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PubMed1994

The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study.

57 patients with advanced prostate cancer and a failure of prior hormonal treatment were selected for a double-blind placebo-controlled trial, in which they were randomly allocated to receive either clodronate (C) or placebo concomitantly with the basic cancer treatment, estramustine phosphate (E) (560 mg daily). The treatment was started intravenously with 300 mg of C or placebo in 5 consecutive days, and thereafter maintained orally with 1600 mg of C or identical placebo daily for 3 months. Bone biopsies were taken at admission and at 3 months. Measurements of serum calcium, phosphate, alkaline phosphatase, prostate-specific antigen and creatinine were made at the time of both bone biopsies and at 1 month. Serum intact parathyroid hormone and vitamin D metabolites were measured at admission and at 3 months. Because of several discontinuations, the study groups at final analysis comprised 20 patients taking E + C and 19 patients taking E and placebo. Bone resorption, as judged by eroded surface and osteoclast number, was markedly increased especially in biopsies taken from tumour-involved bone. Treatments with E + C or E both induced a significant decrease in bone resorption, but were associated with the development of hypocalcaemia, secondary hypoparathyroidism, hypophosphataemia and severe impairment of mineralisation of newly formed bone, i.e. osteomalacia. Since the patients were not vitamin D deficient, we conclude that osteomalacia resulted from a relative deficiency of calcium and phosphate. The transiency of pain relief achieved with anti-resorptive agents in the treatment of bone metastases from prostate cancer may be due to the development of osteomalacia.

Aged↗
PubMed2004

Oral low-dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC).

The chemotherapeutic approach to hormone-refractory metastatic prostate cancer (MHRPC) for a long time included only estramustine. Then, attempts have been made with other various agents as cyclophosphamide, vinblastine, etoposide, taxanes and carboplatinum. Although the new drugs and combinations have increased the response rate of MHRPC, they have had no impact on the natural history of MHRPC, which is about 1 year as median time of survival. After an occasional observation of prolonged response in a patient with MHRPC treated with a very well tolerated oral low-dose of cyclophosphamide, from February 1996 to October 2002, seven more patients with MHRPC and progressive disease were consecutively recruited. Response to treatment was evaluated by conventional radiological procedures and/or serial serum PSA measurements. The decline of PSA value was considered to assess the response consistent with the response guidelines from the prostate specific antigen-working group. All eight studied patients continuously received oral low dose cyclophosphamide until progression or the occurrence of significant toxicity. So far three patients (37.5%) progressed (PD), two (25%) showed PR and the three remaining SD. Response rate was 25%, and clinical benefit occurred in 62.5% of the studied patients. In the five patients with clinical benefit on cyclophosphamide median duration of clinical benefit, PR and SD were 9, 24+ and 8 months, respectively. In these five patients median overall survival times from cyclophosphamide and from the first regimen of chemotherapy were 17 and 33+ months respectively, while in the three patients with PD they were 4 and 13 months. The same interval times in patients with > or =50% decline of serum PSA were 29 and 50.5 months, while in those with <50% decline of the same marker, they were 13 and 32 months, respectively. Grade 2 or 3 neutropenia were observed in all the studied patients. In four (50%) of them pulmonary and urinary infections that were easily cured by the common antibiotics occurred. These data suggest that the metronomic use of cyclophosphamide, given alone, has similar or higher activity with lower toxicity than when administered with other active drugs. So it can be an useful option before or after the use of other single or combined potentially active chemotherapeutic agents.

Administration, Oral↗
PubMed2006

The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking.

ATP-binding cassette (ABC) transporters are a family of proteins that translocate molecules across cellular membranes. Substrates can include lipids, cholesterol and drugs. Mutations in ABC transporter genes can cause human pathologies and drug resistance phenotypes in cancer cells. ABCA2, the second member the A sub-family to be identified, was found at high levels in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine (EM). In vitro models with elevated levels of ABCA2 are resistant to a variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane) (AAPH). ABCA2 is most abundant in the central nervous system (CNS), ovary and macrophages. Enhanced expression of ABCA2 and related proteins, including ABCA1, ABCA4 and ABCA7, is found in human macrophages upon bolus cholesterol treatment. ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and is coordinately expressed with genes involved in cholesterol homeostasis. Additionally, ABCA2 expression has been linked with gene cluster patterns consistent with pathologies including Alzheimer's disease (AD). A single-nucleotide polymorphism (SNP) in exon 14 of the ABCA2 gene was shown to be linked to early onset AD in humans, supporting the observation that ABCA2 expression influences levels of beta-amyloid peptide (Abeta), the primary component of senile plaques. ABCA2 may play a role in cholesterol transport and affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.

ATP-Binding Cassette Transporters↗
PubMed2004

Management of patients with hormone refractory prostate cancer.

Prostate cancer is the second most common cancer in men in the UK, and the incidence of prostate cancer has increased dramatically over the past two decades. Although most men are diagnosed at early stage, more than 50% develop locally advanced or metastatic disease. Androgen ablation with luteinising hormone-releasing hormone (LHRH) agonists alone, or in combination with anti-androgens, is the standard treatment for men with metastatic prostate cancer. Unfortunately, almost all men develop progressive disease after a variable time period, despite the maximal androgen blockade. The management of hormone refractory prostate cancer (HRPC) is challenging, as there is no uniformly accepted strategy. Various treatment options, including second-line hormone therapy, are discussed. Chemotherapy is being increasingly used and, importantly, docetaxel and estramustine may play an important role in the near future. The role of radiotherapy, strontium-89, bisphosphonates, novel agents and future therapies are also outlined.

Antineoplastic Agents↗
PubMed2006

Current indications for chemotherapy in prostate cancer patients.

Recently, data from two randomized studies, TAX327 and SWOG 9916, which compared docetaxel-based chemotherapy to mitoxantrone-based therapy, have demonstrated that treatment with docetaxel can prolong life in a statistically significant way in patients with hormone refractory prostate cancer (HRPC). In the TAX237 trial the median overall survival rates for patients treated with docetaxel every 3 wk was 18.9 mo, compared with 16.4 mo for the patients in the control arm (p=0.009). Patients treated with the combination of docetaxel and estramustine in the SWOG trial had a significant improvement in median survival (18 mo vs 16 mo, p=0.01), longer progression-free survival (6 mo compared with 3 mo, p<0.0001), and a 20% reduction in the risk of death. The optimal timing of docetaxel-based chemotherapy is still unknown because there are no prospective clinical trials indicating whether earlier treatment is more effective than delayed treatment. There are now increasing options also for second-line therapies in the palliative treatment of HRPC, and ongoing studies on new drugs such as satraplatin and ixabepilone will define the role of these agents in this setting. Preliminary neoadjuvant and adjuvant chemotherapy studies in high-risk prostate cancer patients have demonstrated that these approaches are feasible and do not add morbidity to surgery or radiotherapy, but their impact on survival still needs to be proven in randomized studies.

Antineoplastic Agents↗
PubMed2006

The case for early chemotherapy for the treatment of metastatic disease.

PURPOSE: Several important questions are raised by the data from Southwest Oncology Group 99-16 and TAX 327. What is the optimal timing of chemotherapy for metastatic hormone refractory prostate cancer? Should asymptomatic patients be treated? Is there a theoretical survival advantage for treatment for hormone sensitive prostate cancer? We reviewed arguments for the early use of docetaxel in the hormone sensitive and hormone naïve disease states. MATERIALS AND METHODS: Androgen independent prostate cancer was traditionally viewed as a chemoresistant disease. At best palliation of bone pain but not improved survival could be achieved with the combination of mitoxantrone and prednisone. Median survival rates for chemotherapy in this disease state were reported to be between 10 and 12 months. Phase II studies administering docetaxel weekly or every 3 weeks as a single agent or in combination with estramustine demonstrated median survival rates of 14 to 23 months, which appeared to be an improvement over standard therapy. Consequently the 2 randomized trials, Southwest Oncology Group 99-16 and TAX 327, were designed to confirm the preliminary observations of improved survival with docetaxel based therapy. RESULTS: TAX 327 and Southwest Oncology Group 99-16 treated asymptomatic as well as symptomatic patients. Thus, in contrast with mitoxantrone/prednisone, which was approved in symptomatic men with hormone refractory prostate cancer, the exact timing of the initiation of chemotherapy in docetaxel treated patients is still the subject of debate. CONCLUSIONS: Studies should be performed to investigate the optimal timing of chemotherapy as well as sequencing with androgen ablation in patients at high risk for progression and death from metastatic prostate cancer. Prognostic factors for death that have been identified in patients with androgen independent prostate cancer are hemoglobin, alkaline phosphatase, visceral disease and performance status.

Antineoplastic Agents↗
PubMed2005

Docetaxel-based chemotherapy as second-line treatment for paclitaxel-based chemotherapy-resistant hormone-refractory prostate cancer: a pilot study.

OBJECTIVES: To examine docetaxel (DTX)-based chemotherapy in paclitaxel (PTX)-based chemotherapy-resistant hormone-refractory prostate cancer (HRPC) to investigate the activity and degree of toxicity in a pilot study. We have previously reported on the effectiveness of combination chemotherapy with PTX, estramustine (EMP), and carboplatin against HRPC. Although many patients with HRPC initially responded to this PTX/EMP-based combination chemotherapy, most finally progressed to PTX-resistant status within a mean of less than 1 year. DTX is an inhibitor of microtubule depolymerization like PTX and has demonstrated activity against PTX-resistant metastatic tumors. METHODS: The subjects were 15 patients with HRPC who displayed disease progression while receiving PTX/EMP/carboplatin combination chemotherapy. The patients were treated with intravenous DTX 30 mg/m2 weekly, oral EMP 10 mg/kg daily, and intravenous carboplatin (dosed 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. RESULTS: Each patient received a median of eight consecutive cycles. The prostate-specific antigen level decreased by 50% or more in 33.3% of patients and by 90% or more in 13.3%. The median follow-up was 49.6 weeks, with median time to progression of 25.0 weeks and median overall survival of 54.0 weeks. One patient died of interstitial pneumonitis. One patient developed secondary osteomyelodysplastic syndrome. The major severe toxicities were grade 3 or 4 anemia in 66.7% of patients, leukopenia in 26.7%, and thrombocytopenia in 40.0%. CONCLUSIONS: The results of our study have shown that DTX is comparatively active for heavily pretreated patients with PTX-resistant HRPC. However, given the significant toxicities and small subject population, well-designed Phase I-II trials of the improved regimen are warranted.

Adenocarcinoma↗
PubMed1998

Lipophilin, a novel heterodimeric protein of human tears.

We identified a novel heterodimeric protein, lipophilin AC, in human tears. One of its components, lipophilin A (69 residues; mass, 7575.1; pI, 9.47) was homologous to the C1 and C2 components of prostatein ('estramustine-binding protein'), the major secreted protein of rat prostate. Human lipophilin C (77 residues; mass, 8854.1; pI, 4.94) was homologous to the rat prostatein C3 component and to human mammaglobin, a protein overexpressed in some mammary carcinomas. Tear lipophilins A and C expand the roster of human uteroglobin superfamily members and provide models for exploring these typically steroid-regulated and steroid-binding molecules.

Amino Acid Sequence↗
PubMed2001

Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report.

Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing.

Adenocarcinoma↗
PubMed2001

Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.

BACKGROUND: Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. METHODS: 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. FINDINGS: Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29). INTERPRETATION: Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Adult↗
PubMed2003

Current strategies in the management of hormone refractory prostate cancer.

Prostate cancer is the most common cancer diagnosed in American males, and is the second leading cause of cancer-related deaths. Most patients who develop metastatic disease will initially respond to androgen deprivation, but response is invariably temporary. Most patients will develop androgen-independent ("hormone-refractory") disease that results in progressive clinical deterioration and ultimately death. This progression to androgen independence is accompanied by increasingly evident DNA instability and alterations in genes and gene expression, including mutations in p53, over-expression of Bcl2, and mutations in the androgen receptor gene, among others. Treatment options for hormone refractory disease include intensive supportive care, radiotherapy, bisphosphonates, second-line hormonal manipulations, cytotoxic chemotherapy and investigational agents. A post-treatment reduction in the level of prostate specific antigen (PSA) by 50% has been shown to correlate with survival and has been accepted by consensus as a valid endpoint in clinical trials. Chemotherapeutic agents such as mitoxantrone, estramustine, and the taxanes have yielded improved response rates and palliative benefit, but not improved survival. Therefore, current efforts must be focused on enrolling patients onto clinical trials of investigational agents with novel mechanisms of action, and on using survival, time to progression, and quality of life as end points in routine clinical practice.

Antineoplastic Agents↗
PubMed1997

Evolving strategies of cytotoxic chemotherapy for advanced prostate cancer.

Despite the use of cytotoxic chemotherapy for advanced prostate cancer for half a century, its clinical utility in this setting remains undefined. Based on traditional methods of assessment, the list of the most active cytotoxic agents includes cyclophosphamide, doxorubicin, mitoxantrone and cisplatin. With the introduction of more structured methods of assessment, including careful assessment of indices of quality of life and serial measurement of serum prostate-specific antigen (PSA), the role of cytotoxic agents is being re-assessed. In view of the cell cycle characteristics of prostate cancer, there appears to be an emerging role for combination inhibitors of mitosis, including estramustine in combination with the vinca alkaloids, etoposide or paclitaxel.

Antineoplastic Agents↗
PubMed2005

Docetaxel for treatment of solid tumours: a systematic review of clinical data.

Docetaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilising microtubules and inducing cell-cycle arrest and apoptosis. Docetaxel was first approved for the treatment of anthracycline-refractory metastatic breast cancer in the mid-1990s. Since then, several randomised trials have reported improved time-to-progression, overall survival, or both in metastatic breast cancer treated with single-agent docetaxel or docetaxel-based combination regimens. Data from two adjuvant trials have shown a survival benefit with the addition of docetaxel to standard anthracycline-based regimens in patients with high-risk early breast cancer. In four randomised studies, docetaxel improved survival in locally advanced or metastatic non-small-cell lung cancer. Moreover, two trials have shown that docetaxel combined with estramustine or corticosteroids improves survival in metastatic androgen-independent prostate cancer. Here, we review major randomised phase III trials with docetaxel in the treatment of solid malignant disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Chemotherapy in advanced androgen-independent prostate cancer 1990-1999: a decade of progress?

BACKGROUND AND PURPOSE: A great number of clinical research studies have been reported in the field of chemotherapy for advanced androgen-independent prostate cancer during the last ten years. The aims of the present review were to assess their impact on management of the disease and on survival of patients. METHODS: The review of full published reports was facilited by the use of a MEDLINE computer search. RESULTS: Clinical research studies have focused on defining guidelines for eligibility criteria and accurate endpoints for patients to be enrolled onto clinical trials and developing new agents or combination of drugs including estramustine phosphate. Any combination of current chemotherapy has no impact on overall survival of patients. Among drugs in development, only the promising activity observed with docetaxel deserves randomized trials to assess its impact on survival. The major innovative advance of the 90s is the demonstration of the impact of chemotherapy (mitoxantrone + prednisone) on quality of life as compared to prednisone alone. A greater and longer-lasting improvement in quality of life along with a concomitant decrease in costs was observed. CONCLUSIONS: At the present time, chemotherapy should be considered as a palliative treatment in patients with symptomatic androgen-independent disease. The enrollment of patients into clinical trials dealing with quality of life as primary endpoint is strongly solicited. A standard methodology should be used in phase II trials with a primary goal of selection of agents which should progress to randomized trials using survival as an endpoint. Hopefully new specific strategies targeted to reverse the molecular changes that underlie prostate tumorigenesis should rapidly impact the multimodality management of AIPC in the third millenium.

Antineoplastic Agents, Hormonal↗
PubMed1997

Concomitant i.v. and oral clodronate in the relief of bone pain--a double-blind placebo-controlled study in patients with prostate cancer.

Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally randomized for treatment with clodronate or placebo. Clodronate treatment was started with 5 days intravenous administration (300 mg day[-1]) and followed by oral treatment (1.6 g day[-1]) for 12 months. Skeletal pain relief was only about 10% better in the clodronate than in the placebo group. The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only.

Administration, Oral↗
PubMed2005

Drug insight: Use of docetaxel in prostate and urothelial cancers.

Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies, with two taxanes now in clinical use. Their mechanism of action against tumor cells is by alteration of microtubule dynamics, which causes cell-cycle arrest during mitosis. Docetaxel binds to the microtubules with a higher affinity than paclitaxel, and over a broader range of cell-cycle activities. It has also been shown to promote apoptosis via BCL2 phosphorylation. In hormone-refractory prostate cancer, docetaxel has been studied as both a single agent and in combination with estramustine, and in different treatment schedules, with demonstrated efficacy. Two phase III trials have confirmed a survival benefit, making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer. In urothelial cancer, docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens. A phase III trial comparing docetaxel and cisplatin to methotrexate, vinblastine, doxorubicin, and cisplatin was inferior when evaluating response rates and overall survival. More recent phase II trials combining docetaxel with two additional agents have shown promise, but confirmatory trials are needed.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles.

Caspase-cleaved proteins are released from disintegrated apoptotic cells and can be detected in the circulation. We here addressed whether caspase-cleaved cytokeratin 18 (CK18-Asp396) can be used as a serum biomarker for assessment of the clinical efficiency of chemotherapy in hormone-refractory prostate cancer (HRPC). A total of 82 patients with HRPC were evaluated during 751 treatment cycles, either with estramustine (EMP)/vinorelbine or with EMP/docetaxel. The levels of CK18-Asp396 and of total CK18 were measured in patient serum before and during therapy by ELISA. Docetaxel induced significant increases in serum CK18-Asp396 (P<0.0001) and total CK18 (P<0.0002), suggesting induction of apoptosis. Similarly, vinorelbine induced increases in both CK18-Asp396 and CK18 (P<0.001 and 0.011). In contrast, EMP induced increases in total serum CK18 (P<0.0001), but not in CK18-Asp396 (P=0.13). The amplitudes of docetaxel-induced increases were associated with baseline prostate-specific antigen (PSA) and CK18 serum levels in these patients, consistent with tumoral origin of caspase-cleaved fragments. Docetaxel induced significant increases in CK18-Asp396 during second-, third- and fourth-line therapy and induced increased levels of CK18-Asp396 during treatment cycles 1-8. In contrast, vinorelbine induced significant increases only during cycles 1-3. In a subgroup of 32 patients that received EMP/vinorelbine in second line followed by EMP/docetaxel in third line, docetaxel induced stronger increases than vinorelbine (P=0.008). These results show that the CK18-Asp396 serum marker can be used to assess tumour apoptosis in vivo and suggest that the clinical efficiency of docetaxel in HRPC is due to induction of apoptosis during multiple treatment cycles.

Aged↗
PubMed2006

A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer.

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone.

Antineoplastic Agents, Hormonal↗