Sternberg, C.N.

Contemporary role of androgen deprivation therapy for prostate cancer (Article)

2012-01-01T00:00:00Z

Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease. Objective: Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds. Evidence acquisition: A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated. Evidence synthesis: Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality. Conclusions: Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio.

Management of good risk germ-cell tumours (Article)

2009-11-01T00:00:00Z

Following the implementation of cisplatin-containing combined chemotherapy, patients with good-risk metastatic germ-cell cancer have an excellent prognosis. Since the 1980s, bleomycin, etoposide and cisplatin (BEP) have become the standard chemotherapy regimen for these patients. In view of both the high curative potential of BEP chemotherapy and the treatment-related side-effects, trials were carried out in patients with the greatest chance of cure to develop regimens with an improved toxicity profile while maintaining efficacy. Following the results of these trials, the standard chemotherapy in good-risk disease has been reduced from four cycles of BEP (4BEP) to three cycles of BEP (3BEP). Four cycles of etoposide and cisplatin (4EP) is an alternative treatment regimen, with similar efficacy. Studies that explored additional adjustments in the BEP regimen to further decrease toxicity have shown that the lower threshold of efficacy has been reached, and that the efficacy of the chemotherapy is compromised. Especially during the last decade, important long-term side-effects after the treatment of germ-cell cancers have been recognized. Chemotherapy in patients with germ-cell cancer increases the risk of developing cardiovascular disease and second malignant neoplasms. Whether 3BEP or 4EP is the optimal chemotherapy regimen for the future remains to be identified. Possibly differences in acute and late toxicities attributed to chemotherapy might eventually identify the best strategy.

Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets (Article)

2009-10-01T00:00:00Z

Context: Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited. Objective: To review the concepts and rationale behind targeted agents currently in late-stage clinical testing for patients with CRPC. Evidence acquisition: Novel targeted therapies in clinical trials were identified from registries. The MEDLINE database was searched for all relevant reports published from 1996 to October 2009. Bibliographies of the retrieved articles and major international meeting abstracts were hand-searched to identify additional studies. Evidence synthesis: Advances in our understanding of the molecular mechanisms underlying prostate cancer (PCa) progression has translated into a variety of treatment approaches. Agents targeting androgen receptor (AR) activation and local steroidogenesis, angiogenesis, immunotherapy, apoptosis, chaperone proteins, the insulin-like growth factor (IGF) pathway, RANK-ligand, endothelin receptors, and the Src family kinases are entering or have recently completed accrual to phase 3 trials for patients with CRPC. Conclusions: A number of new agents targeting mechanisms of PCa progression with early promising results are in clinical trials and have the potential to provide novel treatment options for CRPC in the near future.

Treatment Decisions for Advanced Genitourinary Cancers: From Symptoms to Risk Assessment (Article)

2009-09-01T00:00:00Z

Context: Current and emerging treatment options for advanced prostate, renal, and bladder cancer were discussed at the annual Interactive Genitourinary Cancer Conference (IGUCC) held in February 2009 in connection with the 2nd World Congress on Controversies in Urology (CURy). Objective: To provide practical clinical guidance for physicians and to promote the implementation of recent advances in the management of genitourinary cancers through closer collaboration among urologists, medical oncologists, and radiation oncologists. Evidence acquisition: This article was developed from presentations given at IGUCC 2009. Evidence synthesis: Docetaxel treatment is established as the standard first-line treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC), based on improvements in overall survival regardless of age, performance status, and pain. Treatment should be introduced according to risk-factor assessment, clinical status, and patient values and preferences. Similarly, management of senior adults with mCRPC should be individually adapted to the patient's health status rather than chronologic age, especially since the benefits and toxicity associated with docetaxel treatment are similar in senior adults and younger patients. Asymptomatic patients with adverse prognostic factors for survival such as visceral metastases, anaemia, and new bone lesions may be candidates for chemotherapy. Prognostic nomograms based on pretreatment parameters aid in identifying patients for earlier chemotherapy. Second-line treatments for CRPC patients are needed, but currently no agent has demonstrated efficacy in phase 3 clinical trials. For patients with a prior response to docetaxel, retreatment at relapse can be effective and well tolerated. There is a strong rationale for targeting angiogenesis in renal cell carcinoma (RCC), and new targeted therapies have changed treatment paradigms for RCC. In contrast, little progress has been made in the treatment of advanced bladder cancer since the introduction of cisplatin-based chemotherapy; new strategies are needed. Conclusions: Docetaxel (every 3 wk) treatment is a therapeutic option in elderly and asymptomatic mCRPC patients. Docetaxel retreatment is effective in initial responders.

Optimizing treatment for men with advanced prostate cancer: Expert recommendations and the multidisciplinary approach (Article)

2008-10-01T00:00:00Z

A multidisciplinary panel of 20 international experts, including urologists, radiation oncologists, and medical oncologists, convened during the Advanced Prostate Cancer Multidisciplinary Team meeting in Rome, Italy, in January 2007, to discuss the multidisciplinary team approach and current patterns of care for patients with hormone-refractory prostate cancer (HRPC). During the meeting, the experts discussed several definitions currently used in prostate cancer management, including those for senior adult patients. In addition, the panel reviewed a series of patient case studies in order to provide feedback on current treatment practices and to identify possible strategies for best practice. It was stressed that treatment decisions for senior adult patients should not be based solely on patient age. Additionally, although historically treatment decisions for advanced prostate cancer have focused on palliative care, given the survival benefit associated with docetaxel-based chemotherapy across patient subgroups, more men are likely to be offered chemotherapy for advanced-stage disease in the future. © 2008.