estramustine and Adenocarcinoma

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

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

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

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

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

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

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

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

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

Topics: Adenocarcinoma; Androgens; Animals; Carrier Proteins; Estramustine; Estrogens; Female; Humans; Islets of Langerhans; Male; Pancreas; Pancreatic Neoplasms; Prostatic Secretory Proteins; Rats; Receptors, Estrogen

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

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

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 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

Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC).. Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles.. Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen.. Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Drug Administration Schedule; Estramustine; Female; Humans; Microtubules; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival; Taxoids; Treatment Outcome; Venous Thrombosis

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

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

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

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

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

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

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

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 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

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

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

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 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

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

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

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

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: 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Estra-1,3,5 (10)-triene-3,17-diol (17 beta)-, 3-[bis(2-chloroethyl) carbamate] (Estramustine EM) was tested for its anticancer effect on human endometrial cancer cell lines: Ishikawa and its estrogen (E) independent sub-clone EIIL (Estrogen Independent Ishikawa Line). The results showed: (1) EM inhibited growth of both cell lines in a dose dependent manner giving ID50 for Ishikawa as 12 microM and for EIIL as 65 microM. (2) The addition of EM to the culture medium caused cell detachment and death associated with a breakdown of DNA to approximately 90 base pair fragments. (3) Reverse transcription-polymerase chain reaction to examine expressions of c-erbB-2, nidogen and fas showed that EM completely abolished fas expression and resulted in a 40% decrease in nidogen expression in Ishikawa but not in EIIL. No change was seen in c-erbB-2 expression. The present data indicate that the E component of EM does not stimulate the growth of Ishikawa or EIIL. Since the growth of both cell lines was inhibited but apparently in an E receptor (ER) dependent manner, EM may be of value in an adjuvant therapy for endometrial cancer, especially an ER positive one.

Topics: Adenocarcinoma; Cell Division; DNA Damage; DNA, Neoplasm; Endometrial Neoplasms; Estramustine; Female; Humans; Molecular Sequence Data; Polymerase Chain Reaction; Receptor, ErbB-2; Tumor Cells, Cultured

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: Adenocarcinoma; Antineoplastic Agents, Hormonal; Estramustine; Female; Humans; Injections, Intralymphatic; Lymphatic Metastasis; Middle Aged; Uterine Neoplasms

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

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

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

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

The effects of Estracyt, a Nitrogen mustard (HN2) derivative of estradiol-17 beta versus the free HN2 on cell kinetics of the estrogen receptor positive human endometrial cancer cell line HEC-1 were investigated using flow cytometry. The results were as follows. The cell killing effects of Estracyt existed in a dependency on dose and time, whereas those of HN2 were dependent on dose alone. HN2 at 1 microgram/ml showed a marked increase in S phase and decrease in G0+1 phase. However, with equivalent doses of Estracyt at 10 micrograms/ml, even more remarkable was the accumulation in the G2+M phase. Synchronization at S phase with MTX showed no increase in sensitivity to these drugs on cells in S phase. Based on the above results, it was suggested that the free HN2 had an affect regardless of the cell cycle phase, whereas the effects of Estracyt corresponded to the cell cycle phase and Estracyt might have a fixed population of non-target cells existing in the G0+1 and S phase. Synchronization in the G1 phase with Sodium n-butylate could increase the target effects of Estracyt in S phase.

Topics: Adenocarcinoma; Cell Cycle; DNA, Neoplasm; Estramustine; Female; Flow Cytometry; Humans; In Vitro Techniques; Interphase; Nitrogen Mustard Compounds; Uterine 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

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

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: Adenocarcinoma; Administration, Oral; Estramustine; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms

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

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

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

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

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

Topics: Adenocarcinoma; Aged; Estramustine; Humans; Male; Neoplasm Metastasis; Nitrogen Mustard Compounds; Prostatic Neoplasms

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