Treatment Of Hormone-refractory Prostate Cancer Research Articles

Is there a standard chemotherapeutic regimen for hormone-refractory prostate cancer? Present and future approaches in the management of the disease.

Prostate cancer that no longer responds to hormonal manipulation can be defined as hormone-refractory prostate cancer. Until recently, there has been no standard chemotherapeutic approach for hormone-refractory prostate cancer. The major benefits of chemotherapy in the treatment of the disease are palliative in nature, in terms of reduction of pain and use of analgesics and improvement of performance status, as followed in the most recent trials. Phase III studies are necessary to better evaluate the efficacy of the different regimens, because several old studies suffer for methodological deficits. There is a promising activity of new drug combinations, such as vinca alkaloids and taxanes. Phase I and II trial are testing combinations of classic chemotherapeutic agents and biologic drugs, and the first results appear interesting. In this article, recent advances in the treatment of hormone-refractory prostate cancer using chemotherapeutic regimens are critically reviewed.

Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells.

Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.

Current Topics in the Treatment of Hormone-Refractory Prostate Cancer

Following endocrine therapy, progression to a hormone-refractory state is inevitable in patients with locally advanced or metastatic prostate cancer, if they survive competing mortality. Current treatment options are essentially palliative, with the aim of maintaining quality of life and prolonging survival. Following the failure of primary androgen ablation, a number of treatment strategies are available. Exploitation of the anti-androgen withdrawal syndrome and further hormonal therapies are well-established treatments. More recently, interest in chemotherapy has been renewed owing to demonstrable benefits in prostate specific antigen (PSA) response and pain palliation, albeit without any improvements in survival. However, future treatment options that can prolong survival and maintain quality of life for patients with hormone-refractory prostate cancer (HRPC) are constantly being sought. An increased understanding of the molecular biology of prostate cancer has led to the identification of novel targets and agents. The evaluation of these, and possible addition of them to our armamentarium against prostate cancer, is the goal of ongoing clinical trials.

The Role of Endothelin in Hormone-Refractory Prostate Cancer

Aggressive chemotherapy has made only a limited contribution to improvements in patient prognosis and well-being in hormone-refractory prostate cancer (HRPC). Such poor progress results from the biological basis of the disease, localisation of the tumour and the relatively high age of affected men, and leaves patients with a dismal prognosis. Given the palliative role of current treatments, attention has focused on the development of therapies targeted at non-androgenic mediators of prostate growth. Endothelin-1 (ET-1), a 21-amino-acid peptide produced by endothelial cells and prevalent in seminal fluid, has been identified as one such mediator. In addition to its potent mitogenic and vasoconstrictive properties, ET-1 has been shown to suppress apoptosis and induce angiogenesis. In HRPC cells, increased levels of ET-1 have been observed. ET-1 mediates its effects through two receptors, of which the endothelin-A (ET A) receptor is most important in prostate cancer. An up-regulation of ET A receptor levels and decreased expression of endothelin-B (ET B) receptors is observed in HRPC cells. Taken together, these factors are thought to play a significant role in the progression of the disease. Research has, therefore, focused on development of ET-1 antagonists to disrupt the mitogenic and angiogenic effects of ET-1 and slow disease progression. As ET-1 is also an important factor in the development of new bone, ET-1 antagonists may potentially inhibit the development of skeletal metastases and associated pain, which characterise this disease. Atrasentan, a highly specific ET A receptor antagonist, is currently in clinical development. Data are awaited from clinical trials to confirm the role of this agent in the treatment of HRPC.

Pharmacotherapy of hormone refractory prostate cancer: new developments and challenges

Hormone refractory prostate cancer (HRPC) remains a challenge in the management of prostate cancer patients. With the widespread use of PSA (prostate specific antigen), recurrent disease after local treatment for localised prostate cancer is usually diagnosed long before evidence of metastatic disease. In many cases, hormonal manipulations are started at the time of biochemical relapse and therefore, patients become ‘hormone refractory’ earlier in the course of their disease, frequently with a good performance status, often with no evidence of metastatic disease, and they still face a considerably long life expectancy. Despite these changes, the need for more options in the treatment of HRPC is obvious. The pharmacological treatments that are in use and those that are under investigation for this group of patients will be discussed and include: cytotoxic agents including the microtubule inhibitors, alone and in combination with other conventional or experimental therapies such as calcitriol or thalidomide; treatment with epothilone analogues; endothelin receptor antagonists; palliative therapy with bisphosphonates, bone-targeted radiopharmaceuticals and other developing treatments such as vaccines, gene therapies and monoclonal antibodies.

TNP-470 combined with nicardipine suppresses in vivo growth of PC-3, a human prostate cancer cell line

We examined effects of TNP-470 with or without nicardipine on in vivo or in vitro growth of a hormone-independent human prostate carcinoma cell line, PC-3. TNP-470 (30 mg/kg, daily) or nicardipine (25 μg/kg, daily) alone had little effects on in vivo growth of PC-3 cells in nude mice, whereas simultaneous administration of both agents significantly inhibited the growth of the xenografts. In vitro proliferarion of PC-3 was not affected by TNP-470 and/or nicardipin. Combination of TNP-470 and nicardipine seems beneficial in the treatment of hormone-refractory prostate cancer.

Synergistic and antagonistic combinations of drugs in human prostate cancer cell lines in vitro.

Microtubulin binding agents such as docetaxel have significant preclinical and clinical activity in the treatment of hormone-refractory prostate cancer. We have previously used median-effect analysis to define both synergistic and antagonistic drug combinations which may be of value in management of human disease. These studies extend our findings in defined prostate cancer cell lines. A semi-automated microtiter culture system was used. Docetaxel was combined with 18 other agents, incubated with DU 145, LnCaP or PC 3 prostate cancer cell lines for 72 h and the cells then incubated with MTT to determine cytotoxic effect. Both doublet and triplet combinations were examined. Synergy and antagonism as measured by the combination index were determined for each combination. The non-mutually exclusive criterion was applied. Docetaxel demonstrated cytotoxic additive effects or synergy with -retinoic acid, cyclosporin A and vinorelbine in all three cell lines. Docetaxel combined with either epirubicin or doxorubicin displayed cytotoxic synergistic effects in hormone-refractory DU 145 and PC 3 cell lines. In contrast, drugs which have been combined clinically to treat hormone-refractory prostate cancer, i.e. cisplatin, carboplatin or etoposide, were antagonistic when combined with docetaxel. We conclude that combinations of docetaxel with either -retinoic acid or vinorelbine may offer an enhanced cytotoxic effect in the management of hormone-refractory prostate cancer and need to be evaluated for therapeutic effect. The combination of docetaxel with an anthracycline was also synergistic in the two hormone-refractory cell lines, DU 145 and PC3, thus suggesting a potential role in advanced disease after endocrine failure. Combinations of docetaxel with platinum or etoposide may lead to subadditive effects in treatment.

Prostate-specific antigen in prostate cancer: A case study in the development of a tumor marker to monitor recurrence and assess response

The serum marker known as prostate-specific antigen (PSA) has established itself as the most important tool for the early detection of prostate cancer. However, more recent data indicate that (post-treatment) PSA and PSA kinetics can be used to predict the outcome of a variety of therapeutic interventions including radical prostatectomy, radiation therapy, androgen deprivation, and treatment of hormone-refractory prostate cancer. PSA recurrence after radiation therapy is now accepted as a harbinger of developing metastatic disease. The American Society for Therapeutic Radiation Oncology (ASTRO) consensus definition is the most widely accepted definition of failure after radiation therapy. Rather than using a specific PSA cutoff, three consecutive PSA rises was felt to be a more reliable indicator of biochemical failure. The PSA nadir (the lowest PSA level achieved after therapeutic intervention) also appears to correlate with the likelihood of remaining disease-free. Similarly, a rapid doubling time is a significant predictor of developing distant metastases. The most appropriate definition for biochemical (PSA) failure following radical prostatectomy is usually considered to be a non-zero value. As is the case after radiotherapy, there appears to be a relationship between the rate of rise of the PSA and the risk of distant failure following radical prostatectomy. In patients with metastatic disease, multiple studies appear to indicate that a fall in PSA, however measured, appears to be predictive of improved outcome in prostate cancer patients treated with androgen deprivation. Multiple reports of trials in the treatment of hormone-refractory prostate cancer (HRPC) appear to substantiate the observation that patients who have a greater than 50% decline in PSA have an improved survival. Correlation of PSA declines with other markers of clinical benefit, including clinically significant “subjective” end points such as pain control, have strengthened the argument that a PSA decline can serve as an intermediate endpoint in clinical trials involving HRPC patients. Semin Oncol 29:264-273. Copyright 2002, Elsevier Science (USA). All rights reserved.

Liposomal Doxorubicin for the Treatment of Hormone-Refractory Prostate Cancer

There is a pressing need for new agents to treat hormone-refractory prostate cancer (HRPC). Doxorubicin has shown modest activity in this setting, but its use is limited by its toxicities. Liposomal encapsulation of doxorubicin appears to promote enhanced tumor accumulation in some tumor types, and toxicity appears to be reduced. A phase II trial of liposomal doxorubicin was therefore conducted in patients with HRPC. Fourteen patients with progressive HRPC were treated. For the first dose only, patients were randomized to receive either doxorubicin 50 mg/m2 or liposomal doxorubicin 50 mg/m2 in order to evaluate exploratory pharmacokinetics. For all subsequent cycles, all patients received liposomal doxorubicin 50 mg/m2. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. All 14 patients were evaluable for response and toxicity. Two patients (14%) had declines in serum PSA of ≥ 50%. The first patient had a baseline PSA of 34.7 ng/mL and a nadir of 17.0 ng/mL. The second patient had a baseline PSA of 5580.0 ng/mL and a nadir of 200.7 ng/mL. The latter of these 2 patients had an unambiguous improvement in bone scan and a reduction in pain. Treatment was well tolerated overall. One patient was removed from treatment after the development of a grade 3 infusion reaction with the first cycle of liposomal doxorubicin. Neutropenia was the most common toxicity; in only 1 case was it grade 3, and no cases of grade 4 were seen. Doxorubicin plasma concentrations were best fit by a linear, two-compartment model. Liposomal doxorubicin plasma concentrations were best fit by a linear, one-compartment model. Treatment with liposomal doxorubicin was well tolerated overall. While monotherapy with liposomal doxorubicin has only modest activity in the treatment of HRPC, it may be of interest to study this agent as part of combination chemotherapy.

Chemotherapy for the Treatment of Hormone-Refractory Prostate Cancer

Men with metastatic prostate cancer treated with androgen ablation therapy respond rapidly and often dramatically, with improvement in bone pain, regression of soft tissue metastases, and decreases in serum prostate-specific antigen (PSA) levels. Unfortunately, few treatment options are available to men with advanced prostate cancer in whom disease progresses after hormonal therapy. The combination of mitoxantrone with a corticosteroid is effective palliative therapy for bone pain; however, it is not associated with an improvement in overall survival. Recent studies have focused on the proteins that regulate apoptosis as a target for the treatment of hormone-refractory prostate cancer (HRPC). Agents that inhibit microtubule-associated proteins, such as estramustine, and agents known to phosphorylate Bcl-2, such as the taxanes, demonstrate high activity in HRPC. Estramustine-based regimens are commonly used for the treatment of men with HRPC. Results of phases I and II clinical trials evaluating the taxanes as single agents and combined with estramustine have demonstrated significant activity in terms of response rate, decrease in PSA level, and improvement of bone pain. Moreover, although completion of phase III trials is awaited, survival data with estramustine-taxane combinations appear promising in phase II trials.

The treatment challenge of hormone-refractory prostate cancer.

Both the demographics and treatment of hormone-refractory prostate cancer (HRPC) are changing. Patients are younger and healthier, with fewer comorbidities. The "no treatment until symptoms" approach is disappearing. Chemotherapy is increasingly being utilized. The authors review the steps involved in hormone management before chemotherapy is considered. The roles for chemotherapy in current clinical trials are examined. Effective hormonal management of the prostate cancer patient incorporates an understanding of the stages of hormone sensitivity and prescribing additional interventions beyond simple castration. Once hormone refractoriness is established, the combination of mitoxantrone and prednisone has become a standard chemotherapeutic approach. New agents such as docetaxel are being tested in phase III trials against mitoxantrone plus prednisone. HRPC is now regarded as a chemotherapy-sensitive tumor. The goals of chemotherapy in HRPC are to decrease PSA level and improve quality of life. New agents and combinations are needed to improve survival.

Oncologists' perceptions and treatment practice variations in the treatment of hormone-refractory prostate cancer (HRPC): a pilot multinational study

Oncologists' perceptions and treatment practice variations in the treatment of hormone-refractory prostate cancer (HRPC): a pilot multinational study

Treatment options in hormone-refractory prostate cancer: current and future approaches.

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

Recent advances in chemotherapy for advanced prostate cancer.

Recently, several important studies have validated prostate-specific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormone-refractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.

Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: A phase II trial

Clinical activity is difficult to assess by traditional response endpoints in patients with advanced prostate cancer. We used clinical benefit response to assess the activity of vinorelbine (Navelbine) in patients with hormone-refractory prostate cancer. Forty-nine men with hormone-refractory prostate cancer received vinorelbine weekly for eight weeks followed by every-other-week dosing. Clinical benefit response was defined by improvement in 1 of the following categories for at least 12 weeks and stable response or better in the other 2: pain index (analgesic consumption and pain intensity), Karnofsky performance status, and tumor status. Of 37 evaluable patients, 14 (39%) achieved clinical benefit for a median duration of 6 months (range 3-24 months). Toxicities consisted primarily of brief neutropenia and mild nausea. These findings indicate that vinorelbine is well tolerated in men with hormone-refractory prostate cancer and produces durable clinical benefit as defined by improvement in pain index and performance status.

Synergistic effect of estramustine and [3′-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells

Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3′-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5–15 μM) and PSC 833 (5 μM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5–15 μM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR ( r = 0.9814), but not the dephosphorylated form of the receptor protein ( r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.

ORAL CHEMOTHERAPY FOR HORMONE REFRACTORY PROSTATE CANCER: The University of Michigan Experience

The use of oral chemotherapy for the treatment of malignant disease is expanding. The authors' experience with oral chemotherapy for hormone-refractory prostate cancer continues to grow. These therapies are well-tolerated and effective. Already, these regimens are being improved by hybridizing them with intravenous agents such as paclitaxel. Also, oral novel agents are being tested that may offer new options for the treatment of hormone-refractory prostate cancer.

Treatment of hormone-refractory prostate cancer

Objective. An increasing number of patients with prostate cancer develop hormone-refractory disease after standard treatment modalities. In these patients, early clinical trials with chemotherapy produced disappointing response rates. However, clinical trials that employ response criteria such as prostate-specific antigen (PSA) and clinical benefit response have produced encouraging responses. This article reviews current and future treatment options for the management of hormone-refractory prostate cancer. Data Sources. A MEDLINE search for the years 1978 to 1998 was completed. The following terms were used in our search: prostate cancer, hormone-refractory, treatment, and chemotherapy. Relevant articles referenced in the literature obtained in our MEDLINE search were reviewed. Study Selection. Randomized and nonrandomized clinical trials were used in our review. Clinical trials using prostate-specific antigen or a palliation of symptoms as primary criteria for response were given priority. Data Synthesis. Several genetic alterations, including the overexpression of bcl-2 or mutations in p53, may lead to the development of hormone-refractory prostate cancer. Agents such as estramustine and taxanes, which affect microtubule function and potentially modulate bcl-2, appear to be particularly active in the treatment of hormone-refractory prostate cancer. In addition, mitoxantrone as well as other agents has been shown to be beneficial in improving the quality of life in patients with hormone-refractory prostate cancer. Conclusion. Hormone-refractory prostate cancer is not a chemotherapy-resistant disease as once believed; significant progress in the treatment of hormone-refractory prostate cancer has been made with new combinations of chemotherapy agents. Promising new treatments are currently under evaluation to assess their potential benefit over the standard treatment modalities that are currently available.

Treatment of hormone-refractory prostate cancer

Treatment of hormone-refractory prostate cancer

Oral Chemotherapy in the Treatment of Hormone-Refractory Prostate Cancer

Oral chemotherapy has become a major component of the treatment of advanced prostate cancer. The recognition that prostate cancer grows very slowly and must be treated continuously with active agents has led to the development of several therapeutic regimens. These regimens employ oral agents such as estramustine, cyclophosphamide, and etoposide, as they can be taken on a daily basis at home by the patients. These regimens have demonstrated activity in patients with hormone-refractory prostate cancer; declines in both prostate specific antigen and soft tissue lesions have been demonstrated.