Management of prostate cancer. Part 3: metastatic disease

Despite the increased detection of prostate cancer at an early stage, men are still dying of this disease. Management of advanced disease focuses on controlling the disease process, palliation of symptoms and improving quality of life. In this review, the basis for androgen deprivation in hormone-dependent disease is discussed and the role of maximum and intermittent androgen deprivation, as well as management options for hormone-refractory disease is addressed. Local radiotherapy continues to be of importance in pain control and the maintenance of quality of life. Radiopharmaceuticals and bisphosphonates also have a role to play, the latter particularly in the reduction of skeletal-related events. Chemotherapy in hormone-refractory disease is now well established following pivotal trials demonstrating a survival benefit with docetaxel. The emergence of novel agents targeting growth factors, angiogenesis and immunotherapy present exciting possibilities for future treatment.     

Emergence of androgen independence at early stages of prostate cancer progression in Nkx3.1; Pten mice

Although androgen deprivation therapy is a widely used treatment for patients with advanced prostate cancer, it ultimately results in the emergence of a hormone-refractory disease that is invariably fatal. To provide insights into the genesis of this disease, we have employed an in vivo model to investigate how and when prostate epithelial cells can acquire the ability to survive and proliferate in the absence of androgens. In particular, we have been studying the evolution of androgen independence in Nkx3.1; Pten mutant mice, which develop prostatic intraepithelial neoplasia and adenocarcinoma as a consequence of aging, as well as androgen-independent phenotypes following castration. We now find that the prostate epithelial cells from these Nkx3.1; Pten mutant mice are capable of surviving and proliferating in the absence of androgens and that they develop androgen-independent phenotypes well before they display overt prostatic intraepithelial neoplasia or cancer phenotypes. Our findings in this mouse model show that acquisition of androgen independence can be uncoupled from overt cancer progression and raise the possibility that hormone-refractory disease can arise at early stages of prostate carcinogenesis.     

Intermittent androgen deprivation

Intermittent androgen deprivation is a controversial approach to management of prostate cancer. Preclinical models have demonstrated delay in time to prostatespecific antigen (PSA) progression in athymic mice bearing LNCaP tumors and a delay in time to androgen independence in androgen-dependent Shionogi carcinoma tumors in castrated animals exposed to intermittent androgen. Phase II clinical trials have demonstrated improved sexual function and quality of life in men discontinuing androgen deprivation. The average percentage of time spent off androgen deprivation ranges from 37% to 58%. Most men respond to retreatment with hormonal therapy. Current ongoing phase III clinical trials of intermittent versus continuous androgen deprivation in men with metastatic disease or recurrent disease after localized therapy will assess the comparative impact on quality of life and survival. Final analyses of these critical trials will define the ultimate role of this approach in prostate cancer. In the interim, intermittent androgen deprivation should be considered an experimental approach.     

Docetaxel for the treatment of prostate cancer

Prostate cancer accounts for 12% of male cancer deaths, amounting to almost 10,000 deaths per year in the UK. Patients that develop metastatic disease may have their prostate cancer controlled for approximately 2 years with androgen deprivation but invariably progress to a castrate-independent state and succumb to metastatic disease. The previous experience of cytotoxic chemotherapy in hormone-refractory prostate cancer has yielded modest improvements in quality of life, with mitoxantrone in widest use. However, following encouraging Phase II data, two Phase III trials have demonstrated a survival advantage associated with the use of the synthetic taxoid cytotoxic docetaxel (Taxotere) over mitoxantrone and prednisolone. Moreover, this treatment was well tolerated. Therefore, docetaxel is set to be the standard by which future interventions are judged and a platform for future trials containing novel molecular therapies.     

Metastatic Prostate Cancer

The treatment of metastatic prostate cancer is based upon the principle that prostate cancer growth is stimulated by androgens. Androgen ablation therapy is an effective treatment for metastatic prostate cancer. The timing of initiation of androgen ablation and the role of combined androgen blockade have been investigated. The utilization of intermittent androgen suppression offers the potential for improved quality of life. Intermittent therapy for metastatic disease is being compared with continuous therapy in an ongoing cooperative group trial. Recent studies have defined the evolving role of cytotoxic chemotherapy in hormone-refractory disease.     

Prostate cancer update

Recent advances in prostate cancer have focused on treatment strategies in patients with biochemical relapse and novel methods of androgen deprivation therapy such as intermittent therapy, the role of bisphosphonates, and immunotherapeutic approaches. Continued investigation into the mechanism of androgen independence and effective treatments for hormone-refractory disease are described. This article reviews the major advances in prostate cancer published between November 1, 2000, and October 31, 2001.     

Should intermittent androgen deprivation be used in routine clinical practice?

For several decades, androgen deprivation (AD) has been the mainstay for treating metastatic prostate cancer. AD can be attained by a variety of means; however, irrespective of modality and a gratifying initial high response rate, almost all patients advance to a state of androgen independence and ultimately a hormone-refractory state. Improved understanding of the biology and mechanisms of progression to androgen independence coupled with promising preclinical data have led to investigating intermittent AD (IAD) as a way of improving disease control while maintaining quality of life. Preliminary published clinical experience, mostly from uncontrolled trials, suggests the feasibility of this approach. Two ongoing cooperative-group phase III trials are evaluating the survival impact of IAD both in patients with metastatic disease and in those with prostate-specific antigen failure post-radiation therapy. There are several unanswered questions regarding this approach, and until more definitive data regarding its safety and impact on survival are available, IAD should be considered experimental. In this review, we detail the background and preclinical scientific rational for investigating IAD, and we review published clinical experience and describe the ongoing phase III clinical trials. We also discuss special considerations for using IAD outside the context of a clinical trial.     

Angiogenesis-targeted therapies in prostate cancer

Most patients with metastatic prostate cancer will respond initially to ablation of gonadal androgen production. Eventually, all patients will develop progressive disease despite continued androgen suppression, a condition called androgen-independent or hormone-refractory prostate cancer. Hormone-refractory prostate cancer is characterized by virulent biologic and clinical behavior. Recently, docetaxel-based chemotherapy has been shown to improve survival and quality of life in this disease when compared with mitoxantrone-based therapy. However, results remain suboptimal. Recently, there have been remarkable advances in the delineation of the mechanisms of cancer growth, metastasis, and the intricate interactions between tumor cells and the surrounding normal tissues. The accumulated evidence has confirmed the importance of angiogenesis in these processes and validated the theory that inhibition of neovascularization is a promising therapeutic anticancer strategy. Currently, dozens of compounds that interfere with different steps of the angiogenic cascade are in preclinical and clinical development. Some of these agents have exhibited promising antitumor activity in hormone-refractory prostate cancer. This review summarizes the molecular mechanisms implicating angiogenesis in the development and progression of advanced-stage prostate cancer, as well as the drug development efforts that are targeting this process.     

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.     

Hormone-refractory Prostate Cancer

Opinion statement For more than five decades, the preferred treatment for advanced prostate cancer has been suppression of androgen production by medical or surgical castration. However, all patients treated with androgen deprivation eventually develop resistant disease as manifested by increasing prostate-specific antigen levels, progressive disease on imaging studies, and ultimately worsening symptoms. The treatment of patients with hormone-refractory prostate cancer (HRPC), once thought to represent a relatively futile endeavor, has changed significantly in the past several years with the development of new therapeutics. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen depri-vation; this approach is predicated on the recognition that HRPC is a heterogenous disease. Some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Furthermore, the application of chemother-apeutic regimens has provided viable treatment options for patients with HRPC.     

Preventing bone complications in advanced prostate cancer

The diagnosis and treatment of prostate cancer have steadily been improving since the late 1980s. However, clinicians still confront a large group of men developing disease metastatic to bone. Adequate control of bone complications plays a fundamental role in achieving control of symptoms and quality of life in this group. Androgen deprivation therapy, the standard treatment for advanced prostate cancer, increases the risk of various complications, including bone disease. This review addresses the prevention of bone complications related not only to prostate cancer metastases but also to impaired bone integrity caused by androgen deprivation therapy.     

Present status and perspectives in the treatment of hormone-refractory prostate cancer

The cornerstone in the treatment of de novo or recurrent metastatic prostate cancer is androgen deprivation. Unfortunately, nearly all patients will develop androgen-independent ('hormone-refractory') disease with progressive clinical deterioration and ultimately death. Chemotherapy has been shown to palliate symptoms of hormone-refractory disease but not to improve survival. Recently, two large phase III trials have demonstrated an overall survival advantage for patients treated with docetaxel-based regimens as compared to the best standard of care. Indeed, investigations into the pathophysiology of this malignancy, novel biological agents, skeletal protectants and radiopharmaceuticals are expanding the clinician's armamentarium and improving the patient's outcome.     

Association de radiothérapie et d’hormonothérapie dans la prise en charge des cancers localisés de la prostate : où en est-on ?

Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups.     

Circulating neuroendocrine markers in patients with prostate carcinoma

BACKGROUND: Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) with the goal to: 1) evaluate the differences in the expression of these markers in patients with benign, premalignant, and primary or metastatic PC; 2) evaluate their prognostic significance; 3) compare values in patients with hormone-naive and hormone-refractory disease; and 4) assess changes after androgen deprivation or chemotherapy. METHODS: Serum neuron specific enolase (NSE) (immunoradiometric assay) and plasma chromogranin A (CgA) (enzyme-linked immunoadsorbent assay) were evaluated in 141 patients with BPH, 54 patients with PIN, and 159 patients with PC; 119 patients were bearing hormone-naive disease and 40 were bearing hormone-refractory disease. CgA was monitored in 31 patients submitted to androgen deprivation and in 24 patients receiving chemotherapy. RESULTS: Supranormal CgA was observed more frequently in patients with American Urologic Association (AUA) Stage D2 disease (45.5%) compared with those with Stage D1 disease (33.3%), Stage C disease (16.7%), Stage A/B disease (18.8%), PIN (25.9%), and BPH (17.0%) (P < 0.02). Supranormal NSE did not change in any of the patient subgroups. Elevated CgA was observed in 36.0% of patients with metastases who had hormone-naive disease and in 45.0% of patients with hormone-refractory disease (P value not significant). Supranormal NSE and CgA values were predictors for poor prognosis in patients with hormone-refractory disease. Elevated baseline CgA values decreased > 50% in 1 of 12 patients who received luteinizing hormone-releasing hormone analogs and in 2 of 12 patients who underwent chemotherapy. CONCLUSIONS: CgA appears to reflect the neuroendocrine activity of PC better than NSE. Elevated CgA values correlate with poor prognosis and are scarcely influenced by either endocrine therapy or chemotherapy.     

Actual chemotherapeutical possibilities in hormone-refractory prostate cancer (HRPC) patients

Androgen deprivation therapy still remains the gold standard in the treatment of advanced prostate cancer. Unfortunately, patients with metastatic prostate cancer treated with androgen deprivation therapy frequently develop androgen-independent prostate cancer. Cytotoxic chemotherapy has not been used routinely and the current standard regimens have not demonstrated any significant alteration in the development of hormone-refractory disease. Recent phase III randomized clinical trials have suggested that docetaxel-based therapy, demonstrating a real increase of survival in treated patients, could represent the new standard treatment for metastatic patients. There is also promising activity of new drug combinations, such as taxanes plus vinca alkaloids, and of classic chemotherapeutic agents plus biological drugs. This review focuses on the current therapies for the treatment of HRPC.     

Risk of Cognitive Effects in Comorbid Patients With Prostate Cancer Treated With Androgen Receptor Inhibitors

Prostate cancer (PC) is primarily a disease of older men. As the risk of neurocognitive decline increases as people age, cognitive dysfunction is a potential complication in men with PC, imposing detrimental effects on functional independence and quality of life. Importantly, risk of cognitive decline may increase with exposure to androgen deprivation therapy and other hormonal therapies. Particular consideration should be given to patients with castration-resistant PC (CRPC), many of whom require continuous, long-term androgen deprivation therapy combined with a second-generation androgen receptor inhibitor. Non-comparative evidence from interventional trials of androgen receptor inhibitors in men with non-metastatic CRPC suggests differential effects on cognitive function and central nervous system-related adverse events within this drug class. Drug–drug interactions with concomitant medications for chronic, non-malignant comorbidities differ among ARIs and thus may contribute further to cognitive impairment. Hence, establishing baseline cognitive function is a prerequisite to identifying subsequent clinical decline associated with androgen receptor-targeted therapies. Although brief, sensitive screening tools for cancer-related cognitive dysfunction are lacking, mental status can be ascertained from the initial medical history and neurocognitive examination, progressing to more in-depth evaluation when impairment is suspected. On-treatment neurocognitive monitoring should be integrated into regular clinical follow-up to preserve cognitive function and quality of life throughout disease management. This review summarizes the multiple factors that may contribute to cognitive decline in men with CRPC, awareness of which will assist clinicians to optimize individual treatment. Practical, clinic-based strategies for managing the risks for and symptoms of cognitive dysfunction are also discussed.     

A mathematical investigation of the multiple pathways to recurrent prostate cancer: comparison with experimental data

Considerable research is aimed at determining the mechanisms by which hormone-refractory prostate cancer develops. In an effort to assist in the understanding of recurrent prostate cancer and the cellular processes that mediate this disease, a mathematical model is presented that describes both the pretreatment growth and the posttherapy relapse of human prostate cancer xenografts. Our goal is to evaluate the interplay between the multiple mechanisms that have been postulated as causes of androgen-independent relapse. Simulations of the model show that molecular events that render the androgen receptor irrelevant to disease progression, such as upregulation of BCL2, can result in relapse after androgen deprivation therapy. However, decreased apoptosis of androgen-independent cells alone overestimates the effects of hormone therapy when compared to experimental data. When decreased apoptosis is combined with continual androgen receptor activation, the posttherapy growth dynamics are in excellent correlation with experimental observations of the growth of LuCaP xenografts. Furthermore, the mathematical model predicts that upregulation of the androgen receptor, together with its increased activation, is alone sufficient to result in the androgen-independent growth of LNCaP xenografts. Recent experimental studies that suggest that the posttherapy increase in and continual activation of the androgen receptor are common and crucial features of recurrent prostate cancer provide validation of the model predictions. This approach provides a framework for using mathematical techniques to study novel therapeutic strategies aimed at controlling this disease.     

Chemotherapy for advanced prostate cancer: Results of new clinical trials and future studies

Our understanding of the role of chemotherapy for advanced prostate cancer has improved considerably in 2004 with the publication of two large randomized phase III trials and the approval by the US Food and Drug Administration of docetaxel and prednisone for metastatic hormone-refractory disease. Although treatment is still considered palliative in nature, studies of chemotherapy for metastatic hormone-refractory prostate cancer (HRPC) have demonstrated improved overall survival compared with older regimens as well as clinically significant improvements in important endpoints, such as quality of life and time to progression. In particular, docetaxel has emerged as first-line therapy on an every-3-week schedule for metastatic HRPC, replacing mitoxantrone, as recently reported in the TAX327 trial. Docetaxel and estramustine combinations have the disadvantage of significant cardiovascular and gastrointestinal toxicity, and further use of estramustine is likely unwarranted as first-line therapy. Future trials examining novel biologic agents and combination therapies should use single-agent docetaxel as the reference standard. The role of chemotherapy for advanced disease in the neoadjuvant or adjuvant setting, in biochemically (PSA) relapsed patients, and as second-line therapy for relapsed disease, remains a subject of active clinical investigation.     

L’oncologue radiothérapeute,un des acteurs du parcours du patient après cancer. Surveillance après cancer de la prostate

Prostate cancer is the most common cancer of men over 50 years old. Localized prostatic cancer treatment may be responsible of a decline of patient's quality of life. The main actors of treatment are now focused on minimizing functional consequences of treatments. The radiation oncologist has a central role in patient monitoring. The follow-up is codified by official recommendations of learned societies to enhance the post-cancer period. The main objective of this article is to review the recommendations for clinical and biological follow-up. An inventory of the functional consequences of the various treatments will be detailed, and particularly those caused by androgen deprivation therapy, with a review of precautions before implementation, adverse effects and their management, as well as monitoring recommendations. The analysis of quality of life after curative treatment and suggestions to improve monitoring will also be discussed.     

Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group

Background

Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases?

Methods

A systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus.

Results

Of the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results.

Conclusion

Docetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted.