-free interval accompanied by an equally considerable alleviation of carcinoma-induced pain. The overall survival time was not influenced by subsequent polychemotherapy. An elevation of liver function parameters was observed in 5 patients. One of these patients died of toxic liver damage, possibly therapy-related, on the basis of a preexisting cirrhosis. Cardiovascular side effects were not observed. With regard to survival time, the positioning of polychemotherapy as a third-line treatment for prostatic cancer should be examined critically. Before administration of high-dose EMP, it is mandatory to control liver functions carefully.

Topics: Aged; Carcinoma; Estramustine; Humans; Liver Function Tests; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Retrospective Studies; Time Factors

An immunohistochemical technique for determination of "estramustine-binding protein" (EMBP) in rat prostate is described. The localization and staining intensity of this protein were correlated to prostatic morphological structures in intact animals and at different time intervals after androgen deprivation by castration. EMBP was found almost exclusively in epithelial cells, while the fibromuscular stroma seemed to be negative. Intracellularly, immunostaining was confined to the cytoplasm, but was absent in nuclei. In intact rats, acinar lumina demonstrated heavy immunostaining, indicating secretion of EMBP. Orchiectomy caused a diminution of EMBP expression as well as secretion, suggesting that EMBP synthesis is under androgenic regulation. Human benign hyperplastic and cancerous prostatic specimens were also examined. All human specimens examined so far exhibited positive epithelial staining although of varying intensity. Therefore, this immunohistochemical technique may be used for studying the correlation of EMBP with tumor malignancy grade and for clinical investigations of how various treatments affect EMBP expression in prostatic carcinomas.

Topics: Animals; Carrier Proteins; Cross Reactions; Estramustine; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Nitrogen Mustard Compounds; Orchiectomy; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Rats, Inbred Strains; Species Specificity

A 69-year-old man initially came to our hospital with the chief complaint of dysuria and hematuria. On rectal examination, the prostate gland was found to be grossly enlarged and rock hard in consistency. Abnormal laboratory data included: lactate dehydrogenase, alkaline phosphatase, acid phosphatase and prostatic acid phosphatase. Chest X-ray revealed multiple nodular lesions in both lung fields. Pathologic findings of the prostate needle biopsy revealed moderately well differentiated adenocarcinoma. Early combined hormonal and chemotherapy (adriamycin, TGF, methotrexate, bleomycin) was performed. After two courses of this regimen, the pulmonary lesions vanished completely. In addition, partial disappearance of osteoblastic lesions on bone scans was recognized.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Estramustine; Humans; Lung Neoplasms; Male; Methotrexate; Orchiectomy; Prostatic Neoplasms; Proteoglycans; Tegafur; Uracil

Estramustine binding protein (EMBP) was purified from the ventral prostate of the rat using DEAE-cellulose chromatography, concanavalin-A affinity chromatography and DEAE-sepharose chromatography. At the final step of the purification, two different peaks (Peaks A and B) of A280 nm were obtained. Peak A had a high binding activity to [3H] estramustine. On the other hand, Peak B had a low binding activity. On the analysis of polyacrylamide gel electrophoresis, Peak A gave two protein bands, whereas Peak B gave a single band. The molecular weight of the markedly stained band of Peak A was approximately 27,000, whereas that of Peak B was 18,000, as estimated by analysis of Fargusson's plot. The antibody against Peak B was used for establishing a radioimmunoassay (RIA) of EMBP. The sensitivity of this assay system was sufficient to measure of 1 ng of EMBP. The dilution curve of rat prostatic cytosol was paralleled with the standard curve. As a result obtained from this RIA, the mean concentration of immunoreactive EMBP was 8.01 ng/mg cytosol protein in human benign hyperplastic prostate (BPH) and 4.28 ng/mg protein in human prostatic carcinoma (PC), respectively. These results here obtained indicate that human prostate has an immunoreactive protein to the purified EMBP obtained from the ventral lobe of rat prostate.

Topics: Animals; Carrier Proteins; Chromatography; Electrophoresis, Polyacrylamide Gel; Estramustine; Humans; Male; Molecular Weight; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values

Sixty patients with prostatic carcinoma localized to the pelvis have been treated by external beam radiation therapy: 2 patients (2%) were Stage A, 12 (20%) Stage B, 14 (23%) Stage C, and 32 (53%) Stage D1. Twenty-two patients received adjuvant therapy (11 estramustine phosphate [Estracyt] and 11 cyclophosphamide [Cytoxan]) after radiation. Progression occurred in 22 patients (37%): 6 (10%) had local recurrence while 16 (27%) failed distally. The incidence of late major complications was 12 percent.

Topics: Adenocarcinoma; Cobalt Radioisotopes; Combined Modality Therapy; Cyclophosphamide; Estramustine; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Prostatic Neoplasms; Radioisotope Teletherapy; Radiotherapy, High-Energy

Fifty-nine hormonally treated prostatic carcinoma patients were prospectively followed by rectal palpation and fine needle aspiration cytology (FNAC) at 6 month intervals for periods ranging from 6 to 120 months (median follow-up, 48 months). The cytologic impressions and palpatory findings were divided into four categories, respectively, ranging from benign to clearly malignant. Cytologic material and palpatory descriptions suitable for evaluation were available for 306 follow-up examinations, with a mean number of follow-up examinations per patient of five (range, 1-13). Tumor relapse was noted in 26 patients and was diagnosed at the same time by FNAC and palpation in six patients. In 16 of the patients tumor progression was first noted by cytology, and in four patients relapse was first detected by rectal palpation. Different patterns of cytologic and palpatory findings during the development of remission and progression of the tumors and drawbacks of the methods are discussed.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Estradiol; Estramustine; Ethinyl Estradiol; Follow-Up Studies; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Palpation; Prospective Studies; Prostatic Neoplasms; Random Allocation; Rectum; Remission Induction

Estramustine-binding protein (EMBP) was determined immunohistochemically in prostatic cancer (PC) specimens taken from patients before and after therapy. The EMBP staining intensity was correlated with the tumor malignancy grade in untreated PCs. The effect of various treatments (i.e., androgen-withdrawal therapy, treatment with estramustine phosphate or radiation) on the expression of EMBP was also investigated. Although a rabbit polyclonal antiserum raised against rat EMBP was used all through the study, all untreated PCs (n = 53) examined so far displayed a positive immunoreaction. The staining intensity was higher in moderately and poorly differentiated than in well-differentiated tumors. Furthermore, two types of staining patterns were observed, that is, a diffuse type in about 70% and a focal in the remaining cases, which might reflect the multifocal appearance of PCs. The prognostic significance of these staining patterns is discussed. Irrespective of the treatment used, EMBP staining was reduced to lower or undetectable levels in PCs where cytological as well as clinical regression were indicated after 6-30 months of therapy. In nonresponders or patients with refractory disease, however, EMBP expression reappeared and returned to pretreatment levels. In a short-term follow-up, the diminuation of EMBP was evident as early as 10 days after androgen-withdrawal therapy and persisted as long as the patient responded to therapy. When estramustine phosphate was given as secondary treatment to hormone refractory PCs, EMBP decreased to undetectable levels in 3/4 of the specimens, suggesting response to therapy. In conclusion, a decreased EMBP staining was well correlated with favorable cytological regression as well as with clinical regression, whereas unchanged staining intensity was indicative of clinical progression and a poor cytological regression grade. The high levels of EMBP in moderately and poorly differentiated tumors as well as in relapsing PCs, despite continued androgen withdrawal, strongly support a regulation of EMBP that is not under androgenic control. Based on the present findings, we suggest the use of EMBP as a therapy marker. Provided that immunohistochemical measurements can be performed on fine-needle aspirates, EMBP analysis may be a direct and early means to distinguish between responding patients and nonresponders.

Topics: Carrier Proteins; Combined Modality Therapy; Estramustine; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Neoplasm Staging; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Remission Induction; Time Factors

Tumor cells from of the Dunning R-3327 PAP tumor were grown in vivo in the flank region of male Copenhagen rats for 4 months. Untreated control animals, castrated animals, and untreated or castrated animals supplemented with testosterone and estramustine (alone or in combination) bearing tumors were used for immunocytochemical studies of the tumor cells. Antibodies against the following secretory proteins were applied to paraffin sections of formalin-fixed tissue: anti-SVS II, anti-PBP, anti-transglutaminase, anti-acid phosphatase (isoenzymes, isoelectric points [pI] 5.6, 7.1, 8.0), non-secretory proteins comprised antiglucocorticoid-receptor, and antibodies against extracellular matrix proteins and intermediate filaments. A differential expression of marker proteins subsequent to the various treatments was observed immunohistochemically. Castration induced a loss of secretory activity, an increase in keratin-immunoreactive cells, and regressive activity in the secretory cells. Immunoreactivity of the glucocorticoid receptor in the nuclei of the basal cells was also decreased. Testosterone substitution only partially restored secretory activity of tumor cells in castrated animals. In experiments where estramustine had been administered to normal or castrated animals, metaplastic transformation of the epithelium, focal reduction, or increase of secretory and/or regressive activity and persistence of glucocorticoid receptor-like immunoreactivity was observed. The findings indicate that different hormonal situations provide conditions for the development of rather heterogeneous reaction patterns of different tumor cells, allowing partial regression of individual clones of tumor cells along with stimulation of others.

Topics: Adenocarcinoma; Animals; Biomarkers, Tumor; Estradiol; Estramustine; Immunohistochemistry; Immunologic Techniques; Male; Neoplasm Proteins; Neoplasm Transplantation; Nitrogen Mustard Compounds; Orchiectomy; Prostate; Prostatic Neoplasms; Rats; Testosterone

Clinical effect of Estracyt was investigated in prostatic cancer patients. Twenty seven patients had been previously treated and 20 had not received prior treatment. Improvement rate of subjective symptoms was 85% in the previously untreated patients and that of objective findings was 85%, while those rates were 44% and 50% in the previously treated patients, respectively. Most of the adverse reactions were changes in mamma and mammary papilla which were considered to be due to the estrogenic activity.

Topics: Aged; Aged, 80 and over; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine, estradiol-3-N-bis(2-chloroethyl)carbamate (EM), has been shown to inhibit growth of the human prostatic carcinoma cell line LNCaP as well as its subline LNCaP-r. The hormone sensitive LNCaP showed greater sensitivity to the drug than the hormoneresistant LNCaP-r. LNCaP has also shown an increasing sensitivity to 10(-7) M EM, when incubated with different concentrations of steroid hormones. We studied whether the increasing sensitivity was caused by increased uptake of EM. 3H-estramustine was added to medium and the cells were incubated 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, and 4 h, or 2 h, 4 h, 6 h, and 8 h. No effect of steroids on the uptake of EM was noted, but LNCaP showed a higher uptake of EM compared to LNCaP-r. The uptake of EM in LNCaP increased for eight hours, whereas LNCaP-r reached its maximum uptake after six hours of incubation.

Topics: Biological Transport, Active; Cell Line; Estramustine; Humans; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms; Steroids; Tumor Cells, Cultured

Seventy seven patients with prostatic carcinoma were treated in our clinic between 1977 and 1986. Most of them were treated by a hormonal agent as the first therapy. None of the 9 stage A1 cases showed any reactivation, but 4 of the 5 stage A2 cases relapsed to metastatic disease. The chemotherapy performed in 3 of the 4 reactivated cases had no obvious effect on the disease. Seven of the 8 patients with stage B disease were alive without relapse. Relapse was seen in the other patient who had poorly differentiated carcinoma and chemotherapy in this case resulted in stable disease for the present. Four of the 15 stage C cases including 3 poorly differentiated carcinomas were hormone resistant or reactivated. For these resistant cases radiotherapy and/or the chemotherapy were performed, but a response was seen in only one case. Consequently, the first therapy for stage A2, B and C of poorly differentiated carcinoma must be improved. Of the 40 stage D cases, 4 patients who were treated by an early combination of hormonal therapy and chemotherapy had a better prognosis than the others. These 4 patients had poorly differentiated carcinomas with multiple bone metastases. Two of these 4 patients were alive without relapse for 17 and 72 months, and one of the 2 patients with relapse was also alive for 75 months. We believe that early chemotherapy is the key for better prognosis in stage D cases.

Topics: Androgen Antagonists; Castration; Combined Modality Therapy; Estramustine; Estrogens; Humans; Male; Neoplasm Staging; Prognosis; Prostatectomy; Prostatic Neoplasms

To further clarify the mode of action of estramustine, the influence on macromolecular synthesis in the human prostatic tumour cell line 1013L was investigated. Cell treatment with estramustine, nor-nitrogen mustard and tauromustine, followed by radioactive nucleotide and leucine incorporations, as a measure of RNA, DNA and protein labelling, were carried out. The initial effect of estramustine clearly differed from that obtained after treatment with nor-nitrogen mustard and tauromustine. No inhibition of DNA synthesis was found whereas an inhibition of overall RNA synthesis was predominant. Adaption of an established RNA separation method was used in an indepth study of RNA labelling after estramustine treatment. An inhibition of 29S, 18S and 4-7S RNA was found after estramustine treatment, indicating disturbances in either RNA processing or RNA transport. The lack of 45S RNA labelling additionally indicates pre-ribosomal inhibition.

Topics: Affinity Labels; Biological Transport; Cell Survival; DNA, Neoplasm; Estramustine; Humans; Leucine; Macromolecular Substances; Male; Nitrogen Mustard Compounds; Nitrosourea Compounds; Nucleotides; Prostatic Neoplasms; RNA, Neoplasm; Taurine; Tumor Cells, Cultured

Topics: Biological Transport; Cell Compartmentation; Cell Nucleus; Estramustine; HeLa Cells; Humans; Male; Nitrogen Mustard Compounds; Nuclear Proteins; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured

The brain metastasis of prostatic carcinoma is rare and is distinguished by its poor prognosis in cases which are not surgically resectable. Herein we report on a case of brain metastasis of prostatic carcinoma which showed a dramatic regression through bilateral orchiectomy and doses of diethylstilbestrol diphosphate and estramustine phosphate. Neurologic and psychiatric symptoms diminished within three months, and the patient is alive and well without any subjective symptoms after twelve months.

Topics: Adenocarcinoma; Aged; Brain Neoplasms; Combined Modality Therapy; Diethylstilbestrol; Estramustine; Humans; Male; Orchiectomy; Prostatic Neoplasms; Radiography

In this paper the authors review the completed and current EORTC Genitourinary Group trials for metastatic carcinoma of the prostate. In terms of time to progression and length of survival, there is no significant difference between any of the effective endocrine treatments that have been studied. The statistical analysis of the different variables used in trials 30,761 and 30,762 determines three risk groups of patients. There is no need for very special laboratory investigations to establish a prognosis. Orchiectomy is the cheapest and safest endocrine treatment in metastatic carcinoma of the prostate.

Topics: Androgen Antagonists; Carcinoma; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Europe; Gonadotropin-Releasing Hormone; Hormones; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms

Prostata cancer is one of the most dangerous tumours occurring in the older man. No general accepted therapy has existed up to now. In this study we were engaged on the pharmacokinetics of fosfestrol (Honvan) after oral administration. Its active principle is E-diethylstilbestrol (E-DES), the main metabolite. 250-1600 ng/ml E-DES are measurable after 60-110 min in the plasma of 11 patients suffering from metastatic prostata cancer who have been administered 360 mg fosfestrol orally. This range is equivalent to E-DES concentrations in plasma of 1-4 x 10(-6) mol/l. Thus that E-DES concentration range (5 x 10(-6) mol/l) is nearly attained for a short time to the concentration which hinders the mitosis of human breast cancer cells. Surprisingly similar but not higher concentration - time courses may be measured after a bolus infusion of 360 mg fosfestrol (lasting 45 min). Furthermore, E-DES-glucuronide, E-DES-sulphate and the mixed E-DES-glucuronide-sulphate could be observed in plasma after oral administration. In spite of the high sensitivity of the analytical method (limit of detection for fosfestrol 0.1 micrograms/ml and for E-DES and its mono-conjugates 2-5 ng/ml) neither fosfestrol nor E-DES-monophosphate are detectable in plasma due to the biotransformation of fosfestrol, which is already metabolized by the enzymes of the gut wall. Both phosphates only exist in plasma after intravenous infusion. Further investigations are linked with the question if phase II-conjugates of E-DES can eventually be prodrugs delivering E-DES by cleavage of the ester bonds.

Topics: Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents; Biological Availability; Biotransformation; Carcinoma; Chemical Phenomena; Chemistry; Diethylstilbestrol; Estramustine; Estrogens; Humans; Ketoconazole; Male; Middle Aged; Neoplasm Metastasis; Pituitary Hormone-Releasing Hormones; Prostatic Neoplasms; Protein Binding

The twofold purpose of the study was (a) to determine if a MAP-1-like protein was expressed in human prostatic DU 145 cells and (b) to demonstrate whether a novel antimicrotubule drug, estramustine, binds the MAP-1-like protein to disrupt microtubules. SDS-PAGE and Western blots showed that a 330-kD protein was associated with microtubules isolated in an assembly buffer containing 10 microM taxol and 10 mM adenylylimidodiphosphate. After purification to homogeneity on an A5m agarose column, the 330-kD protein was found to promote 6 S tubulin assembly. Turbidimetric (A350), SDS-PAGE, and electron microscopic studies revealed that micromolar estramustine inhibited assembly promoted by the 330-kD protein. Similarly, estramustine inhibited binding of the 330-kD protein to 6-S microtubules independently stimulated to assemble with taxol. Immunofluorescent studies with beta-tubulin antibody (27B) and MAP-1 antibody (MI-AI) revealed that 60 microM estramustine (a) caused disassembly of MAP-1 microtubules in DU 145 cells and (b) removed MAP-1 from the surfaces of microtubules stabilized with 0.1 microM taxol. Taken together the data suggested that estramustine binds to a 330-kD MAP-1-like protein to disrupt microtubules in tumor cells.

Topics: Blotting, Western; Electrophoresis, Polyacrylamide Gel; Estramustine; Fluorescent Antibody Technique; Humans; Male; Microscopy, Electron; Microtubule-Associated Proteins; Microtubules; Nitrogen Mustard Compounds; Prostatic Neoplasms; Tumor Cells, Cultured

An analysis of haemostatic variables was done in 31 prostate cancer patients treated with oestrogens (13 pts), estramustine phosphate (7 pts) or orchidectomy (11 pts) before, at about 7 weeks and 6 months of treatment. Six patients treated with either of the drugs developed venous thromboembolism or ischemic vascular disease. Already before treatment there were changes indicating some activation of blood coagulation, fibrinolysis and kallikrein systems. The drug treated group showed significant changes in several variables: i.e. increase in factor VII, plasminogen and prekallikrein but also a decrease in antithrombin and in inhibitors to the fibrinolytic and kallikrein system. Significant difference between the drug treated groups was found in circulating platelet aggregates and in kallikrein inhibiting activity. Tissue plasminogen activator capacity was significantly lower in the drug treated patients with complications than in those without. The study also showed that in addition to the assay of the tissue plasminogen activator capacity during the first weeks of therapy it might be helpful in predicting cardiovascular complications to investigate platelet aggregates, prothrombin complex, factor X, von Willebrand factor antigen, fibrinogen, antithrombin, fibrino-peptide A, and the inhibitors of fibrinolysis as well as C1-esterase inhibitor.

Topics: Blood Coagulation; Cardiovascular Diseases; Estradiol Congeners; Estramustine; Fibrinolysis; Hemostasis; Humans; Male; Orchiectomy; Prostatic Neoplasms; Tissue Plasminogen Activator

Prostatic blood flow in 19 patients with prostatic adenocarcinoma was measured by the hydrogen gas clearance method before and during endocrine treatment. Prostatic volume was reduced to 70 per cent of the pre-treatment volume by 3 months after the beginning of treatment. Prostatic blood flow was remarkably depressed in patients who had never had any treatment of the prostatic carcinoma (22.2 +/- 8.3 ml. per minute per 100 gm.), while prostatic blood flow increased significantly after endocrine treatment (56.3 +/- 21.8 ml. per minute per 100 gm.). It was likely that prostatic blood flow increased as the prostate volume decreased. Final histology of serial prostatic biopsy specimens after endocrine treatment, revealed distinct deterioration of tumor cells and slight stromal hyperplasia compared to the initial pre-treatment biopsy. The stromal-epithelial ratio, which was calculated by computer-assisted image analysis, was markedly increased after endocrine treatment. Our study indicated that endocrine treatment caused a growth-inhibitory effect that was accompanied by increased blood flow in the prostatic carcinoma.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Castration; Combined Modality Therapy; Diethylstilbestrol; Estramustine; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Prostate; Prostatic Neoplasms; Regional Blood Flow

Plasma and tumour concentrations of estramustine, estromustine, estradiol and estrone, the major metabolites of estramustine phosphate (estracyt), were determined in patients with prostatic carcinoma treated between one and nine years with repeated oral doses of estracyt (560 to 840 mg./day). The last dose was given 12 to 16 hours before sampling. The binding of radioactive estramustine and estromustine was determined in the tumour tissue to examine the possible role of estramustine-binding protein for the accumulation of these metabolites into the tumour. Comparison was made with benign prostate hyperplastic tissue from untreated patients. Estromustine was the main metabolite in plasma as well as in the tumour (range 235 to 450 and 205 to 485 ng./gm., respectively), whereas estramustine (20 to 45; 95 to 370), estrone (62 to 140; 63 to 160) and estradiol (8 to 15; 7 to 36) were found in lower concentrations. Interestingly the concentration of estramustine was as an average six times higher in the tumour than in plasma contrasting with the other metabolites which were present in equal amounts of the two localities. Binding of 3H-estramustine and 3H-estromustine was two to three times higher in the tumour than in benign hyperplastic tissue and negligible in plasma samples. The present study is the first where substantial amounts of cytotoxically active estramustine and estromustine are demonstrated in tumour tissue from estracyt treated patients. Our findings suggest a mechanism for selective uptake of these metabolites in prostatic cancer (estramustine-binding protein). The uptake and binding of estramustine and estromustine in the tumour may account for the clinical effects of estracyt in prostatic carcinoma.

Topics: Aged; Carcinoma; Carrier Proteins; Estradiol; Estramustine; Estrone; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins

Staging, therapy and course of disease in 32 patients with carcinoma of prostate less than 60 years old were evaluated retrospectively, 87.5% of the men showed metastases before commencement of therapy. Not one case of cancer was detected during preventive check up; all patients come to urological examination because of characteristic symptoms.33.3% of carcinomas were primarily hormone-resistant. Under pure androgen deprivation (n = 21) 81% of the patients showed progression within a mean period of 9.2 months, whereas in the small group primarily given combined contrasexual cytostatic therapy (n = 5) progression occurred after a time span of 39 months on average. The importance of preventive urological examination and the possibility of primary cytostatic therapy in combination with androgen deprivation in young patients with metastatic cancer of the prostate is stressed.

Topics: Adult; Androgen Antagonists; Combined Modality Therapy; Estramustine; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

The effect of estramustine (EM), estradiol-17 beta (E2) or 5 alpha-dihydrotestosterone (DHT) on the growth of two human prostatic carcinoma cell lines, LNCaP and LNCaP-r was investigated. The hormone resistant subline LNCaP-r was derived in our laboratory, from the hormone sensitive LNCaP cell line. E2, 10(-8) or 10(-5) M inhibited the growth of the LNCaP cells, but did not affect the LNCaP-r. DHT, 10(-8) M, had a stabilizing effect at the stationary phase on the growth of the LNCaP cells whereas at higher concentrations, 10(-5) M, the growth rate was decreased. The LNCaP-r cell line was previously reported to be unaffected by DHT. EM inhibited the growth of both cell lines but LNCaP was more sensitive than LNCaP-r. E2 and DHT modulated the effect of EM. When treated with 10(-7) M EM, addition of E2 or DHT (10(-7)-10(-5) M) further inhibited the growth. When EM was used at a higher concentration (10(-5) M), the enhanced effect of growth inhibition by hormone addition was lost. Based on these results it is suggested that the presence of endogenous hormones, or estrogens released from EM on hydrolysis, may play a contributory role in the cytotoxicity of estramustine.

Topics: Cell Division; Cell Line; Dihydrotestosterone; Drug Resistance; Drug Synergism; Estradiol; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Tumor Cells, Cultured

A 55-year-old man consulted us on December 3, 1986 with the chief complaints of left leg pain, disturbance in gait and dysuria. On digital rectal examination his prostate was found enlarged to a hen's egg size and increased in consistency. He was admitted to the hospital under the suspicion of prostatic cancer on December 8, 1986. Scout kidney-ureter-bladder X-ray revealed extensive osteolytic lesions in the left iliac and pubic bones as well as in the sacrum. Needle biopsy of the prostate demonstrated moderately differentiated adenocarcinoma, leading to a diagnosis of prostatic cancer with osteolytic bone metastases. Bone scintigraphy showed increased radioactivity uptake by the left iliac and pubic bones. Pelvic CT disclosed large tumor masses in the left ilium and sacrum, which on bone biopsy were identified as poorly differentiated adenocarcinoma. Endocrine therapy with estramustinphosphate and castration was performed along with transurethral resection of prostate. At week 16 after initiating the therapeutic regimen the patient was entirely free from disturbance in gait and the tumor mass of the left iliac bone had disappeared almost completely on the computed tomogram at week 18, although osteolytic lesions still persisted on the x-ray. This case deserves special note because endocrine therapy markedly reduced the size of the bone tumors, in spite of osteolytic bone metastases of prostatic cancer with computed tomographic evidence of large metastatic tumor masses.

Topics: Adenocarcinoma; Adult; Bone Neoplasms; Castration; Estramustine; Humans; Male; Osteolysis; Prostatic Neoplasms; Tomography, X-Ray Computed

Estramustine (EM) is a conjugate of estradiol and nor-nitrogen mustard (nor-HN2), which is effective in the treatment of prostate cancer. We have compared the effect of EM with that of the known microtubule inhibitor vinblastine (VLB) on the following functions of malignant MO4 mouse cells and of DU-145 human prostate cancer cells in vitro: directional migration, invasion; and the organization and the assembly/disassembly equilibrium of microtubule complexes. The circular area covered by cells migrating from an aggregate explanted on a solid substrate was taken as an index of directional migration. Invasion was studied through confrontation of MO4 or DU-145 cells with fragments of embryonic chick heart in organ culture. Microtubules were investigated immunocytochemically and through immunodetection on protein blots. VLB and EM inhibited directional migration and invasion of MO4 and DU-145 cells in a dose-dependent manner; equimolar combinations of estradiol plus nor-nitrogen mustard did not mimic these effects. At anti-invasive concentrations VLB led to partial disassembly of microtubule complexes, whereas EM resulted in an abnormal pattern of microtubule complexes without alteration of the overall assembly/disassembly equilibrium. Combined treatment with VLB and EM resulted in an enhanced VLB effect, namely complete disassembly. In all tests DU-145 cells were more sensitive to both VLB and EM than were MO4 cells, and the effects were less reversible. The present experiments showed that EM shares an anti-invasive activity with other microtubule inhibitors.

Topics: Animals; Carcinoma; Cell Movement; Estradiol; Estramustine; Humans; Male; Mechlorethamine; Mice; Microtubules; Nitrogen Mustard Compounds; Organ Culture Techniques; Prostatic Neoplasms; Tubulin; Vinblastine

One problem in the management of prostatic cancer is that about half of the patients with this disease have metastatic lesions at first diagnosis and therefore tend to be given palliative rather than radical therapy. We report here a patient with stage D prostatic cancer who was treated with a single regimen of estramustine phosphate (Estracyt). The patient was a 63-year-old man who was admitted to Keio University Hospital because of sudden onset of double vision. Under a presumptive diagnosis of brain tumor, he underwent thorough examination including brain CT, Ga and bone scan and basic blood tests, which revealed an extraordinarily high level of acid phosphatase. He was therefore referred to our urological division for investigation of possible prostatic cancer. On the basis of the results of urological examinations, a diagnosis of prostatic cancer, stage D, was confirmed. Accordingly, radical surgery was not indicated and instead he was started on oral Estracyt, to which he responded well. He has been enjoying a comfortable life to date, over one and a half years after initial referral.

Topics: Adenocarcinoma; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

The metabolism of estramustine [estradiol-3-N-bis(2-chloroethyl) carbamate] was investigated in the human prostatic tumour cell line 1013L and the human cervix tumour cell line HeLa S3. Uptake studies revealed that estramustine (EM), and its 17-ketoanalogue estromustine (EoM), differed in their nuclear binding pattern in 1013L cells but not in HeLa cells. Most of the nuclear radioactivity from both EM and EoM was found in the fraction containing the majority of the phospholipids. HPLC studies on EM-treated 1013L cells showed the presence of the oxidized metabolite EoM, in the medium, an enrichment of estradiol and estrone in whole cells and EM and EoM bound to the nuclear protein matrix. Similar studies on the HeLa cell line showed a completely different pattern, no metabolites other than EoM were found in the cell medium and whole cells but several very lipophilic metabolites were found bound to the nuclear protein matrix. On investigation of other tumour cell lines these metabolites were found to be unique to HeLa cells. The results extend our knowledge concerning EM and demonstrate that the cell line 1013L is a relevant model system for studying drugs active against human prostatic tumours.

Topics: Cell Line; Cell Survival; Estramustine; Female; HeLa Cells; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Twenty-two orchiectomized men with progressive stage D2 prostate cancer were treated with a 3-week cycle of estramustine phosphate (EMP: from day 3 to day 21) and androgen priming (from day 1 to day 4). A partial response according to the NPCP-USA criteria was shown in 4 of 20 evaluable patients. Median progression-free survival of all patients was 24 weeks (range, 4-48) and median survival, 42 weeks (range, 4-112). Although in two cases treatment had to be stopped due to a marked increase in bone pain, no life-threatening side effects were observed. The androgen sensitivity of tumors was supported by the occurrence of increase in prostatic phosphatase and in bone pain in most patients. In this group of patients, androgen priming did not seem to potentiate the effectiveness of EMP, our results being comparable to those previously reported using EMP alone.

Topics: Aged; Drug Interactions; Estramustine; Fluoxymesterone; Humans; Male; Middle Aged; Neoplasm Staging; Nitrogen Mustard Compounds; Orchiectomy; Prostatic Neoplasms

Endocrine therapy for urological tumor includes estrogen therapy for prostatic carcinoma. This endocrine therapy is one of the most firmly established therapeutic methods in the field of clinical oncology. However, confusion exists about how long this treatment remains effective and whether it prolongs survival, since estrogen can create cardiovascular complications in patients with prostatic carcinoma. Recently, new endocrine agents have been developed to compensate for the problems of estrogen therapy and to make treatment more effective. Estramustine sodium phosphate is medicine for internal use prepared by combining estradiol with nitrogen mustard. This hormonal chemotherapeutic agent has proved effective in 98% of treated patients. Most of the side effects of this agent have been observed in the digestive organs. Chlormadinone acetate, a progestational agent, has proved more effective against early prostatic carcinoma than against late-stage disease. LHRH analogue, which is now drawing much attention as a "chemical castration" agent for prostatic cancer patients, exerts an effectiveness equal to medium-dose estrogen treatment. The above three agents for the treatment of prostatic carcinoma should become increasingly popular in the future.

Topics: Buserelin; Chlormadinone Acetate; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Animals; Buserelin; Carcinoma; Dogs; Estramustine; Gonadotropin-Releasing Hormone; Humans; Japan; Male; Orchiectomy; Prostate; Prostatic Neoplasms; Testosterone; Ultrasonography

Over two decades, experience with estramustine has provided limited data which support an estrogenic mechanism of action and no data which indicate the nitrogen mustard involvement in the cytotoxic properties of the drug. Consideration of the carbamate-ester portion of estramustine supports the pharmacokinetic evidence that estramustine has a long half life since enzymatic hydrolysis of the carbamate is an uncommon event. Using a variety of immunocytochemical and cellular morphology procedures, estramustine per se has been found to express anti-cytoskeletal properties through non-covalent binding to microtubule associated proteins (MAP's). In both fish erythrophores and in dividing human prostatic carcinoma cells, estramustine exerts an antimicrotubule effect at micromolar concentrations. Thus, estramustine possesses unique pharmacology and protein binding specificity. As such, it should not be classified as an alkylating agent. The estrogenic effects, while possibly of relevance to clinical administration, are not the primary mechanism by which the drug exerts cytotoxicity.

Topics: Alkylation; Animals; Cell Line; Cells, Cultured; Estramustine; Fishes; Fluorescent Antibody Technique; Hormones; Male; Microtubules; Mitosis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Skin; Tumor Stem Cell Assay

Topics: Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Aged, 80 and over; Castration; Estramustine; Humans; Lymphocytes; Male; Middle Aged; Prostatic Neoplasms

A 65-year-old man presented with supraclavicular, mediastinal, and retroperitoneal lymphadenopathy clinically thought to be due to malignant lymphoma. Biopsy of a supraclavicular lymph node revealed metastatic adenocarcinoma positive for prostatic-specific antigen. This site of the primary tumor was confirmed by needle biopsy of the prostate gland. The tumor regressed dramatically following treatment with estramustine phosphate.

Topics: Adenocarcinoma; Aged; Biopsy; Estramustine; Humans; Lymph Nodes; Lymphatic Metastasis; Lymphoma; Male; Prostatic Neoplasms

Observations with cytostatic therapy of generalized prostatic carcinoma (PC) over 5 years are reported, cyclophosphamide (cpa) having been administered to hormone-resistant patients. A standard therapeutic and follow-up scheme, enabling the results to be assessed objectively, had been elaborated. Objective remission or stagnation, confirmed on this basis, was attained in 50%, relief of pain in 60% of the cases. Side effects were negligible. Withdrawal of cytostatics was required in 2 cases. The results indicate that secondary cytostatic therapy significantly potentiated the effect of hormone therapy in generalized PC, and in case of hormone resistance it offers the only chance of therapeutic benefit.

Topics: Aged; Aged, 80 and over; Combined Modality Therapy; Cyclophosphamide; Estramustine; Hormones; Humans; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

Eleven patients with newly diagnosed stage D prostate cancer between June, 1984 and June, 1985, were administered 300 mg/day of Honvan in 3 divided portions, 4 capsules/day of Estracyt in 2 divided portions, or 100 mg/day of Prostal in 2 divided portions was administered orally, concomitantly with large-dose intermittent treatment of 1 g/m2/3 weeks of cyclophosphamide. According to the NPCP criteria, of the 5 cases given Honvan 1 case was PR and 4 cases were stable: all 3 cases given Estracyt were stable: and in 3 cases given Prostal, 1 case was stable, 1 case had progression and 1 case dropped out. The response duration of this combination therapy was 3 to 16 months (average: 9.9 months), and obvious improvements in the subjective symptoms and performance status were noted in the cases that responded to the treatment. As for side effects, gastrointestinal symptoms were observed in 9 cases, leucopenia in 3 cases, and thrombocytopenia in 1 case. All these cases, however, were slight and transient. In 1 case, jaundice and an elevation in GOT and GPT were detected, but these changes were also temporary.

Topics: Adenocarcinoma; Aged; Chlormadinone Acetate; Cyclophosphamide; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Middle Aged; Prostatic Neoplasms

Topics: Antineoplastic Agents; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Prostatic Neoplasms

A depletion of intracellular glutathione (GSH) is accompanied by a subsequent inhibition of GSH-S-transferase activity in a DU145 human prostatic carcinoma cell line treated with cytotoxic concentrations of estramustine. When GSH depletion reached approximately 50% of normal (approximately 2 hours after 10 microM estramustine), the mitotic index of logarithmically dividing cultures began to increase. A linear increase from 3.14% to 22.5% occurred during the period of 2-24 hours following 10 microM estramustine. Morphological studies showed that mitotic figures accumulated in metaphase and had abnormalities consistent with spindle malformation. Nocodazole and cytochalasin B also possess anticytoskeletal properties, but had little effect upon the intracellular levels of GSH or its associated transferase enzymes. The constituent moieties of estramustine, estradiol, and nor-mechlorethamine had effects on thiol metabolism which were dissimilar from estramustine, confirming previous findings that the unmetabolized parent drug is responsible for pharmacological activity. Estramustine had no effect upon GSH reductase activity, suggesting that drug toxicity was not a general thiol phenomenon. Buthionine sulfoximine decreased intracellular GSH in DU145 cells and enhanced the cytotoxic potential of estramustine in this cell line. The anticytoskeletal and antimitotic properties of estramustine may be enhanced by the drug-induced GSH imbalance and subsequent effects on GSH-S-transferase enzymes.

Topics: Buthionine Sulfoximine; Cell Line; Cell Survival; Drug Synergism; Estramustine; Glutathione; Glutathione Transferase; Humans; Male; Metaphase; Methionine Sulfoximine; Mitosis; Mitotic Index; Nitrogen Mustard Compounds; Prostatic Neoplasms; Tumor Stem Cell Assay

Our object was to determine if the aromatic nucleus of estramustine (I) is optimal for binding affinity to prostate cytosolic proteins, and if C3 is the preferred position for the N-mustard carbamate moiety. To this end we have submitted 34 steroids for in vitro assay of binding affinity to total prostate cytosolic proteins. Our structures included aromatic and hydroaromatic steroids containing N-mustard carbamate and other substituents at C3, C6, C11, C16, C17, C20, and C21. Our results show that binding affinity to prostate proteins is optimally present in C3-nitrogen mustard carbamates attached directly to a totally planar aromatic ring as in (IV). Partial deviation from total planarity as in enol-carbamates (V) leads to some loss of binding affinity, which largely disappears in hydroaromatic structures (VI). Thus, our data lead to the Ring A aromatic structure (X) as a basis for the design of steroidal N-mustard carbamates with prostate selectivity. Preliminary in vivo studies using the Dunning R3327AT prostatic adenocarcinoma implanted in the Copenhagen rat generally support our in vitro data.

Topics: Adenocarcinoma; Animals; Binding, Competitive; Chemical Phenomena; Chemistry; Cytosol; Estramustine; In Vitro Techniques; Male; Neoplasm Transplantation; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Protein Binding; Rats

A patient with metastatic prostate cancer is described where treatment with Adriamycin (doxorubicin) and estramustine produced severe hypophosphatemia (serum phosphate level, 1.2 mg/dl), which was reversible when treatment was discontinued. Previous studies have shown no effect of Adriamycin on serum phosphate levels. A retrospective study of serial serum chemistry values was done in 15 patients treated with estramustine. A significant fall in the serum phosphate level (mean, 0.8 +/- 0.3 mg/dl) was observed during the first 6 weeks of treatment. When compared with similar patients treated with bilateral orchiectomy, estramustine-treated patients had lower levels of serum calcium, fractional excretion of calcium, serum phosphate, and renal tubular threshold for phosphate reabsorption (TmPO4/GFR). Qualitatively similar but quantitatively smaller effects were also seen in a group of patients treated with diethylstilbestrol (DES) in a dose of 1 to 3 mg daily. Estramustine appears to have significant effects on bone mineral metabolism, particularly on renal phosphate handling resulting in significant hypophosphatemia. This is probably due to an estrogenic effect.

Topics: Adenocarcinoma; Bone and Bones; Calcium; Creatinine; Diethylstilbestrol; Estramustine; Estrogens; Humans; Kidney; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Orchiectomy; Phosphates; Prostatic Neoplasms

The effect of estramustine [estradiol 3-N-bis(2-chloroethyl)carbamate] on the human prostatic tumor cell line 1013L was investigated. Cell proliferation experiments revealed that estramustine cytotoxicity varied during the different phases of cell growth. Maximum cell killing was found in early log phase, but cell death also occurred in the stationary phase. Mitotic arrest was found at cytotoxic concentrations throughout the log phase. Subcellular distribution studies showed that the cellular uptake of estramustine increased throughout the log phase and remained steady during the stationary phase. Nuclear uptake in contrast was similar in all phases, whereas a preferential binding to the nuclear protein matrix was found to increase throughout the log phase and even during the stationary phase of growth. This implicates the nuclear protein matrix as a target for estramustine cytotoxicity.

Topics: Cell Line; Cell Nucleus; Cell Survival; Estramustine; Humans; Male; Mitotic Index; Nitrogen Mustard Compounds; Nucleoproteins; Prostatic Neoplasms

Chemilumenescence (CL) occurs due to the phagocytosis of bacteria and of tumor cells by polymorphonuclear neutrophils (PMN). Levels of CL were measured in patients with prostatic cancer and from normal subjects. Patients with advanced disease (stage C, D) showed no elevated CL levels as compared to healthy individuals or patients with minimal disease (stage A, B). Following external radiation therapy in patients with stage A-C prostatic carcinoma high levels of CL were recorded. Estrogen medication also resulted in increased CL levels, while estramustine did not affect phagocytic activity. Intradermal BCG vaccination caused increased PMN activity. Progressive prostatic cancer in hormone treated patients was associated with increased CL as compared to patients with stable or regressive disease.

Topics: Antineoplastic Agents; BCG Vaccine; Diethylstilbestrol; Estramustine; Granulocytes; Humans; Luminescent Measurements; Male; Phagocytosis; Prostatic Neoplasms

Estramustine phosphate disodium (Estracyt) was used in the treatment of 40 patients with prostatic carcinoma. Of these 20 patients 18 were treated with Estracyt as primary treatment and 22 had been treated with diethyl stilbestrol dephosphate and/or bilateral orchiectomy for more than 4 months before the Estracyt treatment. The drug was given orally in a dose of 560 mg/day in 2 divided oral doses. The clinical evaluation was done after 3 months treatment. The response in subjective symptoms and objective signs were documented and evaluated according to 5 criteria. In this study, Estracyt showed 80% improvement of dysuria, 60% of nykturia, 35% of pain and 55% of general condition. In objective signs, it showed 52.5% improvement of size of the prostate, 42.5% of consistency and 70% of residual urine. It would be emphasized that Estracyt had almost equal efficacy in both the primary treatment group and secondary treatment group. As side effects of this drug, gynecomastia, gastro-intestinal disturbance, angina pectoris like chest pain were observed.

Topics: Drug Evaluation; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Fluorescence-microscopic studies with dansylated estramustine (DnsEM) has permitted investigation of the mechanism of estramustine (EM) uptake in live human prostatic tumor cells (DU 145). DnsEM appeared to enter cells rapidly at the peripheral cell margins. A progressive increase in fluorescence was observed until the perinuclear material and cytoplasm were labeled brightly and the nucleoplasm was labeled faintly. Light microscopy showed that DnsEM is assimilated first in preexisting vesicles and then in numerous newly created vesicles that accumulate in the cytoplasm and around the nucleus. Colony-forming assays showed EM and DnsEM to be equally cytotoxic to cultured DU 145 cells. Cellular uptake and subsequent manifestation of cytotoxicity are presumably dependent upon these vesicles. However, after uptake of DnsEM, its diffusion into the cytoplasm was observed.

Topics: Animals; Biological Transport; Cell Nucleus; Cell Survival; Cells, Cultured; Cytoplasm; Dansyl Compounds; Estramustine; Fishes; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Skin; Temperature

In vitro incubations of human testicular tissue responded to human chorionic gonadotrophin with testosterone release in a dose-dependent manner. The release of testosterone increased with incubation time. The stimulated release of testosterone was inhibited by oestradiol and ethinyl oestradiol in a dose-dependent manner, suggesting that these oestrogens exert direct inhibitory effects on the human Leydig cells. Estramustine phosphate, estromustine, diethylstilboestrol and diethylstilboestrol diphosphate did not inhibit testosterone release. Hypophysectomized rats were treated for 8-9 days with human chorionic gonadotrophin, which maintained testicular blood flow within the physiological range. Some of the animals received additional treatment with oestradiol or estromustine. Oestradiol and estromustine depressed plasma testosterone concentration. In contrast to estromustine, oestradiol inhibited testicular blood flow, as measured by the microsphere technique. Intact rats were castrated, supplemented with testosterone and concomitantly treated with different oestrogenic substances. Testosterone supplementation induced increase of prostatic blood flow, which was inhibited by oestradiol, ethinyl oestradiol or diethylstilboestrol. Estramustine and estromustine had no effect on prostatic blood flow. The growth of a transplantable rat prostatic carcinoma (Dunning R3327H) was studied after castration, testosterone substitution or testosterone substitution in combination with oestradiol treatment. Oestradiol inhibited tumour growth, possibly by direct action. The blood flow in tumours in intact animals decreased with increasing tumour volume. Oestradiol treatment enhanced tumour blood flow. The oestrogenic effects of estramustine phosphate, ethinyl oestradiol/polyoestradiol phosphate or orchiectomy were studied in previously untreated prostatic carcinoma patients by measuring serum levels of liver proteins (pregnancy zone protein and sex hormone binding globulin) and pituitary hormones (luteinizing hormone, follicle stimulating hormone and prolactin) during a 6 month period. Both medical treatments induced marked but quite comparable changes of the proteins. Apart from the increase of follicle stimulating and luteinizing hormones, no changes were observed in these serum proteins after orchiectomy.

Topics: Adenocarcinoma; Animals; Estradiol; Estramustine; Estrogens; Ethinyl Estradiol; Humans; In Vitro Techniques; Male; Orchiectomy; Prostate; Prostatic Neoplasms; Rats; Regional Blood Flow; Testis; Testosterone

Current management techniques for metastatic prostatic cancer have given rise to controversies regarding the optimal timing, form, and degree of androgen deprivation. Low-dose diethylstilbestrol (DES) or orchiectomy decrease serum testosterone levels while posing less cardiovascular risk than high-dose DES. LH-RH analogues, such as leuprolide or buserelin, also inhibit testosterone production. Some studies suggest that some tumor cells may be relatively, rather than absolutely, androgen dependent. This has been the rationale for the combined use of a pure antiandrogen and an LH-RH agonist. Unfortunately, while this combination has been found effective in previously untreated patients, it has not been equally effective in those who have undergone prior therapy and demonstrated disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Castration; Cyclophosphamide; Diethylstilbestrol; Estramustine; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Androgen Antagonists; Antineoplastic Agents; Buserelin; Combined Modality Therapy; Estradiol Congeners; Estramustine; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Lymphatic Metastasis; Male; Neoplasm Staging; Orchiectomy; Prognosis; Prostate; Prostatectomy; Prostatic Neoplasms

We studied 32 patients with prostatic cancer before, and after 1 and 6 months of treatment with orchiectomy, estramustine phosphate or conventional estrogens (polyestradiol phosphate plus ethinyl estradiol). Lipid metabolism was evaluated by lipoprotein analysis and the intravenous fat tolerance test. Effects on the cardiovascular system were studied by exercise electrocardiography, blood volume estimation and thoracic electrical impedance measurement, a sensitive method to detect early signs of fluid retention. Present treatment programs for prostatic cancer seem to result in effects on lipoprotein metabolism that probably are of minor importance for the development of atherosclerotic manifestations. Measurement of thoracic impedance may be of value to detect fluid retention in individual patients.

Topics: Aged; Blood Pressure; Blood Volume Determination; Cardiography, Impedance; Cardiovascular Diseases; Castration; Combined Modality Therapy; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Exercise Test; Fat Emulsions, Intravenous; Humans; Lipoproteins; Male; Middle Aged; Prostatic Neoplasms; Time Factors

Androgen-responsive cells: To determine if testosterone or dihydrotestosterone is the main trophic hormone of prostatic adenocarcinoma, we have treated Dunning R3327H prostatic adenocarcinoma-bearing rats with 6-methylene progesterone, which blocks conversion of testosterone to dihydrotestosterone. Copenhagen-Fisher rats were treated with steroid (20 mg/Kg daily) immediately following implantation of tumor and thereafter for 117 days. There was a 92% inhibition of growth of tumors and a lesser effect upon prostate and seminal vesicles. Tumor-free body weights remained unchanged. Both treated and untreated tumors had equivalent DNA content on a per weight basis. This result supports the thesis that prostatic adenocarcinoma requires dihydrotestosterone for growth. Androgen-insensitive cells: Advanced prostate cancer does not respond to endocrine therapy but is temporarily controlled by the cytotoxic steroid estramustine. The latter shows significant selective binding to prostatic protein. To develop chemotherapeutic agents that will control androgen-insensitive cells and possess improved selectivity for prostatic protein, we have studied a number of steroids for their ability to displace 3H-labeled estramustine from prostatic cytosolic proteins. Surprisingly, a carbamido substituent at the C17 position was found to confer significant binding affinity for prostatic estramustine-binding protein. Extension of this structural characteristic to the estramustine type of molecule is being studied.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Animals; Carrier Proteins; Disease Models, Animal; Estramustine; Male; Neoplasm Transplantation; Organ Size; Progesterone; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Structure-Activity Relationship

One hundred and twenty-seven patients with locally advanced prostatic cancer were evaluated for the presence and progress of bone metastases before and during hormonal therapy, by serial radionuclide imaging and frequent measurement of plasma acid (tartrate-labile) and alkaline phosphatase. For comparison, serial changes in imaging and phosphatases were classified in each patient into one of six groups. Of 71 patients with negative imaging before treatment, 82% had normal alkaline phosphatase levels and 83% had normal acid phosphatase levels. Of 56 patients with bone metastases at presentation, false negative alkaline and acid phosphatase levels were noted in 18% and 36% respectively, though a few patients eventually developed abnormal levels. Serial plasma biochemistry and particularly alkaline phosphatase showed a response to treatment which was not always obvious on imaging. An assessment of the hepatic component of alkaline phosphatase by reference to plasma gamma glutamyl transpeptidase and isoenzyme electrophoresis was helpful in the evaluation of a false positive result but unnecessary where imaging was positive and phosphatase elevated. It is concluded that serial alkaline phosphatase estimation is essential in the follow-up of patients with prostatic cancer and bone metastases, and probably renders serial imaging studies superfluous once the presence of skeletal metastases has been proven. By comparison, acid phosphatase is a much less effective marker.

Topics: Acid Phosphatase; Aged; Alkaline Phosphatase; Bone and Bones; Bone Neoplasms; Diethylstilbestrol; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Prostatic Neoplasms; Radionuclide Imaging

Estramustine [17 beta-estradiol 3 N bis(2-chloroethyl)carbamate; EM] is a stable conjugate of estradiol and nor-nitrogen mustard that is used for the treatment of human prostatic carcinoma. We have studied the cytotoxic effects of EM on the cytoskeletal organization of squirrelfish pigment cells (erythrophores) and human prostatic tumor cells (DU 145) in culture. Light and whole-mount electron microscopy studies reveal that, at microM levels (60 to 120 microM), EM has a dose-dependent disruptive effect on cell shape, cytoskeletal organization, and intracellular transport. Upon removal of the drug, the cytological effects of EM are rapidly reversible in fish cells but not DU 145s. Immunofluorescent studies reveal that EM produces microtubule disassembly in fish erythrophores and DU 145 cells. A concomitant disruption of actin-microfilament arrays also occurs in DU 145 cells. These morphological data suggest that EM, in contradistinction to its constituent estradiol: nitrogen mustard species, induces cytotoxicity as an antimicrotubule drug. The observed disruption of the microtubules and cytomatrix of interphase cells is not reversible in the prostatic carcinoma cells. The disruptive action of EM on the cytoskeleton could ultimately produce a cytotoxic antimitotic effect in dividing cells.

Topics: Animals; Biological Transport; Calcium; Cell Line; Estramustine; Fishes; Humans; Male; Microscopy, Electron; Microscopy, Fluorescence; Microtubules; Mitosis; Nitrogen Mustard Compounds; Pigments, Biological; Prostatic Neoplasms

Topics: Antineoplastic Agents; Castration; Diethylstilbestrol; Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Aged; Drug Evaluation; Drug Resistance; Estramustine; Estrogens; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

There is so far no evidence that the newest hormone compounds, such as progestational agents, antiandrogens or estramustine phosphate, yield better results than low dose estrogens or orchidectomy in previously untreated patients. Castration and the other modalities of androgen deprivation, although they can cause a measurable objective regression in less than half of cases, do often induce a marked, sometimes long-lasting subjective improvement and can delay progression. It has not yet been clearly established whether or not hormone therapy can bring about a prolongation in survival. The critical point still remains our poor understanding of the causes of acquired hormone resistance and our inability to prevent it. Further studies on hormone receptors and steroid metabolism in normal and neoplastic cells might lead to progress in this field. The unsolved problem, whether resistance is due to a selection of clones resistant to hormones ab initio or to acquired biochemical characteristics in cells that were initially responsive, might be of great practical significance. A reliable test, able to detect sensitivity or resistance towards hormone therapy before any treatment is given, would be extremely helpful. Unfortunately, neither the most sophisticated hormone balance studies nor receptor determinations have led to clinically useful implications.

Topics: Androgen Antagonists; Dihydrotestosterone; Drug Resistance; Estramustine; Estrogens; Humans; Luteinizing Hormone; Male; Orchiectomy; Progestins; Prostatic Neoplasms

In some clinical trials the use of criteria of stable response of hormone-escaped prostate cancer is justified on the ground that it delineates patients with markedly improved survival, similar to that of partial regression patients. Forty-three patients with hormone-escaped prostate cancer were studied in order to identify other factors which might also predict improved survival. Fifteen patients received palliative treatment only, 17 secondary hormone therapy and 11 chemotherapy. Only one objective partial regression was seen. Thirty-seven patients have died of prostatic cancer, 3 have died of other causes and 3 remain alive. The mean initial hormone response was 14.8 months, the mean time from progression to death 11.3 months, and the mean time from symptoms to death 5.9 months. There was no significant correlation between length of initial response and survival following progression (r = 0.25). Six features of progression were reviewed. Patients presenting with one feature of progression had a significantly better mean survival, 14.8 months, compared with 8.2 months when multiple features indicated progression. It is concluded that the stable state is not an objective response in hormone-escaped carcinoma of prostate but a reflection of the patient's natural disease progression and that the mode of presentation may be a significant prognostic indicator.

Topics: Drug Resistance; Estramustine; Hormones; Humans; Male; Palliative Care; Prognosis; Prospective Studies; Prostatic Neoplasms; Time Factors

The assay of hormone receptors in neoplastic tissues recognizes their sensitivity or autonomy with regard to the hormonal action. The hormone dependency of the activity of neoplastic tissues can be employed to select the cases having the highest probability to be benefited by the treatment with anti-hormones, castration or hypophysectomy, as in breast and prostatic cancers. Examining the case for prostatic cancer, the authors indicate that there is a good correlation between the predictive assay and the clinical evolution of the treated prostatic carcinoma employing the determination of cell receptors for 5-alpha-dihydrotestosterone (DHT) by exchange at 15 degrees C with the synthetic steroid methyltrienolone. The electrophoretic determination of binding of DHT to cell receptor a 4 degree C is a much less efficacious procedure.

Topics: Diethylstilbestrol; Electrophoresis, Agar Gel; Estramustine; Estrenes; Humans; Male; Metribolone; Orchiectomy; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Receptors, Estradiol

Estracyt is a new drug for treatment of prostatic cancer, which is a molecule combining estradiol and nornitrogen mustard by a carbamate link. Estracyt is completely dephosphorylated prior to reaching the peripheral circulation after oral administration of the drug to men. Estramustine, i. e. dephosphorylated Estracyt, appears to be metabolized in liver as follows: Estramustine leads to estromustine leads to nitrogen mustard + estrone. There is a large amount of estramustine binding protein (EMBP) in the cytosol 3.5 S fraction of human prostatic cancer tissue, which is involved with the selective uptake and long term retention of both estramustine and estromustine in prostate. The anticancer action of Estracyt appears to be the sum of the direct prostatic action of estramustine and estromustine and the indirect prostatic action of free estradiol-17 beta and estrone via the inhibition of hypothalamo-pituitary axis. Estracyt Research Group in Japan concluded that Estracyt was effective in 38% of reactivated prostatic cancer patients (15% (I-C, I-B), 23% (I-A, O-B, O-C]. Side effects of this drug at the time of 3 months treatment is as follows: gastrointestinal disturbance in 36%, edema in 15%, and hepatic disorder in 7%.

Topics: Animals; Antineoplastic Agents; Estramustine; Estrone; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Mechlorethamine; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Rats

Estracyt (estramustine phosphate) is a nitrogen mustard derivative of estradiol-17 beta which is rapidly dephosphorylated to yield estramustine. Estramustine is metabolized to estromustine mainly in the liver. Both estramustine and estromustine are retained in rat prostate with a high degree of specificity. This retention is due to the binding of estramustine and/or estromustine to a protein called EMBP (estramustine binding protein). When estimated by HPLC, the molecular weights of these estramustine binding components in rat prostate are 45,000-50,000 and 25,000-30,000, respectively. HPLC and glycerol density gradient analysis clearly demonstrated the occurrence of EMBP in a cytosol preparation from human prostatic cancer tissue. When estimated by HPLC, the molecular weights of estramustine binding components are 45,000 and 25,000 daltons, respectively. In addition, results of effectiveness of Estracyt studied under a cooperative research group in Japan, are reported in this paper. Effectiveness was evaluated at 3 months of the treatment on 121 patients with untreated prostatic cancer (Study I) and 95 patients with reactivated cancer (Study II), at 12 months of the treatment on 68 patients in Study I and 85 patients in Study II, and at 24 months on 37 patients in Study I and 23 patients in Study II. At 3 months of the treatment, Estracyt was effective in 89% of untreated prostatic cancers, and 38% of reactivated prostatic cancers. At 24 months of the treatment, this drug was effective in 65% of untreated prostatic cancers and 30% of reactivated ones. Estracyt is especially recommended as a first-choice drug for both the untreated patients with poorly differentiated adenocarcinoma and reactivated cancer.

Topics: Animals; Cytosol; Estramustine; Humans; Liver; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Protein Binding; Rats; Subcellular Fractions; Tissue Distribution

The treatment of prostatic carcinoma with estrogens is associated with an increased risk of cardiovascular as well as thromboembolic complications. In the present study, patients harboring highly or moderately differentiated prostatic carcinoma without signs of metastases were treated with either polyestradiolphosphate + etinylestradiol, estramustine phosphate or given no treatment. Subsequently, these patients were investigated regarding factors (platelet aggregation, plasma and platelet phospholipid composition and lipoprotein patterns) that might contribute to increased thrombogenesis and cardiovascular risk. The results indicate the presence of increased in vitro platelet aggregation in patients treated with polyestradiolphosphate + etinylestradiol compared to those treated with estramustine phosphate or given no treatment. A possible relationship between the availability of arachidonic acid in platelet membrane phospholipids and in vitro platelet aggregation is suggested. On the other hand the alterations in plasma lipoproteins observed during treatment are generally considered positive from an atherogenic point of view and do not seem relevant to the elevated incidence of cardiovascular disease in these patients.

Topics: Aged; Apolipoproteins; Carcinoma; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Estradiol; Estradiol Congeners; Estramustine; Ethinyl Estradiol; Fatty Acids; Humans; Lipoproteins; Male; Nitrogen Mustard Compounds; Platelet Aggregation; Prostatic Neoplasms; Risk; Thromboembolism; Triglycerides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Castration; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Estramustine; Fluorouracil; Humans; Male; Middle Aged; Postoperative Care; Prostatic Neoplasms

Estramustine phosphate, a combination steroid and alkylating agent, has been used for treatment of cancer of the prostate since 1969. We treated 32 patients with Stages C and D prostate cancer with this compound. Using the National Prostatic Cancer Project criteria of response, no patient achieved complete or partial objective response. Sixty-two per cent of the patients without prior hormonal manipulation and 12 per cent of those who were progressing following hormonal therapy met the criteria for a stable response. Both Stage C patients, 50 per cent of D1 and 28 per cent of D2 patients achieved disease stabilization for a mean duration of 14.8 months. There was no correlation between tumor grade and response to treatment. Fifty per cent of the patients whose elevated acid phosphatase declined remain stable, whereas 80 per cent in whom the acid phosphatase did not decline have progressed. Estramustine is effective in patients without prior hormonal manipulation. In those refractory to hormones, the prognosis is poor yet data exist to support the superiority of estramustine phosphate over conventional therapy.

Topics: Aged; Carcinoma; Estramustine; Hormones; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Thirty-five patients with advanced cancers were treated with estramustine phosphate tablets (Estracyt). Doses ranged between 420 mg and 700 mg daily. One partial response was documented in a hormone resistant prostatic cancer patient. Four minor responses (less than 50% responses, or less than one month more than 50% response) were obtained; one in a hormone resistant prostatic cancer, two in metastatic colorectal cancers; and another in a malignant melanoma. Toxicity phenomena included nausea (9/35 - 25%), water retention (4/35 - 11.5%) and mild elevation of alkaline phosphatase (2/35 - 6%). Other toxicity effects were vaginal bleeding in two women, acne in one woman and mild pruritus in another patient. Myelosuppression and immune suppression were not significantly detected.

Topics: Adult; Aged; Colonic Neoplasms; Drug Evaluation; Drug Resistance; Estramustine; Female; Humans; Male; Melanoma; Middle Aged; Neoplasms; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rectal Neoplasms

In growth proliferation experiments on two human prostatic carcinoma cell lines, DU 145 cells were found to be more sensitive to the cytotoxic effect of estramustine and nor-nitrogen mustard than PC-3 cells. Estramustine was, however, much more cytotoxic in both cell lines than nor-nitrogen mustard. Cytogenetic experiments revealed that estramustine produced a drastic increase of the mitotic index in both these cell lines. This increase could be accounted for by the arrest of cells in their first treatment-metaphase. The arrested metaphases exhibited all the characteristics commonly found for stathmokinetic agents such as colchicine and vinca-analogues. No mitotic arrest was found for nor-nitrogen mustard but chromosomal aberrations were found at toxic concentrations. Estradiol exhibited minimal toxicity and caused no mitotic arrest in these cell lines. The mitotic arrest induced by estramustine was found to be reversible on removal of the drug.

Topics: Carcinoma; Cell Line; Cell Survival; Cells, Cultured; Drug Evaluation, Preclinical; Estramustine; Humans; In Vitro Techniques; Karyotyping; Male; Mitosis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

This report is an evaluation of the changes in bone scans in certain patients entered into the EORTC protocol 30762 and discusses the relevance of these expensive investigations.

Topics: Bone Neoplasms; Diethylstilbestrol; Estramustine; Humans; Male; Prognosis; Prostatic Neoplasms; Radionuclide Imaging

The pharmacokinetics of estramustine phosphate (EMP) was studied in five prostatic cancer patients given single i.v. and oral doses of EMP in a cross-over study. Plasma and urinary concentrations of parent drug, estramustine, estromustine (the estrone analogue), estradiol and estrone were followed by 32 h. The elimination of intravenous EMP from plasma was biphasic. The mean volumes of distribution were small, being 43 and 108 ml/kg for the central and peripheral compartments, respectively. The plasma clearance was 64 ml/kg/h, and the half-lives of the two phases were 0.16 and 1.27 h. Metabolism was the major route of elimination of EMP. It was readily dephosphorylated and oxidized to yield the cytotoxic metabolites estramustine and estromustine. Estromustine was the main metabolite in plasma. When given orally EMP underwent extensive presystemic dephosphorylation, which started in the gastrointestinal tract. The relative bioavailability of estromustine after administration of EMP-capsules was 44%, which reflects incomplete absorption of EMP rather than first-pass metabolism of estromustine. The terminal half-life of estromustine was 10-20 h, which suggests that EMP might be given once or twice a day.

Topics: Administration, Oral; Aged; Biological Availability; Biotransformation; Estramustine; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Models, Biological; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate ( Estracyt ) was used in 32 patients with a mean age of 73 and a half years suffering from oestrogen-resistant carcinoma of the prostate. These carcinomas were advanced and were divided into 26 stage D and 6 stage C. Treatment was given orally at a dose of 600 mg per day. Results were assessed on the basis of reliable subjective and objective selected criteria. Objective responses were obtained in 28,1% of cases and subjective responses in 40.6%. All the patients in whom there was an objective response showed a subjective response. Objective action was more marked on the primary tumour than on metastases. There was a decrease in bone pain, an improvement in general condition and disappearance of dysuria in more than a third of all cases. When there was a response, it always occurred before the end of the 2nd month and was maximal at 3 months. The mean duration of a response was 29.1 months for objective responses and 27.7 months for subjective responses. Survival of patients responding to treatment was markedly longer (by 15 months on average) than in patients who failed to respond. The low level of toxicity of the compound, even after prolonged use, makes its use possible in all patients. Thus Estracyt is felt to have a role in the treatment of the severe forms represented by hormone-resistant carcinomas of the prostate.

Topics: Adenocarcinoma; Aged; Bone Neoplasms; Drug Resistance; Estramustine; Estrogens; Follow-Up Studies; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

Topics: Drug Utilization; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Norway; Prostatic Neoplasms

Topics: Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Using cultured HeLa S3 cells an ID50 of 2.5 micrograms/ml was found after a twenty-four-hour incubation with estradiol-17 beta- 3N -bis-(2-chloroethyl) carbamate (estramustine). Similar ID90 values were found in two Walker 256 rat carcinoma cell lines which were either sensitive or resistant to nitrogen mustards. Alkaline elution methodology revealed the complete absence of DNA strand breaks or cross-links in cells receiving up to 10 micrograms/ml estramustine for twenty-four hours. Nuclear uptake was 1.34 per cent of the available drug, one third of which was hydrophobically associated with the protein/phospholipid components of the nuclear matrix. In the human prostatic cell lines DU145 and PC3 , estramustine caused a drastic dose-dependent increase in the mitotic index. This increase resulted from an arrest of cells in metaphase, with highly contracted disoriented chromosomes present. Rapid reverse of the arrest on removal of drug resulted in cell death. Neither nor-nitrogen mustard nor estradiol demonstrated antimitotic properties. The lack of macromolecular alkylation together with the observed antimitotic effects predict a mechanism of action for estramustine which is distinct from either of its constituent components.

Topics: Alkylation; Animals; Carcinoma 256, Walker; Cells, Cultured; Drug Evaluation, Preclinical; Estramustine; Female; HeLa Cells; Humans; Male; Mammary Neoplasms, Experimental; Mitosis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rats; Structure-Activity Relationship

Topics: Antineoplastic Agents; Castration; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

Topics: Biopsy, Needle; Cell Nucleus; DNA, Neoplasm; Drug Evaluation; Estramustine; Humans; Male; Neoplasm Staging; Nitrogen Mustard Compounds; Photometry; Prospective Studies; Prostate; Prostatic Neoplasms; Time Factors

The Scandinavian countries, especially Sweden and Norway, have a high incidence of prostate cancer. The tumor classification has been mainly uniform in recent years, according to the TNM system. Transrectal fine-needle biopsy and cytologic malignancy grading were introduced in Sweden and were gradually accepted in other countries. The treatment of prostate cancer has been mainly conservative as it is in most parts of Europe. For a long period endocrine therapy was given in the vast majority of cases. In recent years radiotherapy has also been used in cancer of low differentiation with no evidence of dissemination. In poorly differentiated and disseminated disease, Estracyt is the standard therapy. Estracyt is also given in disseminated carcinoma nonresponsive to ordinary hormone therapy. In this category of patients other chemotherapy is the second therapeutic alternative. Various techniques of endocrine therapy, chemotherapy, and radical surgery are subject to controlled trials.

Topics: Antineoplastic Agents; Castration; Combined Modality Therapy; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Scandinavian and Nordic Countries

A high incidence of urethral strictures was noted in patients with prostatic cancer who were treated by antiandrogen therapy. Retrograde urethrograms showed urethral stricture in 24 of 42 patients (57%) after or during the therapy, despite the fact that no stricture was found before initiation of therapy. The stricture was long and the entire penile urethra was narrowed, associated with more severely constricted portions. All of the patients with urethral stricture had received estrogens, while none of the patients who had undergone castration alone or had not received any therapy showed a stricture. The strictures disappeared after the cessation of estrogen administration. These results indicate that estrogen administration induces stricture in the male anterior urethra. It is suggested that large amounts of estrogen cause atrophy and fibrosis of the spongy and cavernous bodies of the penis, depriving the urethra of its normal elasticity, which results in urethral stricture. The stricture is one of the complications of estrogen therapy for cancer of the prostate.

Topics: Aged; Diethylstilbestrol; Estramustine; Estrogens; Hexestrol; Humans; Male; Prostatic Neoplasms; Radiography; Urethral Stricture

Topics: Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

In addition to surveying biochemistry, clinical findings and side effects of Estramustin Phosphate therapy, this paper gives an account of our own results with primary and secondary Estramustin Phosphate therapy. A total number of 118 patients have been examined in three different studies since 1970. Apart from conventional clinical control examinations, an additional accurate parameter applied to control therapy response was cytological analysis of therapy induced regression signs in primary tumor. Thus objective therapy response was established for 87% resp. 93% of the patients on primary Estramustin Phosphate therapy, and for 35% resp. 45% of those on secondary therapy. Patients with cytologically poor therapy response 3 months after beginning of therapy entered significantly earlier into clinical progression than patients with favorable therapy response, with clinical progression being additionally and essentially influenced by the pretherapeutical metastatic stage. Gastro-intestinal side-effects were prevalent in 79% of cases on intravenous administration of the drug, while on oral administration they were found to be three times less.

Topics: Aged; Estramustine; Gastrointestinal Diseases; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rats

The proliferative responses of human prostatic carcinoma have been evaluated in organ culture using [125I]-iododeoxyuridine ([125I]UdR) to monitor DNA synthesis. The morphological preservation was not influenced by the addition of fetal calf serum or insulin (5 mu gm/ml), transferrin (10 mu gm/ml), and thyrotropin releasing hormone (10(-9) M) to the active medium. Testosterone (4 X 10(-7) M) stimulated [125I]UdR uptake, whereas diethylstilboestrol (4 X 10(-6) M) had no direct effect on uptake. Both estramustine phosphate (4 X 10(-6) M) and oestradiol-17 beta (4 X 10(-6) M) inhibited uptake in a similar manner. Thus while explants of human prostatic carcinoma derived from transurethrally resected specimens can be well maintained in organ culture for a few days, proliferative responses are small and difficult to measure for individual patients.

Topics: Adenocarcinoma; Animals; Culture Media; Diethylstilbestrol; Estradiol; Estramustine; Humans; Male; Organ Culture Techniques; Prostate; Prostatic Neoplasms; Rats; Testosterone

Topics: Aged; Bone Neoplasms; Drug Resistance; Estramustine; Estrogens; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Dunning R3327H prostatic adenocarcinoma was bilaterally transplanted in the flanks of animals at the Papanicolaou Institute in Miami, and the animals were received at the Cross Cancer Institute (Edmonton, Alberta, Canada) each month. The animal flanks were palpated weekly, and when tumor volumes reached a size of approximately 300 mm3 the animals were randomized into treatment groups for the assessment of various therapies. Tumor volumes were determined each week before and after various treatments, and tumor growth was compared to that in untreated controls. Ionizing radiation at relatively small single doses completely inhibits tumor growth for a period of up to 6 months. Some interesting characteristics of this radiation-induced growth arrest are that tumors do not die and shrink away as with some other tumor models but remain static in size and show histologic evidence of viable tumor cells. The hypoxic cell radiosensitizer misonidazole potentiates radiation response in this tumor model. Cisplatin, vincristine, etoposide, and estramustine phosphate administered in drug doses approaching their toxic limits have a partial effect on tumor growth.

Topics: Adenocarcinoma; Animals; Cisplatin; Estramustine; Etoposide; Female; Male; Neoplasm Transplantation; Prostatic Neoplasms; Rats; Vincristine

Topics: Bone Neoplasms; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Adenocarcinoma; Administration, Oral; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

The [3H]estramustine-binding macromolecule in human prostate was partially characterized using a number of chromatographic procedures. Although human estramustine-binding protein (HEMBP) had a marked tendency to aggregate in several systems, a molecular weight of about 54,000 was determined by gel filtration on Sephacryl S-200 Superfine and high-performance liquid chromatography. A sedimentation-coefficient of about 3.6S was obtained for HEMBP when analyzed by sucrose density gradient centrifugation. Isoelectric focusing in polyacrylamide gels indicated an isoelectric point of 4.7 to 4.8, which was in agreement with the elution position of HEMBP following chromatofocusing on Polybuffer Exchanger 94. Furthermore, HEMBP was eluted from diethylaminoethyl-Sepharose with 0.23 M KCl, was retained by concanavalin A-Sepharose (indicating that HEMBP is a glycoprotein), but did not interact with Affi-Gel Blue. Special efforts were concentrated on establishing that HEMBP was a species distinct from human serum albumin. Separation between the [3H]estramustine-labeled HEMBP and the [3H]estramustine-human serum albumin complex was obtained both on sucrose density gradients by chromatography on Affi-Gel Blue, by chromatofocusing, by gel filtration, by isoelectric focusing, and on concanavalin A-Sepharose by affinity chromatography. Twenty-two of 27 human benign hyperplastic prostate cytosol samples were found to contain protein immunochemically similar to estramustine-binding protein (EMBP) purified from rat ventral prostate as determined by the EMBP radioimmunoassay method. Concentrations from 0.2 to 139.6 ng EMBP per mg of total cytosolic protein (mean, 19.3) were determined. Furthermore, four of seven prostatic cancer specimens as well as two of two normal prostatic specimens were also found to contain rat EMBP-immunoreactive material. The unequivocal demonstration of the presence of a HEMBP is of great potential interest in consideration of estramustine phosphate (Estracyt) therapy against prostatic carcinoma. It is not inconceivable that the concentration of HEMBP in the carcinomatous tissue will be of significance in determining the drug uptake in the malignant tissue.

Topics: Animals; Carrier Proteins; Centrifugation, Density Gradient; Chromatography, Affinity; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay; Rats; Serum Albumin

Estramustine at concentrations ranging from 3-40 x 10(-6) M inhibited the cell growth and clonogenic survival of a human prostatic carcinoma cell line (DU 145). This cell line was found to be unresponsive to estradiol and testosterone at concentrations ranging from 10(-9) M to 5 x 10(-5) M. Metabolism studies with estramustine showed that only a few per cent of the ester linkage was cleaved during the exposure period. This small amount of metabolism could possibly lead to the release of nor-nitrogen mustard, which was however found not to be as inhibitory as estramustine in this cell line. The results indicate that estramustine per se causes the cell death of hormone unresponsive human prostatic carcinoma cells in cell culture.

Topics: Carcinoma; Cell Line; Cell Survival; Cells, Cultured; Estradiol; Estramustine; Humans; In Vitro Techniques; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone

From September, 1978, to November, 1980, 69 consecutive patients with locally advanced (T3-T4) prostatic adenocarcinoma, with or without distant metastases, were treated with oral estramustine phosphate. Dosage was 15 mg/kg/day for 2 months, followed by 5 mg/kg/day until progression. In the 48 evaluable patients with progressive disease that entry in the study, 1 complete response, 7 partial responses, 31 disease stabilizations, and 9 progressions were encountered (81.2% NPCP response rate). Karnofsky performance status equal to or less than 50 was predictive of poor response to estramustine phosphate. In the 10 evaluable patients with stabilized disease at entry in the study after orchiectomy, 2 complete responses, 4 partial responses, 3 disease stabilization, and 1 progression were noted. The major side effects observed were gynecomastia, nausea, and vomiting.

Topics: Adenocarcinoma; Aged; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

A human prostatic adenocarcinoma, growing as a transplantable line in nude mice, was subjected comparatively to the usual endocrine treatment schedules including orchiectomy, estrogens, estramustine phosphate, and a study with flutamide (SCH 13521) and cyproterone acetate. The regression under treatment in tumor volume and in the histological pattern in demonstrated, and the possibilities and limitations of the nude mouse model are discussed.

Topics: Adenocarcinoma; Animals; Castration; Estramustine; Estrogens; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Prostatic Neoplasms

Topics: Diethylstilbestrol; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

The responsiveness to diethylstilbestrol (DES) and estramustinephosphate (EMP) of human peripheral blood lymphocytes to T-cell mitogens has been investigated in vitro and in vivo. EMP demonstrated potent inhibition of both Con A- and PHA-induced lymphocyte proliferation in vitro, while it had no detectable effects when given to patients with cancer of the prostate. DES reduced the response to Con A in vitro, but had only marginal effects on PHA-induced mitogen response. In contrast, the response to Con A was unaltered, while the response to PHA was significantly diminished after DES therapy in patients with prostatic cancer. This effect, however, was only seen when high doses of DES not included in conventional regimen were given. The proliferative response to T-cell mitogens in patients with prostatic cancer was not affected by serum source in the assay, indicating the absence of humoral factors able to inhibit mitogen response in these patients.

Topics: Adult; Concanavalin A; Diethylstilbestrol; Estramustine; Humans; In Vitro Techniques; Lymphocyte Activation; Male; Middle Aged; Nitrogen Mustard Compounds; Phytohemagglutinins; Prostatic Neoplasms

The low incidence of measurable or evaluable metastases in patients with prostatic cancer makes evaluation of response difficult. This is particularly true in patients with bone metastases only. With a digital model it is possible to measure quantitatively from the radioisotope bone scan the total area of skeletal involvement by metastatic tumor. Definitions of response in bone have been derived from this model. These response criteria have been compared to response in acid phosphatase determinations and clinical status in a study of 44 patients with advanced prostatic cancer treated with estramustine phosphate. Based on serial quantitative bone scans, serial measurements of acid phosphatase levels and repeat clinical evaluations a system is proposed for defining response to systemic therapy that is applicable to the majority of patients with metastatic prostatic cancer.

Topics: Acid Phosphatase; Adenocarcinoma; Adult; Aged; Bone Neoplasms; Diphosphates; Diphosphonates; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Radionuclide Imaging; Technetium

Topics: Adamantane; Alkylating Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cisplatin; Estramustine; Fluorouracil; Humans; Male; Prostatic Neoplasms

We treated 41 patients with advancing metastatic carcinoma of the prostate in our hospital for 21 days by giving 2 X 150 mg Estracyt intravenously per day. We saw good clinical results in 32 of the 41 patients (= 78%). We found a statistically significant (P less than 0.05) decrease of the acid and prostatic phosphatases. There was a significant (P less than 0.05) increase of the alkaline phosphatases. We did not see any renal or hematologic toxicity. Ten % of our intravenously treated patients experienced thrombophlebitis at the site of injection. Estracyt showed good clinical results.

Topics: Acid Phosphatase; Aged; Alkaline Phosphatase; Estramustine; Humans; Male; Middle Aged; Neoplasm Staging; Nitrogen Mustard Compounds; Prognosis; Prostate; Prostatic Neoplasms

Twenty-five patients with histologically proved adenocarcinoma of the prostate were divided into two groups and submitted to combination therapy with estramustine (Estracyt), cyclophosphamide (Cytoxan), 5-fluorouracil, and Cisplatin. Group A consisted of 10 patients newly diagnosed Stage D disease with no prior treatment. Group B consisted of 15 Stage D patients who had become hormonally unresponsive. Group A patients demonstrated an initial 100 per cent response rate including 70 per cent partial objective responses and 30 per cent stabilizations. Group B patients had a 46 per cent response with 39 per cent complete and partial responses and 6 per cent as stabilized. Toxicity was tolerable judged by the NPCP criteria. Both groups of patients are still under study for up to two years to determine if this therapy is superior to other traditional therapies.

Topics: Adenocarcinoma; Antineoplastic Agents; Cisplatin; Cyclophosphamide; Drug Therapy, Combination; Estramustine; Fluorouracil; Humans; Male; Nitrogen Mustard Compounds; Pilot Projects; Prostatic Neoplasms

We evaluated the effect of treatment of patients with prostatic cancer with estramustine phosphate or the combination diethylstilbestrol-polyestradiol phosphate on the natural killer cell activity in peripheral blood. Although estramustine phosphate did not affect natural killer cell activity, diethylstilbestrol-polyestradiol phosphate substantially reduced natural killing after a treatment period of 1 week. The activity was only slightly further lowered after 4 weeks of treatment. Possible clinical implications of the difference in susceptibility of natural killer cells to these agents are discussed.

Topics: Aged; Cytotoxicity, Immunologic; Diethylstilbestrol; Estradiol; Estramustine; Humans; Killer Cells, Natural; Male; Middle Aged; Nitrogen Mustard Compounds; Organophosphorus Compounds; Prostatic Neoplasms; Time Factors

Topics: Drug Resistance; Estramustine; Estrogens; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Plasma samples from patients with prostatic cancer under oral treatment with estramustine phosphate (Estracyt) were quantitatively analyzed for the presence of the parent drug and some of its possible metabolites. Specific methods based on radioimmunoassay and gas chromatography-mass fragmentography were used. Dephosphorylation and oxidation at the 17-position of estradiol were shown to be the major metabolic routes. The estrone analogue of estramustine was found to be the main metabolite in plasma. Elevated levels of estradiol and estrone showed that hydrolysis of the carbamic ester also occurred in these patients. Their estrogen levels were compared with those of another group of prostatic cancer patients receiving conventional hormonal therapy, polyestradiol phosphate (Estradurin). Similar concentrations of estradiol were found in the two groups but the concentrations of estrone were higher in patients given estramustine phosphate.

Topics: Aged; Estradiol; Estramustine; Humans; Kinetics; Male; Nitrogen Mustard Compounds; Organophosphorus Compounds; Prostatic Neoplasms

Transrectal ultrasonotomography was performed in 44 patients with prostatic cancer before, during, and after estramustine phosphate (Estracyt) administration. In 75.7% of 37 previously untreated patients, the deformity of the horizontal section of the prostate with prostatic cancer was corrected considerably, while in 89.2%, prostatic weight was remarkably reduced. In 57.1% of seven previously treated patients, appreciable changes were also observed in the shape and weight of the prostate. We concluded that estramustine phosphate was effective not only for untreated prostatic cancer, but also, at least in some degree, for relapsed cases.

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Organ Size; Prostate; Prostatic Neoplasms; Rectum; Ultrasonography

Cardiovascular complications in patients with carcinoma of the prostate have been studied in relation to 3 methods of treatment, namely stilboestrol, estramustine phosphate (Estracyt) and bilateral orchiectomy. One hundred and sixteen patients were studied over a 4-year period on a prospective basis, 48 being treated with stilboestrol, 31 with estramustine and 37 with bilateral orchiectomy. The incidence of the cardiovascular side effects of these 3 treatment regimes in the first year of treatment was recorded after the patients had been divided into those with localised (MO) disease and advanced disease with metastases (M1). In patients treated with stilboestrol 29% had cardiovascular complications with a mortality rate of 16%. With estramustine 25% had complications with a 16% mortality rate, but with orchiectomy the complication rate was only 8% with a 3% mortality rate. It is recommended that stilboestrol and estramustine phosphate should not be used in the presence of cardiovascular disease and that the primary form of treatment in prostatic carcinoma should be bilateral orchiectomy, especially in patients with localised disease.

Topics: Aged; Cardiovascular Diseases; Castration; Diethylstilbestrol; Estramustine; Humans; Male; Prostatic Neoplasms

Plasma concentrations of estramustine phosphate and its major metabolites were measured in patients with prostatic carcinoma treated with increasing oral doses, 70-650 mg/day, of estramustine phosphate (Estracyt). Parent drug and estradiol were measured by radioimmunoassay, and estramustine and its estrone analogue (Leo 271) utilizing gas chromatography. The concentrations of estramustine phosphate and estramustine were below or close to the limits of the methods. A linear correlation was found between the daily dose of estramustine phosphate, and plasma concentrations of Leo 271-the main metabolite-and estradiol, which suggests that no capacity limiting processes are involved in the pharmacokinetics of estramustine phosphate in man. Plasma was also analyzed during prolonged treatment with 560 mg/day. The metabolite pattern was not changed by two to three years of estramustine phosphate treatment.

Topics: Administration, Oral; Aged; Carcinoma; Estradiol; Estramustine; Estrone; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

23 patients with prostatic cancer were treated with (Estracyt) estramustine phosphate disodium, (Hexron) hexestrol, and (Honvah) diethylstilbestrol 4, 4-diphosphoric ester. 16 cases were given 560-840 mg of Estracyt, 6 cases 30 mg of Hexron, and 1 case 200 mg of Honvan orally daily. Fasting serum lipids and lipoproteins fractions were measured before and during this treatment with these drugs. The results were as follows. 1) In the 1-2 months of Estracyt administration a decrease of (TC) total cholesterol and extreme increase of (TG) triglycerides were confirmed. 2) In those 5 cases where 840 mg of Estracyt/day was given, almost no difference was observed in their TC, (NEFA) free fatty acids, or (PL) phospholipid values. 3) Cardiovascular complications although not serious, were found in 2 cases of the group receiving Estracyt. With these 2 cases, their beta+pre-beta/alpha lipoprotein fraction ratio decline was either very gradual or rather turned to increase markedly despite the extreme rise of their TG values. 4) The serum lipid values in the group receiving Hexron did not show any obvious changes in TG. These values did not change much in the first 5-6 months but an increase was seen between 7-9 months. Lipoprotein fractions were similar to those in the Estracyt group. 5) With those receiving Honvan, TG values began to rise 2-4 weeks following administration. In view of the above results, the coronary risk factors which are a consequence of Estracyt, Honvan, or Hexron ingestion for treatment of prostatic cancer must be taken very seriously and must be closely monitored. (Authors' modified)

Topics: Aged; Diethylstilbestrol; Estramustine; Hexestrol; Humans; Lipids; Lipoproteins; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Hyperplasia; Prostatic Neoplasms

Topics: Castration; Diethylstilbestrol; Estramustine; Humans; Male; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Palliative Care; Prostatic Neoplasms; Time Factors

Topics: Aged; Diethylstilbestrol; Estramustine; Humans; Male; Middle Aged; Prednimustine; Prostatectomy; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, High-Energy; Testosterone; Testosterone Congeners

Since the introduction of estrogen treatment of prostatic carcinoma in 1941 this treatment has been considered the treatment of choice until recently, when both conventional cytotoxic compounds and hormone cytotoxic agents have been used. Preliminary results are in many aspects very promising (Jönsson, Högberg & Nilsson, 1977). However, controlled randomized series are badly needed to give a final answer how to proceed. So far chemotherapy has been given only for palliation but new approaches and combined treatment modalities might point forward to a treatment that, hopefully, will cure prostatic carcinoma especially if the treatment is started in the very early stages.

Topics: Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Ninety patients with poorly differentiated prostatic carcinoma have been treated with Estramustine phosphate (Estracyt). Seventeen of them had clinically metastases and had had no previous therapy. Seventy-three were initially given oestrogens and/or irradiation. Objective response was observed in 59%. The best effect was seen in patients primarily untreated.

Topics: Acid Phosphatase; Bone Neoplasms; Estramustine; Humans; Lymphatic Metastasis; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Pain; Prostatic Neoplasms

Topics: Estradiol; Estramustine; Estrone; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

9 advanced prostate cancer patients were given a dose of 1-(2-chlorethyl-3[4-methyl cyclohexyl]-1-nitrosourea) (MeCCNU) 175 mg/m2 orally every 6 weeks. All of them had previously failed on hormonal therapy. 8 patients have progressed during the chemotherapy and only 1 was considered to be stable during a period of 18 weeks. Hematologic toxicity was seen in 3 patients. 21 patients with advanced prostatic carcinoma who failed hormonal therapy were treated with a combination of estracyt (600 mg/m2/day) plus MeCCNU (175 mg/m2/6 weeks) in oral doses. 1 patient had stable disease for about 30 weeks and another one had a subjective response for 12 weeks. 11 patients had hematologic toxicity and 5 of them required dose modification. 10 patients with stage D carcinoma of the prostate were given oral estracyt at a dose of 600 mg/m2/day plus cis-diamminedichloroplatinum (DDP) at an intravenous dose of 60 mg/m2 twice a week repeated every 3 weeks plus methotrexate (MTX) at an i.v. dose of 100 mg/m2 twice a week, repeated every 3 weeks. All of the patients had failed on prior therapy. 9 patients are evaluable, 4 patients had an objective response and 2 others had a subjective response. 2 patients had hematologic toxicity (life threatening) and 2 others had a decrease in creatinine clearance to 60 mg/min and required dose modification. The combination of estracyt + DDP + MTX or a modification seems to be promising.

Topics: Antineoplastic Agents; Bone Marrow; Cisplatin; Drug Evaluation; Drug Resistance; Drug Therapy, Combination; Estramustine; Hormones; Humans; Male; Methotrexate; Prostatic Neoplasms; Semustine

Topics: Cisplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Estramustine; Fluorouracil; Humans; Hydroxyurea; Lomustine; Male; Melphalan; Methotrexate; Prednimustine; Prostatic Neoplasms

Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.. This study attempted to determine whether oral administration of diethylstilbestrol (DES) or estramustine phosphate, a mustard compound derivative with unknown mechanism of action, is as effective in the treatment of prostate cancer as castration. Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (aged under 50 years or over 65 years) and in 7 groups of prostatic cancer patients treated by endocrine manipulation, including orchiectomy and DES or estramustine phosphate. 133 persons were studied. Total serum testosterone levels were significantly higher in younger vs. older controls and testosterone-estradiol binding globulin levels were significantly higher in the older men. Although orchiectomy reduced serum testosterone to low concentrations, the binding globulin level was not altered by surgery. In contrast, estramustine phosphate and DES therapy, administered to intact or castrated patients, led to depressed testosterone and markedly elevated binding globulin levels in serum; this effect was most pronounced among estramustine phosphate users. Therefore, it is concluded that DES or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting concomitant elevation of the testosterone-estradiol binding globulin and a depression of total testosterone.

Topics: Adult; Aged; Diethylstilbestrol; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Testosterone

Topics: Drug Evaluation; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

81 patients with advanced prostate carcinoma, mainly estrogen resistant, were treated with Estracyt. After a pilot study had shown encouraging results in the first 39 cases, the preparation was used on a further 42 patients and for 38 of these its therapeutic effectiveness was evaluated according to internationally defined clinical criteria. In this way, an objective therapeutic success quota of 55% of all 38 patients was obtained. In the group with estrogen-resistant tumors the value was still found to be as high as 35%. These clinical results were confirmed by cytomorphological control of the degree of regression of the tumor effected by the therapy, and also by single-cell cytophotometric analysis of the DNA content of various prostate carcinomas treated wtih Estracyt.

Topics: Biopsy, Needle; DNA, Neoplasm; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Photometry; Prostatic Neoplasms

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of estramustine and its 17-keto metabolite in plasma. The assay involves extraction of the compounds into hexane from plasma buffered to pH 9.0, the residue obtained by evaporation of the hexane extract is dissolved in the mobile phase hexane-ethanol (92.5:7.5) with HPLC analysis performed on a 5-micrograms silica gel column using a fluorescence detector with excitation at 195 nm and emission at wavelengths greater than 250 nm. The overall recoveries and limits of sensitivity for estramustine and the 17-keto metabolite are 74.7% and 40 ng/ml of plasma and 85.1% and 50 ng/ml of plasma, respectively. The method was used to obtain plasma concentration-time profiles in three subjects with prostatic cancer following oral administration of a single 7 mg/kg dose of estramustine phosphate.

Topics: Chromatography, High Pressure Liquid; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Spectrometry, Fluorescence

Topics: Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Thirty patients with advanced carcinoma of the prostate were treated with estramustine phosphate. All patients were followed up for a minimum of 9 months. Of 15 not previously treated with oestrogens 9 responded objectively and 11 subjectively. Of 15 patients whose tumours had failed to respond to at least 2 oestrogens, 3 responded objectively and 5 subjectively. Adverse effects consisted of cardiovascular complications, gynaecomastia and impotence. Gastrointestinal side effects were minimal and no hepatic, renal or marrow toxicity was seen. The criteria of assessment of response are discussed.

Topics: Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Time Factors

Topics: Animals; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Protein Binding; Rats; Receptors, Steroid

Topics: Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

We report on 51 patients with hormone-resistant, stage D prostatic carcinoma who were treated with estramustine phosphate and followed for at least 6 months. Of the 51 patients 5 (10 per cent) had a partial objective response, 30 (59 per cent) remained stable and 16 (31 per cent) had progression of the disease. All of those patients who had a partial response or remained stable also experienced subjective improvement as judged by relief of pain and performance status. Approximately 8 per cent of the patients will be unable to take estramustine phosphate because of intolerable gastrointestinal side effects.

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Nausea; Nitrogen Mustard Compounds; Prostatic Neoplasms; Vomiting

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9% of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.

Topics: Chlorambucil; Drug Therapy, Combination; Estramustine; Humans; Male; Nausea; Neoplasm Metastasis; Nitrogen Mustard Compounds; Pain; Prednisolone; Prostatic Neoplasms; Vomiting

In a 68-year-old man metastasis to the penis was diagnosed about two years after transurethral resection of the prostate because of adenocarcinoma. Diethylstilboestrol has been given postoperatively. Initially the metastasis was interpreted as primary cancer of the penis, as biopsy findings indicated a spinocellular carcinoma. Subsequent biopsies, however, showed the same histologic pattern as in the original cancer of the prostate. Up to 1976 about 170 cases of metastasis to the penis were reported in the literature. The prognosis as a rule is very poor. In the present case estramustine phosphate (Estracyt) seemed to improve the patients's general health, but did not affect the penile metastasis. The patient died 18 months after the metastasis had been demonstrated.

Topics: Adenocarcinoma; Aged; Castration; Diethylstilbestrol; Estramustine; Humans; Male; Penile Neoplasms; Prognosis; Prostatic Neoplasms

Topics: Chlorambucil; Estramustine; Hematopoiesis; Humans; Male; Nausea; Prednimustine; Prostatic Neoplasms; Vomiting

Topics: Diethylstilbestrol; Drug Administration Schedule; Estramustine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Aged; Biopsy, Needle; DNA, Neoplasm; Estradiol; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prospective Studies; Prostate; Prostatic Neoplasms

Estramustine phosphate, a drug effective in a substantial number of patients with cancer of the prostate who had failed on other forms of therapy, has been shown to be split into its constituents, that is estradiol-17beta and the carbamate nitrogen mustard by non-cancerous and cancerous human prostatic tissues. This fact may explain, in part, the mechanism of action and efficacy of the drug in patients with cancer of the prostate. In addition to presenting results on the hydrolysis and its products accomplished by human prostatic tissues we discuss the limitations of extrapolating animal results with estramustine phosphate to the human condition and possible parameters that bear upon the insignificant toxic and estrogenic effects observed in patients given estramustine phosphate.

Topics: Adenocarcinoma; Animals; Carbamates; Culture Techniques; Estradiol; Estramustine; Humans; Hydrolysis; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Neoplasms; Receptors, Estrogen

Two drugs, 2,6-cis-diphenylhexamethylcyclotetrasiloxane (Cisobitan) and estramustine-17-phosphate (Estracyt) were given to patients with poorly differentiated metastatic carcinoma of the prostate. The effect of the drugs on blood coagulation was investigated. Some parameters showed changes during the treatment: Antithrombin III decreased in the Estracyt treated patients to a level which might imply a thrombogenic effect. Fibrinogen decreased, whereas factor VIII showed no consistent change. Normotest changes appeared to correlate with liver damage whereas antithrombin III showed no change. Increased levels of fibrinogen degradation products and fibrinopeptide A (FPA) were more frequent in the group of deteriorating patients. However, the number of FPA analyses were too small for any definite conclusions regarding possible disseminated intravascular coagulation.

Topics: Afibrinogenemia; Aged; Antithrombins; Blood Coagulation; Estradiol Congeners; Estramustine; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Prothrombin; Silicones; Siloxanes

Topics: Chlorambucil; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prednisolone; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Estramustine; Humans; Male; Progestins; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid

Topics: Adenocarcinoma; Drug Therapy, Combination; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prognosis; Prostatic Neoplasms; Streptozocin

Topics: Adenocarcinoma; Aged; Bone Neoplasms; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms; Radiography; Remission, Spontaneous

Estramustine phosphate (Estracyt), a combination of estradiol and nitrogen mustard given to males with prostatic carcinoma, had the same effect on serum lipids, lipoproteins, and serum phosphoglyceride fatty acid composition as ethynyl estradiol (Etivex). The characteristic effects on serum lipids caused by both drugs, i.e., a reduction in serum cholesterol and an increase in serum phospholipids, were apparently expressions for reduced low density lipoproteins and increased alpha-lipoproteins. Serum lecithin fatty acid composition revealed during the administration of both drugs a characteristic increase in palmitic acid (16:0) and a decrease in stearic acid (18:0), interpreted as evidence for a cholestatic, although subclinical, liver involvement. Similar changes have earlier been revealed in women given ethynyl estradiol; however, the increase in serum triglycerides and very low density lipoprotein cholesterol in young women was not duplicated in aged males with prostatic carcinoma. Furthermore, in aged males, the administration of these estrogens did not change carbohydrate metabolism but did produce an increase in adipose tissue lipoprotein lipase.

Topics: Adipose Tissue; Aged; Carbohydrate Metabolism; Estramustine; Glycerophosphates; Humans; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

40 patients with inoperable, histologically proved carcinoma of the prostate were treated with estramustine phosphate. 35 patients had progressive, symptomatic, metastatic disease unresponsive to conventional oestrogens and/or castration Estramustine phosphate was given intravenously initially at a dose of 150 mg/day increasing to 300 mg/day. After 3 weeks or more oral therapy was substituted in 23 patients at a dose of 560 mg/day. Of 23 evaluable patients given the drug by both routes, 17 died after a mean treatment period of 12.5 months and 6 are alive and well after a mean treatment period of 27.7 months. The cause of death in 2 patients was probably, and in a third certainly, due to myocardial infarction. The other 31 deaths were due to carcinoma of the prostate. 18 patients showed transient toxic side-effects. No haematological abnormalities were found during treatment. An attempt at active treatment with estramustine phosphate in patients with prostatic cancer is justified when the disease is resistant to treatment with conventional oestrogens.

Topics: Aged; Carcinoma; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

We treated 21 patients with stage D prostatic adenocarcinoma who had had unsuccessful hormonal therapy with a combination of 600 mg. per M.2 per day estramustine phosphate (Estracyt) and 15 mg. per M.2 per day prednimustine (Stereocyt, Leo 1031) in daily oral doses. Estramustine is a combination of estradiol and nitrogen mustard, and alone has shown objective responses in advanced prostatic cancer. Prednimustine is an ester of chlorambucil and prednisone. The preliminary results (after 2 to 9 months of therapy) show 5 patients (24 per cent) did not benefit from the drug and 7 patients (33 per cent) are stable. These preliminary results indicate the possible advantage of adding an alkylating agent (prednimustine) to estramustine in advanced prostatic carcinoma. Currently, a national randomized trial by the National Prostatic Cancer Project is evaluating this therapeutic innovation.

Topics: Aged; Antineoplastic Agents; Chlorambucil; Drug Therapy, Combination; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prednisolone; Prostatic Neoplasms

Estramustine phosphate is a nitrogen mustard derivative of estradiol that has been advocated for the treatment of prostatic cancer. The compound was designed with the hope that the estrogen moiety would direct the alkylating moiety to estrogen-dependent malignancies, where the alkylating moiety would be released specifically. Preclinical and clinical data are reviewed to determine to what extent that challenging concept is fulfilled. In addition, we have examined critically the efficacy of this drug for the treatment of prostatic cancer. From available data it appears that there is no evidence that the alkylating moiety of estramustine phosphate is specifically freed in estrogen-dependent tissues. Estramustine phosphate appears to be an active compound with acceptable toxicity in prostatic cancer. However, further clinical trials must be undertaken to clarify the future role of estramustine phosphate in the treatment of prostatic cancer.

Topics: Administration, Oral; Drug Evaluation; Estramustine; Humans; Injections, Intravenous; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate, a nor nitrogen mustard derivative of estradiol 17-beta-phosphate, was introduced in the treatment of prostatic carcinoma in 1966. Until March 1975, 466 patients have been reported on this treatment in open clinical trials: 82% of the patients were in stage IV. In 402 patients, nonresponsive to previous estrogen therapy, signigicant improvement occurred in 55%. In 64 previously untreated patients there was a favourable response in 83%. Side-effects were mainly bone marrow suppression. liver disturbance, thrombophlebitis following intravenous injection, and gastrointestinal troubles, mainly following oral administration. A prospective, randomized study comparing oral estramustine phosphate and conventional estrogen therapy in carcinoma of the prostate is in progress.

Topics: Administration, Oral; Bone Marrow; Estramustine; Gastrointestinal Diseases; Humans; Injections, Intravenous; Liver; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Thrombophlebitis

Topics: Bone Marrow; Estramustine; Humans; Leukocytes; Lithium; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estracyt (estramustine phosphate) injected intraperitoneally, 100 mg, per Kg. three days a week for four weeks, retarded growth of the R-3327 tumor in intact rats and in orchiectomized rats given androgen. The growth inhibition was accomplished by reduction of tumor deoxyribonucleic acid concentration and of the activities of acid phosphatase, leucine aminopeptidase, and other hydrolases. Histologic examination revealed cellular necrosis particularly prominent in the orchiectomized, androgen-treated rats. Estracyt did not affect the uptake of 65-Zn in the tumors but markedly reduced the high uptake in the dorsolateral prostate. There was no accumulation of 3H or 14C in the tumors after intravenous administration of 3H, 14C-labeled Estracyt, but the isotope concentrations decreased much in the same way as they decreased in the dorsolateral prostate. The isotopes were retained in the ventral prostate, where their concentrations were approximately twenty times higher than those in the muscle four hours after injection. The results demonstrate the value of the R-3327 tumor in the evaluation of drugs of potential clinical use for the treatment of prostatic cancer. The results also show that Estracyt has an antitumor effect which is not dependent on the antigonadotropic action of the drug.

Topics: Acid Phosphatase; Androgens; Animals; Carbon Radioisotopes; Castration; Depression, Chemical; DNA, Neoplasm; Estramustine; Leucyl Aminopeptidase; Male; Neoplasms, Experimental; Nitrogen Mustard Compounds; Prostatic Neoplasms; Rats; Tritium; Zinc Radioisotopes

Hormone analyses of plasma were done on 9 patients with prostatic carcinoma before, during and after treatment with estramustine phosphate. In previously untreated men estramustine phosphate suppressed the plasma testosterone levels. Furthermore, suppression of increased gonadotropins was obtained in irradiated or orchiectomized patients. These hormone changes were caused by high plasma levels of estradiol and/or total estrogens during treatment, with estramustine phosphate, which were still present 2 to 3 months after discontinuation of the drug. We conclude that estramustine phosphate acts, at least partially, as an estrogen and may cause estrogen-dependent side effects.

Topics: Castration; Chemical Phenomena; Chemistry; Estradiol; Estramustine; Estrogens; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Humans; Hydrocortisone; Luteinizing Hormone; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone

Specific cytoplasmic androgen and estrogen binding has been measured in human benign prostatic hypertrophy and carcinomatous tissue. In vitro support for the binding of estramustine phosphate (Estracyt) to both estradiol- and dihydrotestosterone-binding sites is presented, which in part could explain the clinical effect of estramustine phosphate when pure estrogenic compunds are not effective.

Topics: Androgens; Binding Sites; Cytoplasm; Estradiol; Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Hyperplasia; Prostatic Neoplasms

Topics: Aged; Castration; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Estramustine; Fluorouracil; Flutamide; Humans; Male; Megestrol; Middle Aged; Prostatic Neoplasms; Radiotherapy Dosage; Research; Streptozocin

Histochemical and ultrastructural investigation of the prostate in baboons treated parenterally with saline revealed that the epithelial cells in the caudal prostatic lobe possess very high acid phosphatase activity, moderate nonspecific esterase activity and alkaline phosphatase activity, and little or no amino-peptidase or beta-glucuronidase activity. Only a few lipofuscin granules were found. Ultrastructurally, the epithelial cells had a characteristic polar appearance with a supranuclear zone dominated by large secretory vacuoles. Secretory granules were abundant in the apical zone. No clear difference was found between the cranial and the caudal prostate except that the acid phosphatase activity of the epithelial cells was much lower in the former. In baboons treated with estraumustine phosphate, diethylstilbestrol diphosphate, or with flutamide, i.e., drugs used in the treatment of advanced prostatic carcinoma, the epithelial cells in the caudal prostatic lobe showed a varying degree of atrophy, which was least in the flutamide-treated animals. The histologic changes were accompanied by only minor changes in the enzyme activities, but the number of histochemically demonstrable lipofuscin granules were substantially increased, a finding confirmed by electron microscopy. The drugs did not notably affect the cranial prostate. The findings showed that the caudal, but not the cranial, lobe of the prostate of the baboon resembles the human prostate and can be affected by drugs known to have a desirable effect on the carcinomatous human prostate.

Topics: Acid Phosphatase; Aminopeptidases; Anilides; Animals; Atrophy; Diethylstilbestrol; Epithelial Cells; Epithelium; Estramustine; Flutamide; Glucuronidase; Haplorhini; Humans; Male; Nitrogen Mustard Compounds; Papio; Prostate; Prostatic Neoplasms

40 patients with prostatic carcinoma were treated with parenteral and/or oral Estracyt (estramustine phosphate) until 55 months. Metastases were present in 37 patients (stage D). 35 of the 40 patients developed metastases in spite of estrogen therapy and/or orchidectomy. Diminution of metastasic bone pain as well as improvement of hydroureteronephrosis was frequently observed. Paraplegia secondary to metastatic disease improved in 1 case for 6 months. Side effects were relatively rare and were mainly gastrointestinal. A possible hepatotoxic action of the compound has been pointed out previously. On the basis of our studies Estracyt is recommended in the treatment of primary estrogen resistent prostatic carcinoma and in metastatic carcinoma of the prostate not responding to conventional antiandrogenic therapy anymore.

Topics: Administration, Oral; Aged; Bone Neoplasms; Carcinoma; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; Estramustine; Estrogens; Humans; Injections, Intravenous; Long-Term Care; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Estramustine; Humans; Injections, Intravenous; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estraumustine phosphate (estradiol, 3-N-[bis(2-chloroethyl)-] carbamate-17beta-dihydrogenphosphate (Estracyt) labeled with 3H in the estradiol moiety and 14C in the carbamate moiety was synthesized, and its absorption, metabolism, and excretion were studied after oral administration to three patients with prostatic carcinoma. One of the patients was also given the same dose by intravenous injection. In addition to monitoring isotope levels in peripheral blood, urine, and feces, samples of portal vein blood were obtained through a catheter in the umbilical vein. Analyses of portal blood samples revealed that most of the estramustine phosphate was dephosphorylated to estramustine during absorption. Estramustine was found to be the major metabolite in peripheral blood after oral as well as after intravenous administration. The urinary excretion data appeared to warrent the conclusion that most of the carbamate ester of estraumustine is hydrolyzed before it is excreted. In the patient given estramustine phosphate by both routes the absorption of the compound when given by mouth was found to be approximately 75 per cent.

Topics: Administration, Oral; Animals; Estramustine; Injections, Intravenous; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Acid Phosphatase; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone

Topics: Aged; Estramustine; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Aged; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate has been used as primary treatment in 38 patients with advanced prostatic carcinoma. Of these 38 patients 36 responded objectively to treatment, regression occurring in 10 patients with soft tissue metastases, 3 with pulmonary metastases and 3 with bony metastases. Primary cytotoxic treatment in patients with far advanced prostatic carcinoma is advocated and a randomized clinical study is suggested.

Topics: Aged; Estramustine; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

Topics: Administration, Oral; Aged; Drug Evaluation; Estradiol; Estramustine; Humans; Injections, Intravenous; Male; Mechlorethamine; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

We treated 50 patients with stage D carcinoma of the prostate with 15 mg. per kg. per day oral estramustine phosphate for 3 to 24 months. We are able to evaluate 44 patients. Objective remissions were induced in 8 of the 44 patients (19 per cent) and subjective remission occurred in all objective responders and in 7 additional patients for a subjective response of 15 of 44 (36 per cent). No hematologic or renal toxicity was encountered. Transient nausea occurred early in half of the patients and was dose limiting in 3 patients. One case of hepatic toxicity was seen. Oral estramustine phosphate is well tolerated and long-term therapy is feasible.

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Estramustine; Estrogens; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

Estramustine phosphate has been useful in the treatment of advanced carcinoma of the prostate. Objective remissions were obtained with this therapy in 6 of 17 patients (35 per cent). The results presented herein indicate that the clinical response is to a certain extent caused by an estrogen effect, which was clearly demonstrable in a previously untreated patient. A specific cytostatic effect of estramustine phosphate, which is not yet clearly explained, may be responsible for remissions in some patients who have become resistant to conventional hormonal treatment.

Topics: Aged; Castration; Estramustine; Estrogens; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

The respiration and glycolysis of prostatic tissue from baboons, rhesus monkeys, dogs and rats were compared to the respiration and glycolysis in human prostatic tissue. All the primate prostates had a high glycolytic ability and a low respiration in contrast to the rat and dog prostate. Treatment of baboons with drugs clinically effective against prostatic cancer did not change the prostatic metabolism despite a marked prostatic atrophy. In vitro the drugs reduced respiration markedly. The metabolic similarity between the human and the baboon and rhesus monkey prostate indicates that nonhuman primates should be investigated in the evaluation of chemotherapeutic agents for treatment of prostatic cancer.

Topics: Animals; Diethylstilbestrol; Dogs; Dose-Response Relationship, Drug; Estramustine; Flutamide; Glycolysis; Haplorhini; Humans; In Vitro Techniques; Macaca; Macaca mulatta; Male; Oxygen Consumption; Papio; Prostate; Prostatic Neoplasms; Rats

The chemical ester of a nitrogen mustard with estriol was tested for its antiprostatic effects in dogs and rats. The E33-mustard was shown to interfere with the uptake of labeled estriol in the dog prostate and by the ventral prostate of the rat; and to increase the uptake of the radioactivity associated with testosterone in the dog prostate. The weights of the ventral and dorsolateral prostates of the rat were significantly reduced following the administration of E3-mustard for 2 days. The results are interpreted to be very similar to those obtained with the mustard of E (Estracyt) and the effects are probably a combination of the actions of the released estrogen (D) and/or mustard, either adding individually or in concert.

Topics: Animals; Castration; Dogs; Drug Combinations; Estramustine; Estriol; Male; Nitrogen Mustard Compounds; Organ Size; Prostate; Prostatic Neoplasms; Rats; Testosterone; Tritium

Estramustine phosphate administered orally at 900 mg. daily depressed plasma testosterone levels in 10 consecutive patients who had previously been treated with estrogen hormones and/or orchiectomy and who were all in relapse from carcinoma of the prostate. Approximately one half of the patients responded to the treatment clinically. The decrease in plasma testosterone did not correlate with the clinical response. The clinical effect of estramustine phosphate may be due to decreased plasma testosterone levels, inhibiton of 5-alpha reductase activity, and a local cytotoxic effect.

Topics: Aged; Depression, Chemical; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms; Testosterone

Plasma transcortin and cortisol levels, which are significantly elevated by estrogens, were determinied in a group of patients with prostatic cancer who were on estramustine phosphate (Estracyt) therapy. In a series of 44 male patients studied transcortin and corticol levels became elevated above normal and were maintained at these high levels as long as the patients were on estramustine phosphate therapy. The levels observed in this study may serve as reliable indices to monitor patients who are on this drug.

Topics: Diethylstilbestrol; Estramustine; Feminization; Humans; Hydrocortisone; Male; Models, Biological; Nausea; Nitrogen Mustard Compounds; Prostatic Neoplasms; Transcortin

The quotient between the activities of acid phosphatase and beta-glucuronidase in biopsy specimens of malignant prostatic tissue varied among 11 patients with reactivated, estrogen-resistant prostatic carcinoma. No correlation was found between the quotient and the therapeutic response to estramustine phosphate. In biopsy specimens obtained after 2 months' treatment, the quotient was lower in those patients who responded to the treatment. Thus, the quotient before treatment is of no prognostic use but diminution of the quotient found after treatment for 2 months is a sign of good clinical effect of the therapy.

Topics: Acid Phosphatase; Estramustine; Glucuronidase; Humans; Male; Prostate; Prostatic Neoplasms

3 therapeutic regimens for cancer of the prostate were evaluated in 24 patients. The patients received either 160 mg/month intramuscularly of polyestradiol phosphate (PEP; Estradurin), PEP plus 150 mcg/day ethinyl estradiol (PEP + EE), or 600 mg/day of estramustine phosphate (EMP; Estracyt). On the basis of 5-year survival rates, PEP + EE was found to be superior to PEP alone, while EMP could not be properly evaluated. Nonetheless, it appears that EMP may be valuable in advanced cases that are unresponsive to other estrogen therapies. As determined by their inhibitory effect on levels of circulating gonadotropins, circulating steroid levels and plasma prolactin and cortisol levels, EMP and PEP + EE exhibited stronger estrogenic effects than PEP alone, with EMP showing the greatest potency.

Topics: Aged; Androgens; Drug Synergism; Estradiol; Estramustine; Estrogens; Ethinyl Estradiol; Gonadotropins, Pituitary; Humans; Hydrocortisone; Male; Middle Aged; Nitrogen Mustard Compounds; Organophosphorus Compounds; Polymers; Prostatic Neoplasms