Antiangiogenesis Therapy in Breast Cancer

Increased expression of the vascular endothelial growth factor (VEGF) is a poor prognostic factor in breast cancer, indicating that antiangiogenic therapies may improve outcomes. Novel antiangiogenic agents targeting the proangiogenic VEGF ligand and receptor tyrosine kinase inhibitors have been developed. Of these, bevacizumab, a humanized monoclonal antibody directed against VEGF, is very promising in breast cancer. A large phase 3 clinical trial demonstrated a statistically significant improvement in progression-free survival with the addition of bevacizumab to paclitaxel as first-line treatment of advanced breast cancer, establishing the benefit of antiangiogenic therapy in breast cancer. Additional studies of bevacizumab in the metastatic, adjuvant, and neoadjuvant settings are underway. Ongoing trials are also evaluating the efficacy of multitargeted tyrosine kinase inhibitors in advanced breast cancer. This article reviews the results of the key trials evaluating antiangiogenic agents in breast cancer with particular emphasis on bevacizumab and future directions of antiangiogenic therapy.     

Review of bevacizumab in the treatment of metastatic breast cancer

Vascular endothelial growth factor (VEGF) inhibition is a rational therapeutic approach in breast cancer because VEGF plays an important role in tumour blood vessel growth, tumour progression and metastasis. Bevacizumab is a recombinant humanised antibody targeted at VEGF. As VEGF is overexpressed in early tumour development, there is a strong rationale for studies using bevacizumab in a first-line setting. The €2100 trial demonstrated significantly greater progression-free survival and overall response rates with a bevacizumab plus paclitaxel combination compared with paclitaxel alone as first-line therapy in previously untreated metastatic breast cancer patients. Other studies in heavily pretreated patients have shown that bevacizumab in combination with capecitabine confers varying survival benefits, which might be due to the decreased significance of VEGF in advanced stages of tumour development.     

曲妥珠单抗治疗141例人表皮生长因子受体2阳性乳腺癌的回顾性分析

目的 总结曲妥珠单抗在人表皮生长因子受体2(Her-2)阳性乳腺癌患者新辅助、辅助和复发转移治疗中的临床应用经验,评价其与化疗联用的疗效.方法 对2004年1月至2008年12月门诊应用曲妥珠单抗治疗的141乳腺癌患者进行回顾性分析.随访时间为3～319个月.分析患者的无病生存时间(DFS),比较患者辅助、复发转移一线及二线使用曲妥珠单抗治疗的总生存时间(OS)、治疗失败时间(TTF)和临床有效率的差异.结果 与曲妥珠单抗治疗联用的新辅助化疗中,紫杉醇联合卡铂方案占66.7%;辅助治疗中,蒽环类和蒽环类序贯紫杉类方案占53.9%.复发转移的患者治疗后中位DFS为17个月.复发转移的患者经一线曲妥珠单抗联合化疗治疗后,临床总有效 率为84.5%,中位TTF为24个月;二线治疗有效率为44.4%,中位TTF为5个月.两者比较,差异有统计学意义(P=0.002).结论 紫杉醇和卡铂化疗联合曲妥珠单抗,值得在新辅助治疗中推广,紫杉类和蒽环类联合或序贯靶向治疗仍是辅助治疗的标准方案.转移性乳腺癌一线应用曲妥珠单抗联合化疗比二线治疗的临床有效率更高,在继续应用曲妥珠单抗的基础上改用化疗方案,可提高治疗有效率,减少治疗失败的概率.     

Evolution of bevacizumab-based therapy in the management of breast cancer

Combination therapy comprising bevacizumab with paclitaxel recently received accelerated approval from the US Food and Drug Administration (FDA) for use in the first-line treatment of patients with metastatic breast cancer. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), providing direct inhibition of angiogenesis. The evolution of bevacizumab use in the first-line treatment of patients with breast cancer has been characterized by a logical progression of phase II and III trials that have demonstrated that angiogenesis plays an important role throughout all stages of breast cancer growth and progression. In the phase III clinical trial E2100, which provided the basis for FDA approval, the use of bevacizumab (10 mg/kg on days 1 and 15) plus paclitaxel (90 mg/m2 days 1, 8, and 15 every 28 days) given until disease progression approximately doubled median progression-free survival (PFS; 11.8 months vs. 5.9 months; hazard ratio = 0.60; P < .001) compared with paclitaxel alone; by contrast, a statistically significant improvement in overall survival was not seen with the addition of bevacizumab, although a post hoc analysis demonstrated a significant increase in 1-year survival for the combination arm. The E2100 study, as well as the majority of clinical trial designs for bevacizumab, has used PFS as the primary efficacy endpoint, and, in this review, the development of PFS as a measure of clinical benefit is outlined. This review also discusses the importance of VEGF signaling in early phases of breast tumor progression, which has provided a rationale for the investigation of bevacizumab in early-stage settings.     

Bevacizumab in the first-line treatment of metastatic breast cancer

Bevacizumab plus paclitaxel has proven efficacy as first-line therapy for metastatic breast cancer based on the results of a randomised, phase III study (E2100). It has been recently reported that the addition of bevacizumab to paclitaxel doubled the median progression-free survival from 5.9 to 11.8 months (hazard ratio [HR] = 0.60, p< 0.0001). This benefit was corroborated in an analysis submitted to health authorities globally, using the intent-to-treat population; median progression-free survival of 5.8 increased to 11.4 months (HR = 0.42, p< 0.001), and confirmed by an independent review facility (5.8 vs. 11.3 months, HR = 0.48). This significant progression-free survival benefit was maintained across a number of patient subgroups, including those who had received prior adjuvant taxane chemotherapy. While there was no significant difference in overall survival, the addition of bevacizumab to paclitaxel increased the 1-year survival rate (81.2% vs. 73.4%, p = 0.01). As compared with bevacizumab use in other indications, no new safety signals were evident with the combination therapy, which was generally well tolerated. The only grade 3 and 4 toxicities that were increased by ≥5% with the addition of bevacizumab to paclitaxel were hypertension, sensory neuropathy, fatigue and neutropenia, the latter ones likely to be caused by the increased duration of paclitaxel treatment.     

Bevacizumab in the treatment of breast cancer: rationale and current data

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.     

Paclitaxel in Breast Cancer

Paclitaxel has emerged as an important agent in the treatment of breast cancer. The efficacy and tolerability of this agent, as well as its lack of cross-resistance with anthracyclines, have spurred intensive clinical investigation worldwide. Optimization of paclitaxel dose and scheduling and evaluation of the drug in combination regimens are a central focus of investigations. Recent clinical evidence suggests that optimal dose of single-agent paclitaxel by 3-h infusion is 175 mg/m². Trials evaluating administration schedule have not found either a 24-h or 96-h infusion to be superior to a 3-h infusion. Weekly moderate-dose paclitaxel administration is also generating much interest, given the high relative dose intensity and dose density delivered, yet very modest myelosuppression and manageable neurotoxicity observed. As first-line therapy in metastatic disease, multiple studies have documented overall response rates in the range of 30%-60%. As second-line or salvage single-agent therapy in metastatic patients, paclitaxel generally affords an overall response rate of 20%-40%, even in anthracycline-resistant patients. The novel mechanism of action and manageable toxicity of paclitaxel has led to successful incorporation into combination chemotherapy regimens. The combination of paclitaxel and doxorubicin has been the most extensively studied, with the role of this regimen continuing to evolve. Other combination regimens that appear to hold substantial promise as first-line metastatic treatment are paclitaxel with carboplatin and paclitaxel with trastuzumab (anti-HER2 antibody). The favorable results obtained in the metastatic setting have prompted phase II and phase III investigations of paclitaxel in the adjuvant and neoadjuvant settings. In the adjuvant setting, a recent phase III study has indicated that the addition of sequential paclitaxel to standard therapy affords both disease-free and overall survival benefits. Current investigations with paclitaxel will continue to optimize the role of this agent in the treatment of early- and advanced-stage breast cancer, addressing not only response rates but also survival and quality-of-life issues. The use of paclitaxel on a weekly schedule or with new therapeutic modalities, such as monoclonal antibodies, is also receiving much attention. While it is clear that paclitaxel is a very active agent in the treatment of breast cancer, it is hoped that these innovative trials will further maximize the potential of this agent in patients with breast cancer.     

Bevacizumab in the treatment of breast cancer

The monoclonal antibody bevacizumab, targeted against the angiogenesis factor VEGF has clinical activity against several common cancers. In metastatic breast cancer it improves response rate and time to progression in combination with paclitaxel/docetaxel compared with paclitaxel/docetaxel alone; the drug is currently being investigated in other combination regimens and as adjuvant and neoadjuvant therapy in early breast cancer. It is generally well tolerated. Side effects, including hypertension, proteinuria, thrombosis and bleeding, are uncommon and usually managed easily. Based on the clinical efficacy of bevacizumab, other small-molecule oral antiangiogenesis agents are now also under development.     

Bevacizumab in the treatment of breast cancer

The monoclonal antibody bevacizumab, targeted against the angiogenesis factor VEGF has clinical activity against several common cancers. In metastatic breast cancer it improves response rate and time to progression in combination with paclitaxel/docetaxel compared with paclitaxel/docetaxel alone; the drug is currently being investigated in other combination regimens and as adjuvant and neoadjuvant therapy in early breast cancer. It is generally well tolerated. Side effects, including hypertension, proteinuria, thrombosis and bleeding, are uncommon and usually managed easily. Based on the clinical efficacy of bevacizumab, other small-molecule oral antiangiogenesis agents are now also under development.     

Revisiting the Role of Bevacizumab in the Treatment of Breast Cancer

Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF) that interferes with VEGF binding to its receptor on vascular endothelium. Bevacizumab has been approved for the treatment of various malignant tumors, and has been studied in combination with several cytotoxic agents in the treatment of breast cancer. In 2008, the US Food and Drug Administration granted accelerated approval for the use of bevacizumab in combination with weekly paclitaxel for first-line treatment of HER2-negative metastatic breast cancer. However, this approval was later reversed in 2010 because of concerns for safety and lack of improvement in overall survival in randomized clinical trials. In this review, we summarize relevant clinical studies conducted to investigate the role of bevacizumab in the management of breast cancer, both in the early stage and in the metastatic disease settings. We also provide commentary regarding the future of this agent in breast cancer treatment.     

Role of epirubicin in advanced breast cancer

Anthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease. Unfortunately, their clinical value is limited by late-onset ventricular dysfunction. Epirubicin, an anthracycline analogue, does not eliminate the risk of cardiotoxicity but is less cardiotoxic and myelotoxic than doxorubicin at equimolar doses, thereby allowing the safe administration of cumulative doses between 950 and 1000 mg/m2. The inclusion of epirubicin in combination regimens, such as fluorouracil/epirubicin/cyclophosphamide (FEC), has been shown to be safe and active as first-line treatment for metastatic breast cancer. In the past few years, new drugs, including taxanes, have shown a high level of activity as single agents in the treatment of advanced breast cancer. Doxorubicin/paclitaxel combinations have shown high overall response rates (90%) as first-line chemotherapy of advanced breast cancer; however, congestive heart failure has been reported in up to 20% of patients. Epirubicin/paclitaxel combinations have been associated with grade 3 cardiotoxicity (6%) in only one study. We report findings of a trial of combination epirubicin/paclitaxel as first-line treatment of advanced breast cancer, with overall response rates (ORRs) of 84% and a complete response (CR) rate of 19%. Achieving a CR to first-line chemotherapy for advanced breast cancer appears to predict survival, and adding an active drug with a different mechanism of action and nonoverlapping toxicity might increase the percentage of CRs. We therefore tested the feasibility and activity of 6 to 8 courses of first-line treatment with a three-drug combination (gemcitabine 1000 mg/m2 days 1 and 4, epirubicin 90 mg/m2 day 1, and paclitaxel 175 mg/ m2 over 3 hours on day 1) in a phase II study of 36 metastatic breast cancer patients. Treatment was well tolerated, with an ORR of 92% (95% confidence interval: 77.53%-98.25%) and a CR of 31%. In considering retreating patients who progress or relapse after receiving an anthracycline-/taxane-containing regimen with the same active drugs, epirubicin appears ideal in both the adjuvant and metastatic breast cancer settings.     

Patients With Metastatic Breast Cancer Using Bevacizumab as a Treatment: Is There Still a Role for it?

OPINION STATEMENT: Over the last few decades, the angiogenesis mechanism has increasingly been studied and implicated in cancer pathophysiology. At present, it is known that angiogenesis plays a relevant role in tumor growth, and more importantly many new molecules exists can potentially interfere with this process. Bevacizumab, a humanized monoclonal antibody targeting the vascular endothelial growth factor A (VEGF-A) now commonly used in the treatment of colorectal, renal cell, and brain cancer, is the first anti-angiogenesis drug delivered in combination with chemotherapy that has consistently shown clinical efficacy in the treatment of breast cancer. Since the ECOG 2100 trial has shown that bevacizumab added to paclitaxel as a first-line treatment for advanced breast cancer nearly doubled the time to progression and tumor response rate, its approval was granted almost worldwide. However, other phase III trials revealed a smaller absolute improvement in progression-free survival (PFS) and response rates, and no trials yet have demonstrated survival enhancement which led to a great controversy and debate over the use of bevacizumab. The discrepancy between PFS and overall survival also raises the question of whether or not bevacizumab has been applied sub-optimally in some of the studies, if a predictive biomarker(s) exists to select the group of patients whom would receive the greatest benefit and what is the appropriate clinical end-point for approval and funding of new targeted agents. In this article we will review the bevacizumab mechanism of action and the clinical trials that assessed its benefit in the treatment of metastatic breast cancer (MBC).     

Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial

The aim of the study was to demonstrate the superiority of docetaxel and epirubicin vs docetaxel alone as first-line therapy in metastatic breast cancer patients pretreated with adjuvant or neoadjuvant epirubicin. We compared single agent docetaxel 100 mg m-2 (D) with the combination of docetaxel 80 mg m-2 and epirubicin 75 mg m-2 (ED). The response rate (72 vs 79%), the progression-free survival (median 9 vs 11 months) and the overall survival (median 18 vs 21 months) were not significantly different between the ED (n=26) and D arms (n=25), respectively. Leucopaenia, nausea and stomatitis were significantly worse with ED. In conclusion, epirubicin should not be administered in combination with taxanes in metastatic breast cancer patients relapsed after an anthracycline-based adjuvant or neoadjuvant therapy.     

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.     

The future development of bevacizumab in colorectal cancer

Bevacizumab (Avastin), the first approved therapy designed to inhibit tumor angiogenesis, has significant clinical benefits in the management of colorectal cancer (CRC). When bevacizumab is added to IFL (5-fluorouracil [5-FU]/leucovorin [LV]/irinotecan [Camptosar)]) as first-line therapy for metastatic CRC, significant overall and progression-free survival benefits are obtained. Similar survival benefits may be achieved when bevacizumab is added to 5-FU/LV alone. In addition, additive and synergistic effects with a range of chemotherapeutic agents illustrate that bevacizumab has considerable potential in combination with existing therapeutic options. Clinical data indicate that bevacizumab is the only agent in addition to chemotherapy that has demonstrated survival benefit in the first- and second-line settings. In addition, bevacizumab is expected to produce clinical benefit in the adjuvant setting: inhibition of vascular endothelial growth factor should prevent the angiogenic switch in micrometastases, which is a key factor in malignancy. The clinical program is examining the activity of bevacizumab in combination with the likely future standard of care in both the metastatic and adjuvant treatment settings. Phase III trials (NO16966C, CONcePT and TREE-2) are studying the benefit of combining bevacizumab with oxaliplatin (Eloxatin)-based regimens. Similarly, in the adjuvant setting, phase III trials are assessing the efficacy and tolerability of bevacizumab in combination with oxaliplatin-based chemotherapy (AVANT, NSABP C-08).     

Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced breast cancer

OBJECTIVES: To assess the efficacy and tolerability of gemcitabine and paclitaxel as first-line treatment in advanced breast cancer. METHODS: Patients with histologically confirmed metastatic or metastatic plus locally advanced breast cancer received gemcitabine 1,200 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days for 8 cycles. RESULTS: From December 1999 to August 2001, 45 patients, with a median age of 53.5 years (range, 22-77), received a total of 260 cycles. All were assessable for response and toxicity. Twenty-seven patients had prior adjuvant therapy. Hormonal receptor status was positive in 31.1% and negative in 40.0% of patients. Main metastatic sites included soft tissue (62.2%) and lung (53.3%). The objective response rate was 66.7%; complete response, 22.2%; partial response, 44.4%; stable disease, 15.6%; progressive disease, 17.8%. Median duration of response was 18 months and median time to tumor progression was 11 months. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia developed in 13.3% of patients, and 15.5% developed grade 3/4 mucositis. No treatment-related deaths occurred. Median overall survival was 19 months. CONCLUSIONS: Gemcitabine plus paclitaxel is an active combination with a favorable toxicity profile as first-line treatment for patients with advanced breast cancer.     

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional ‘window of opportunity’ endpoints should be included.     

Should bevacizumab be continued beyond progression in colorectal cancer?

Medical therapy for advanced colorectal cancer has seen significant changes over the past decade. Most recently, molecular targeted agents such as antibodies against the epidermal growth factor receptor and the vascular endothelial growth factor (VEGF) have become integral components of treatment algorithms for this disease. The anti-VEGF antibody bevacizumab has been found to significantly prolong progression-free and overall survival when used (in conjunction with chemotherapy) as part of first-line or second-line treatment. Recent preclinical and clinical data suggest that continuing bevacizumab beyond first progression could be associated with a relevant clinical benefit for patients with advanced colorectal cancer, but there are no data from randomized clinical trials on this issue. This review discusses the current state of the science and the rationale for and against continuing bevacizumab as part of antitumor therapy beyond progression of colorectal cancer.     

Major clinical research advances in gynecologic cancer in 2013

In 2013, 10 topics were selected for major clinical research advances in gynecologic oncology; these included three topics regarding cervical cancer, three regarding ovarian cancer, two regarding endometrial cancer, and one each regarding breast cancer and radiation oncology. For cervical cancer, bevacizumab was first demonstrated to exhibit outstanding clinical efficacy in a recurrent, metastatic setting. Regarding cervical cancer screening, visual inspections with acetic acid in low-resource settings, p16/Ki-67 double staining, and the follow-up results of four randomized controlled trials of human papillomavirus-based screening methods were reviewed. Laparoscopic para-aortic lymphadenectomy before chemoradiation for locally advanced cervical cancer was the final topic for cervical cancer. Regarding front-line ovarian cancer therapies, dose-dense paclitaxel and carboplatin, intraperitoneal chemotherapy, and other targeted agents administered according to combination or maintenance schedules were discussed. Regarding recurrent ovarian cancer treatment, cediranib, olaparib, and farletuzumab were discussed for platinum-sensitive disease. The final overall survival data associated with a combination of bevacizumab and chemotherapy for platinum-resistant disease were briefly summarized. For endometrial cancer, the potential clinical efficacy of metformin, an antidiabetic drug, in obese patients was followed by integrated genomic analyses from the Cancer Genome Atlas Research Network. For breast cancer, three remarkable advances were reviewed: the long-term effects of continued adjuvant tamoxifen for 10 years, the effects of 2-year versus 1-year adjuvant trastuzumab for human epidermal growth factor receptor 2-positive disease, and the approval of pertuzumab in a neoadjuvant setting with a pathologic complete response as the surrogate endpoint. Finally, the recent large studies of intensity-modulated radiotherapy for gynecologic cancer were briefly summarized.     

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.