The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer

Hormone therapy is commonly used for many patients with prostate cancer. Radiotherapy occupies a prominent role in the treatment of locally-advanced, localised, and postsurgical prostate cancer. Hormone therapy and radiotherapy are often used in combination. In this article, the major features of the hormone/radiotherapy interactions are reviewed, with emphasis on the role of combination treatment for locoregional disease. The reported results suggest a biochemical survival advantage to the use of hormone therapy with radiotherapy, in virtually all settings of non-metastatic disease, with the weakest database being in the setting of low-risk, early-stage disease. Further data are needed in order to identify the optimum target population, combination of agents, and hormone duration, as a function of patient and disease factors.     

Management strategies for locally advanced prostate cancer

Locally advanced prostate cancer represents a subpopulation of prostate cancer diagnosed in patients who are either untouched by screening efforts or whose disease has an unusually rapidly progressive natural history. The diagnostic work-up for the locally advanced patient is distinct from that of early stage disease in several respects in that it is related principally to ruling out metastases. The typical metastatic work-up consists of a serum alkaline phosphatase, bone scan, CT of the abdomen/pelvis, and chest x-ray. Once metastatic disease has been ruled out, individual components of the management of locally advanced prostate cancer patients may include surgery (palliative or curative), external beam radiation therapy (with photons or particles) or brachytherapy (with low-dose rate/permanent or high-dose rate/temporary radiation sources), and hormone therapy. Unlike in early stage disease, observation/watchful waiting is typically not a treatment option in locally advanced prostate cancer. Of the curative local control modalities, the one most commonly used, and the one which has emerged as the clinical standard, is photon external beam radiotherapy (EBRT). Numerous randomised studies have shown that androgen ablation has an established role in conjunction with radiotherapy for locally advanced disease--the current standard of care is thus photon EBRT plus neoadjuvant and adjuvant androgen ablation. Long-term androgen ablation appears to be better than short-term ablation, even when hormone complications are considered. EBRT is typically delivered to the prostate, seminal vesicles and pelvic lymph nodes, although in some circumstances local fields to the prostate and seminal vesicles may be adequate. New treatment planning and delivery techniques, such as intensity-modulated radiotherapy and organ motion tracking, are being developed to reduce the morbidity of radiotherapy while permitting a higher delivered dose. Further work is necessary to determine the precise sequencing and duration of hormone therapy in conjunction with radiotherapy and the optimum radiotherapy treatment volume. Additional work is also needed to determine the precise groups benefiting from other local control modalities such as surgery and brachytherapy. Finally, novel investigational strategies such as chemotherapy and gene therapy are being applied in an attempt to improve outcomes of locally advanced prostate cancer patients.     

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.     

Value of endocrine therapy for early and locally advanced prostate cancer

Prostate-specific antigen-based screening and increased public awareness of prostate cancer have led to earlier detection of localised and potentially curable tumour stages. Nevertheless, disease recurrence after radical treatment of prostate cancer remains a problem for a considerable number of patients. Endocrine therapy plays a role in the treatment of almost all stages of prostate cancer, either as definitive or as temporary therapy. Neoadjuvant hormonal treatment has its place mainly in the external beam radiotherapy setting, where it reduces target volume and adverse effects. When used prior to and during external beam radiotherapy, endocrine therapy has shown a survival advantage in the subset of patients with locally advanced prostate cancer (cT2-4, N0-1, M0) with Gleason scores 2-6. Several studies have shown that adjuvant endocrine treatment is able to delay disease progression in any stage. There is, however, an ongoing controversy regarding the possible survival benefit of such treatment that has to be balanced against its considerable adverse effects and costs. Survival improvements associated with adjuvant hormonal treatments have mainly been seen in patients with lymph node metastases or those with a high probability of micrometastatic disease. Several large studies are under way to investigate the role of adjuvant treatment in the field of early prostate cancer.     

对前列腺癌的基因放射联合疗法的生物学效应观察

目的：探讨基因治疗和放射治疗联合应用于前列腺癌的治疗效果和安全性。方法：应用单纯自杀基因，射线照射及联合方法分别处理2种前列腺癌细胞．alamarBlue还原法观察细胞生长情况，绘制细胞生长曲线。结果：由细胞生长曲线可以看出较低浓度的基因转染和低剂量的照射联合应用，获得了比常规剂量的单纯治疗更好的治疗效果。结论：联合治疗中两种治疗可以相互促进，低剂量的联合应用就可以达到甚至超过常规剂量的单纯治疗，同时剂量的降低也提高了治疗的安全性，为进一步研究和临床应用提供了实验基础。     

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.     

Pharmacotherapy for prostate cancer,with emphasis on hormonal treatments

For more than half a century, hormonal therapy has been one of the cornerstones of prostate cancer therapy. However, the position and timing of androgen deprivation therapy is continuously challenged. Nowadays, it is often combined with other types of treatment in a multi-modal approach, especially with radiation therapy. Besides the well-known luteinising hormone-releasing hormone agonists, several developments have been introduced (e.g., luteinising hormone-releasing hormone antagonists or improved depot formulations achieving a better pharmacokinetic slope and lower testosterone levels). Research developments include a better understanding of the different gonadotropin-releasing hormone isoforms, the ligand-independent transformation of the androgen receptor and androgen receptor overexpression in hormone-insensitive disease. Prostate cancer, previously thought to be chemotherapy insensitive, is now treated at the metastatic stage by taxane-based chemotherapies. The combination of hormonal therapy and chemotherapy is currently studied at various stages of the disease, as early as localised or locally advanced prostate cancer. It is very likely that, in the future, pharmacological treatment for prostate cancer will include combination therapies rather than monotherapies. The authors suggest an in-depth re-evaluation of the place of androgen deprivation therapy in prostate cancer.     

Pharmacotherapy for prostate cancer, with emphasis on hormonal treatments

For more than half a century, hormonal therapy has been one of the cornerstones of prostate cancer therapy. However, the position and timing of androgen deprivation therapy is continuously challenged. Nowadays, it is often combined with other types of treatment in a multi-modal approach, especially with radiation therapy. Besides the well-known luteinising hormone-releasing hormone agonists, several developments have been introduced (e.g., luteinising hormone-releasing hormone antagonists or improved depot formulations achieving a better pharmacokinetic slope and lower testosterone levels). Research developments include a better understanding of the different gonadotropin-releasing hormone isoforms, the ligand-independent transformation of the androgen receptor and androgen receptor overexpression in hormone-insensitive disease. Prostate cancer, previously thought to be chemotherapy insensitive, is now treated at the metastatic stage by taxane-based chemotherapies. The combination of hormonal therapy and chemotherapy is currently studied at various stages of the disease, as early as localised or locally advanced prostate cancer. It is very likely that, in the future, pharmacological treatment for prostate cancer will include combination therapies rather than monotherapies. The authors suggest an in-depth re-evaluation of the place of androgen deprivation therapy in prostate cancer.     

Therapeutic effects of leuprorelin microspheres in prostate cancer

Leuprorelin has demonstrated effectiveness comparable to orchiectomy and oral diethylstilboestrol for the palliation of advanced prostate cancer. Unlike orchiectomy, leuprorelin's effects are reversible; also leuprorelin is not associated with the cardiovascular or thromboembolic adverse effects of oestrogens. For these reasons, leuprorelin has been widely used as an alternative to surgical castration or to oestrogens in the treatment of metastatic prostate cancer. Sustained-release leuprorelin microsphere formulations have been developed which exhibit zero order release of active drug from the injection site, such that in the United States the 7.5 mg dosage strength is recommended to be administered once a month and the 22.5 mg dosage strength once every three months. Although most patients will have suppressed release of pituitary luteinizing hormone by the third or fourth week after the first dose of depot leuprorelin, 4-5% of treated patients have been reported to have delayed responses, taking many more weeks or months to respond. A transient biochemical hormone escape has also been reported, although worsening of clinical symptoms has not accompanied the elevation of serum testosterone levels during treatment. Usually, leuprorelin is initiated as monotherapy when patients with advanced prostate cancer become symptomatic. However, newer studies of combination therapy of luteinizing hormone releasing hormone analogs with antiandrogens suggest that early initiation of therapy, at the time of diagnosis of advanced disease, may be beneficial, particularly in a subgroup of patients with small volume disease and good performance status. Leuprorelin is also undergoing evaluation as neoadjuvant therapy prior to radical prostatectomy for localized prostate cancer. Preliminary studies suggest that neoadjuvant leuprorelin in combination with an antiandrogen may be effective in downstaging prostate tumours. Leuprorelin commonly produces several adverse effects: hot flashes, decreased libido and impotence, and tumour flare.     

比卡鲁胺治疗前列腺癌的临床应用

比卡鲁胺是一种新型的非甾体抗雄激素药物,内分泌治疗是前列腺癌治疗的主要手段。本文就比卡鲁胺单药治疗前列腺癌、联合化疗治疗前列腺癌及联合放疗或去势手术治疗前列腺癌的临床疗效作一综述。     

Hormone refractory prostate cancer (HRPC): present and future approaches of therapy

The mainstay of therapy for patients with advanced prostate cancer still remains androgen deprivation, although response to this is invariably temporary. Most of the patients develop hormone-refractory disease resulting in progressive clinical deterioration and, ultimately, death. Until recently there has been no standard chemotherapeutic approach for hormone refractory prostate cancer (HRPC), the major benefits of chemotherapy being only palliative. The studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic HRPC with minimal toxicity and a significant palliation could be provided. Recently, results from 2 phase III randomized clinical trials demonstrating that a combination of docetaxel plus prednisone can improve survival in men with HRPC have propelled docetaxel-based therapy into the forefront of treatment options for these patients as the new standard of care. There is a promising activity of new drug combinations such as taxanes plus vinca alkaloids; bisphosphonates are assuming a prominent role in prostate therapy through their ability to prevent skeletal morbidity. Combinations of classic chemotherapeutic agents and biological drugs began to be tested in phase II-III trials and the first results appear interesting. This article focuses on combinations recently evaluated or under clinical development for the treatment of HRPC.     

The estrogenic burden on vascular risk in male-to-female transsexuals

Transsexualism refers to individuals that identify themselves as members of the opposite gender and who strive to acquire the physical appearance and psychosocial role compatible with that gender. Gender reassignment therapy is applied through hormonal treatment ± surgical intervention in addition to psychological support. Hormone treatment for male-to-female transsexuals includes estrogen supplementation ± suppression of androgen secretion or action. Sex hormones are important determinants of the metabolic profile. The impact on cardiovascular disease appears to be gender-related but overall evidence remains conflicting. Gender reassignment therapy has been associated with elevated triglyceride concentrations, often accompanied by an increase in high density lipoprotein levels, reduced circulating homocysteine (Hcy), uric acid and creatinine levels as well as an adverse effect on glycemic control. Markers of inflammation, oxidative stress and endothelial function are also affected in various ways, while alterations in hemostatic and fibrinolytic factors favor thrombosis (arterial and/or venous). Male-to-female transsexuals may be adversely affected by both estrogen administration and androgen deprivation, as reported in prostate cancer. Therefore, vascular risk factor screening and potential intervention may be required prior to and during gender reassignment therapy (both hormone and surgical).     

Etoposide in prostate cancer

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

Goserelin acetate in combination with radiotherapy for prostate cancer

Improvements in longer-term survival rates have been demonstrated for locally advanced prostate cancer patients treated with adjuvant androgen deprivation therapy (ADT), and in subsets of men with clinically localized disease treated with ADT combined with external-beam radiotherapy (RT). In these studies, ADT was administered in the form of surgery (orchiectomy) or with a class of drugs called luteinizing hormone-releasing hormone agonists. Goserelin acetate is a member of this class, and 10 of 11 major Phase III trials demonstrating better outcomes with ADT and RT used goserelin acetate. The reduction in deaths from prostate cancer noted in the mid-1990s may largely be due to the early use of these agents in men with intermediate-to-high-risk disease.     

Quality of life and economic considerations in the management of prostate cancer

The purpose of this article was to provide an overview of the morbidity and mortality of prostate cancer, QOL issues and the economic impact of the disease. We searched Medline (from 1990 onwards) for all studies dealing with prostate cancer epidemiology, treatment, screening and staging, and critically reviewed the most relevant articles, focusing on pharmacoeconomic issues.Prostate cancer is the most common cancer in men. In the US, new estimated cases of prostate cancer represented 14.8% of all new cancer cases for 2000, with estimated deaths from prostate cancer comprising 5.8% of all deaths from cancer. Current options for prostate cancer management include radical prostatectomy, cryosurgery, radiotherapy, hormone therapy and watchful waiting. Many of the long-term effects of treatment, such as urinary incontinence, impotence and radiation-induced proctitis, have a large impact on patients' quality of life and, in some patients, may offset the clinical benefits. Regulatory bodies and managed care organisations are assigning increasing importance to the evaluation of QOL benefits as an independent clinical endpoint and a measure of patient satisfaction. Several screening programmes for early detection of prostate cancer, mostly based on prostate-specific antigen (PSA) measurement or digital rectal examination, have been proposed, but their routine implementation in all asymptomatic elderly men has been questioned. There is still no definite proof that patient outcomes are improved by extensive PSA screening. Furthermore, the total cost of a screening programme is difficult to define since it extends well beyond the initial test. Several instruments are used for QOL assessment in prostate cancer, some of which have been specifically developed for, or adapted to, patients with this disease, such as the Functional Assessment Cancer Therapy (FACT) tool, Prostate Cancer Treatment Outcome Questionnaire (PCTO-Q) and Prostate Cancer Specific Quality of Life Instrument (PROSQOLI). More than 50% of treatment costs for prostate cancer are accrued during the patient's last year of life, and total initial care costs decrease with increasing age. In the US, initial average inpatient costs were estimated at $US 2253, in 1995, for men aged > or =80 years, compared with $US 4540 for men aged 35-64 years. In recent years, treatments based on combined modalities (i.e. radiotherapy/prostatectomy plus hormonal therapies) have emerged. Although cost-effectiveness analyses of various treatment options have been attempted, the strength of their conclusions appears to be limited by the lack of homogeneous literature data on the effects of such interventions on survival and morbidity.     

Treatment of hot flushes in breast and prostate cancer

Hot flushes, the most common health problem reported by menopausal-age women, can lead to significant morbidity and affect the social life, ability to work and sleep pattern of the sufferer. Women treated for breast cancer and men receiving androgen ablation for prostate cancer experience hot flushes that are more frequent, severe and longer lasting than those experienced by the general menopausal population. In women with breast cancer, hot flushes can result from chemotherapy-induced menopause, hormonal therapy, or ovarian suppression. In men with prostate cancer, hot flushes occur after surgical or medical castration. Hormone replacement therapy with oestrogen-based compounds has been a mainstay of treatment for hot flushes during the perimenopausal period. However, recent studies have shown that, in healthy menopausal women, hormone replacement therapy is associated with an increased risk of breast cancer, myocardial infarction, thrombo-embolic events and stroke. Thus, identifying nonhormonal agents that can control hot-flush symptoms is essential to the quality of life of a growing population of cancer survivors. The most promising agents act on the CNS and include selective serotonin reuptake inhibitors, as well as venlafaxine and gabapentin.     

An evaluation of bicalutamide in the treatment of prostate cancer

Prostate cancer is a major health problem in men, causing significant morbidity and mortality. Although traditionally considered a disease of old age, improved diagnostic techniques have resulted in earlier diagnosis and many men are now treated while still physically and sexually active. Current therapies for prostate cancer, which include medical or surgical castration, have a significant impact on many aspects of quality of life. The non-steroidal antiandrogen bicalutamide (Casodex?, AstraZeneca) has a favourable tolerability profile with demonstrated efficacy in several stages of prostate cancer and represents an alternative therapeutic strategy to castration. Mature survival data from men with previously untreated, locally-advanced disease reveal that bicalutamide monotherapy provides survival benefits that do not differ significantly from castration, while offering important advantages with respect to the maintenance of physical capacity and sexual interest. Recent data from a prospective randomised trial, the largest prostate cancer treatment study ever conducted, demonstrate that immediate therapy with bicalutamide (alone or as an adjuvant to therapy of curative intent) significantly reduces the risk of objective disease progression in patients with localised or locally-advanced prostate cancer. Antiandrogens are also used in combination with castration (combined androgen blockade) for advanced disease. Another large, randomised trial demonstrated that combined androgen blockade with bicalutamide is associated with a similar survival outcome to combined androgen blockade with flutamide and is better tolerated. The evidence reviewed demonstrates that bicalutamide currently has a favourable risk:benefit ratio in several stages of prostate cancer. The role of bicalutamide will be further defined by ongoing studies.     

Rational use of agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH) in the treatment of hormone-sensitive neoplasms and gynaecologic conditions

Analogues of luteinizing hormone-releasing hormone (LH-RH) have made possible new approaches to the treatment of some hormone-dependent cancers and diseases and conditions which result from inappropriate sex hormone levels. In the fields of both gynaecology and oncology, the development of sustained delivery depot systems has played a key role in the clinical use of LH-RH agonists and will be also essential for the LH-RH antagonists. Clinical results show that therapy with agonists of LH-RH is the preferred method of treatment for men with advanced prostate cancer. For prostate cancer and other indications, the new LH-RH antagonists such as Cetrorelix may offer an advantage based on the fact that they inhibit LH, FSH and sex-steroid secretion from the start of the administration and thus reduce the time of the onset of therapeutic effects. The use of antagonists would avoid the temporary clinical "flare-up" of the disease which can occur with the agonists in men with prostate cancer. The rapid shrinkage of the prostate and improvement in urinary symptoms obtained with Cetrorelix in men with benign prostatic hyperplasia (BHP) suggests that LH-RH antagonists offer a therapeutic alternative in patients who are considered poor surgical risks. Various experimental and clinical studies suggest that analogues of LH-RH might be useful for treatment of premenopausal women with oestrogen-dependent breast cancer. LH-RH antagonists such as Cetrorelix could be also considered for hormonal therapy of epithelial ovarian cancer which responds only marginally to the agonists, and for treatment of endometrial cancer. Many investigators have reported beneficial effects of LH-RH agonists in the treatment of patients with leiomyomas. LH-RH antagonists also appear to be promising for therapy of uterine leiomyomas, and in addition might be useful for treatment of endometriosis and polycystic ovarian disease (PCOD). LH-RH agonists have been employed in in vitro fertilization and embryo transfer (IVF-ET) programs to prevent a premature rise in LH and various results suggest that the use of antagonist Cetrorelix in assisted reproduction procedures, could be even more advantageous. For most of these indications, the use of sustained release depot preparations will be required.     

An evaluation of bicalutamide in the treatment of prostate cancer

Prostate cancer is a major health problem in men, causing significant morbidity and mortality. Although traditionally considered a disease of old age, improved diagnostic techniques have resulted in earlier diagnosis and many men are now treated while still physically and sexually active. Current therapies for prostate cancer, which include medical or surgical castration, have a significant impact on many aspects of quality of life. The non-steroidal antiandrogen bicalutamide (Casodex, AstraZeneca) has a favourable tolerability profile with demonstrated efficacy in several stages of prostate cancer and represents an alternative therapeutic strategy to castration. Mature survival data from men with previously untreated, locally-advanced disease reveal that bicalutamide monotherapy provides survival benefits that do not differ significantly from castration, while offering important advantages with respect to the maintenance of physical capacity and sexual interest. Recent data from a prospective randomised trial, the largest prostate cancer treatment study ever conducted, demonstrate that immediate therapy with bicalutamide (alone or as an adjuvant to therapy of curative intent) significantly reduces the risk of objective disease progression in patients with localised or locally-advanced prostate cancer. Antiandrogens are also used in combination with castration (combined androgen blockade) for advanced disease. Another large, randomised trial demonstrated that combined androgen blockade with bicalutamide is associated with a similar survival outcome to combined androgen blockade with flutamide and is better tolerated. The evidence reviewed demonstrates that bicalutamide currently has a favourable risk:benefit ratio in several stages of prostate cancer. The role of bicalutamide will be further defined by ongoing studies.     

Degarelix for prostate cancer

The growth of prostate cancer cells is hormone dependent in the majority of patients with the disease. Lowering testosterone either surgically or medically (usually with a gonadotropin releasing hormone (GnRH) agonist) is the standard of care in patients with metastatic prostate cancer. Degarelix is a new GnRH antagonist for the treatment of patients with prostate cancer. In contrast to GnRH agonists, the development of GnRH antagonists was hindered for a long time owing to histamine-releasing activity and lack of potency and water solubility. Recently, however, degarelix has been approved by the FDA for the treatment of advanced prostate cancer. This review summarizes the preclinical and clinical data available for degarelix and describes its potential role in the market of prostate cancer therapeutics.