Current status of prognostic factors in patients with metastatic renal cell carcinoma

In recent years, the induction of novel agents, including molecular‐targeted agents and immune checkpoint inhibitors, have dramatically changed therapeutic options and their outcomes for metastatic renal cell carcinoma. Several prognostic models based on the data of patients with metastatic renal cell carcinoma treated with targeted agents or cytokine therapy have been useful in real clinical practice. Serum or peripheral blood markers related to inflammatory response have been reported to be associated with their prognosis or therapeutic efficacy. In addition to them, investigation for novel predictive factors that represent the efficacy of agents, the risk of adverse events and the prognosis are required for the advance of therapeutic strategies. The present review discusses the conventional prognostic models and clinical factors, and recent advances of the identification of some of the most promising molecules as novel biomarkers for metastatic renal cell carcinoma.     

肾癌的分子靶向治疗

随着对肾癌发病机制包括细胞学、分子生物学研究的不断深入,肾癌发生中细胞信号转导通路中的一些关键分子成为治疗的靶点。以VEGF、VEGFR等为靶点的肾癌靶向治疗药物,如贝伐单抗、苏尼替尼、索拉非尼等在临床试验中已显示出很好的疗效。现就肾癌的分子靶向治疗的分子机理、临床试验研究、评价标准变化及应用前景作一简介。     

Recent advances in the treatment of metastatic renal cell carcinoma

In the past 5 years, the treatment of patients with metastatic renal cell carcinoma has changed dramatically from being largely cytokine‐based with the emergence of targeted therapy. Following the elucidation of various molecular pathways in renal cell carcinoma, targeted agents (particularly vascular endothelial growth factor‐targeting antiangiogenic agents) now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma and the outcome of treatment has improved. However, many tumors eventually develop resistance to targeted therapy due to secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. On the other hand, there are new forms of immunotherapy that hold the promise of improving the outcome for patients with metastatic renal cell carcinoma. In this article, we describe some of these new therapies, including the anti‐vascular endothelial growth factor monoclonal antibody bevacizumab, several receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, and tivozanib), the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and new immunotherapy modalities, such as anti‐cytotoxic T‐lymphocyte‐associated antigen 4 antibody and anti‐programmed cell death 1/programmed cell death‐ligand 1 antibody. We also discuss their role in the current management of patients with metastatic renal cell carcinoma.     

Sequential therapy with targeted agents in metastatic renal cell carcinoma: beyond second-line and overcoming drug resistance

Renal cell carcinoma comprises 2–3 % of all adult malignancies and its incidence is increasing. Overall survival of patients with advanced disease has increased over the last decade due to the development of many effective targeted agents. Unfortunately, most patients inevitably develop resistance to these agents. While our understanding of the underlying resistance mechanisms has improved, there remain multiple challenges in order to overcome resistance to targeted agents. Sequential and combination therapy with a variety of novel drugs has been evaluated to maintain ongoing clinical benefit and potentially overcome drug resistance. Retrospective data suggest that further anti-angiogenic therapy may be beneficial in advanced renal cell carcinoma after prior progression on two targeted agents with a similar or different mechanism of action. However, further randomised data are needed to better define the role of these agents beyond second-line therapy in the treatment of renal cell carcinoma.     

Evidence‐Based Clinical Practice Guideline for Renal Cell Carcinoma: The Japanese Urological Association 2011 update

Remarkable advances have been made in medical practice in relation to renal cell carcinoma in recent years, and a large amount of new evidence has been accumulated. In keeping with the plan at the time the first version of the “Evidence‐Based Clinical Practice Guideline for Renal Cell Carcinoma” compiled by the Japanese Urological Association was published in 2007, the Japanese Urological Association has just published a revised 2011 version. The main revisions regard the selection of treatment methods according to prognostic factors, reconsideration of treatment methods for small‐diameter renal cell carcinoma and selection criteria for medical treatment of advanced renal cell carcinoma, including selection of neoadjuvant treatment with molecular targeted medicines. This Guideline presents clinical practice methods that are thought to be the most standard methods in Japan at the present time. In this English translation of a shortened version of the original Guideline, we cited particularly important clinical questions and references.     

Recent advances in the treatment of advanced renal cell carcinoma: towards multidisciplinary personalized care

What's known on the subject? and What does the study add? With recent improvements in the prognosis for patients with metastatic renal cell carcinoma (mRCC), focus is now shifting towards maximising clinical benefit from targeted therapies. Factors other than efficacy data are increasingly being considered when selecting a treatment strategy, with a view towards optimising clinical outcomes. This review examines the development and efficacy of targeted agents for the management of mRCC and discusses the potential factors, including resistance mechanisms, sequential therapy, prognostic and predictive markers of response, and adverse event management, that may contribute to successful individually tallored treatment of patients with this disease.

• ? Targeted agents have substantially improved outcomes for patients with metastatic renal cell carcinoma (mRCC).
• ? Treatment focus is now shifting towards achieving a continuum of care such that long‐term benefit and extended survival may be achieved through the optimal use of targeted agents.
• ? To achieve this goal, a number of factors which impact on treatment selection and outcomes need to be considered when treating patients with mRCC, such as the optimal sequence of targeted therapies (and the related issue of resistance mechanisms).
• ? Recent advances are also likely to impact on the future treatment of mRCC. Examples include the identification of predictive biomarkers as well as a consideration of patient risk profiles or the safety profile of the selected targeted agent. In addition, attention is focusing on re‐defining the role of surgery for the treatment of RCC in the context of targeted therapies.
• ? This review examines the recent and future advances that offer the potential for personalizing treatment by selecting the most appropriate treatment for each patient with a view towards optimizing clinical outcomes.

     

The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy

PURPOSE: Thoughtful integration of surgical and medical approaches to metastatic renal cell carcinoma is paramount for maximizing disease control. Accomplishing this in the current era of targeted molecular therapies presents unique challenges and opportunities. MATERIALS AND METHODS: A systematic review of the MEDLINE and PubMed databases, and relevant urological and oncological journals was performed pertaining to cytoreductive nephrectomy, metastasectomy, targeted molecular therapies for renal cell carcinoma, and neoadjuvant and adjuvant approaches to the management of advanced renal cell carcinoma. RESULTS: Cytoreductive nephrectomy provides an overall survival advantage in select patients with metastatic renal cell carcinoma who receive subsequent interferon-alpha. However, cytokine therapies are now being supplanted by targeted molecular approaches that block the effects of vascular endothelial growth factor and other molecular events. Although cytoreductive nephrectomy remains a standard of care, limited insight into the biological effects of nephrectomy on mechanisms such as immunoregulation and angiogenesis precludes definitive statements about how to integrate surgery and targeted agents. Ongoing investigation involving basic science and translational research is required to optimize the integration of these approaches. Adjuvant and neoadjuvant vascular endothelial growth factor targeted approaches to renal cell carcinoma are now also being explored and the unique side effects of these agents, including potential effects on wound healing and vascular integrity, require careful consideration. CONCLUSIONS: Integrated approaches involving surgery and vascular endothelial growth factor targeted therapies hold much promise for the management of advanced renal cell carcinoma. Prospective clinical testing with vigilant attention to the risk-benefit ratio and thoughtful evaluation of biological correlates are required to optimize these approaches.     

To combine or not combine: the role of radiotherapy and targeted agents in the treatment for renal cell carcinoma

Introduction

Renal cell carcinoma is counted among the most resistant tumors to chemotherapy and radiotherapy, respectively. However, therapeutic options expanded since the introduction of molecular agents, targeting specific pathways such as the vascular endothelial growth factor (VEGF)-α, the VEGF receptor (VEGFR), or the mammalian target of rapamycin (mTOR) pathway. These new agents almost doubled the time to tumor progression and in some trials even improved overall survival. Against this background, the role of local treatment strategies in metastasized or inoperable primary renal cell carcinoma has to be redefined. With the onset of new technical developments in radiotherapy and the possibility to precisely deliver higher doses per fraction, encouraging response and control rates have been reported for kidney cancer, supporting a possible role for irradiation in this setting. This overview summarizes the preclinical data and clinical experiences of modern radiotherapy with focus on possible synergies and toxicities when combined with molecular targeted agents.

Methods

The available literature on preclinical and clinical data comprising prospective trials, retrospective analyses and case reports was reviewed.

Conclusion

With the recent developments in stereotactic and image-guided radiotherapy, encouraging data concerning local control in the treatment for metastasized renal cell carcinoma have been generated and are therefore recommended whenever possible. It seems that with these high- precision irradiation schedules, the combination with targeted agents is feasible with no increase in severe adverse events. Nevertheless, the addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case.     

Therapy management of cardiovascular adverse events in the context of targeted therapy for metastatic renal cell carcinoma

Targeted agents have significantly improved outcomes in patients with metastatic renal cell carcinoma, and are changing long‐term expectations in these patients. Experience with these agents highlights a distinct safety and tolerability profile, differing from that observed with conventional chemotherapy and radiotherapy. Cardiovascular adverse events have been observed when treating with targeted agents. This is of particular importance for patients with metastatic renal cell carcinoma who are elderly and present with significant comorbidities. A multidisciplinary approach and close collaboration between oncologists and cardiologists is essential for optimal management of cardiovascular adverse events. Strategies for the management of these adverse events include assessment of cardiovascular status at baseline and at regular intervals, patient education, and the use of supportive medication. Effective therapy management allows patients with cardiovascular adverse events to receive and continue targeted therapy with careful monitoring. Implementation of therapy management measures contributes towards maximizing treatment outcomes with targeted agents in patients with metastatic renal cell carcinoma.     

Immunotherapy for genitourinary tumors

The present review provides an update about the major achievements and recent advances of immunotherapy in renal cell carcinoma, urothelial carcinoma, and prostate cancer. Although the treatment strategy for renal cell carcinoma and urothelial carcinoma includes traditional cancer immunotherapies, such as interleukin‐2 and interferon‐alfa, the clinical outcomes of these therapies are unsatisfactory. In recent years, the development of immune checkpoint inhibitors has drastically changed the treatment strategy for various cancers, including genitourinary cancer. The present review summarizes the approved cancer immunotherapies for renal cell carcinoma, urothelial carcinoma and prostate cancer. Furthermore, we review the response evaluation and biomarkers for immune checkpoint inhibitors with a distinctive mode of action that is different from cytotoxic agents. Finally, future perspectives for cancer immunotherapy are discussed.     

Current status of pharmacotherapy against metastatic renal cell carcinoma in Japan

So far, metastatic renal cell carcinoma has been one of the most treatment‐resistant cancers. The extensive use of cytokines, such as interferon‐α and interleukin‐2, were carried out for metastatic renal cell carcinoma. However, significant advances in understanding the molecular mechanisms underlying renal cell carcinoma have led to the development of molecular target‐based drugs, which were desperately awaited for a long time, and now two types of molecular target‐based drugs are available. Two vascular endothelial growth factor receptor tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have been approved and available in Japan. The molecular target‐based drugs have unique and characteristic adverse events, whose profile are not well understood in Japanese patients, because most of the clinical trials were carried out in Europe and America. In contrast, immunotherapy is being reconsidered in the selection of more appropriate patients or as a combined treatment form with other drugs, because of few complete responses obtained and unexpected adverse events by molecular targeted treatments. We have several molecular targeted‐drugs available at present and will have more, and we will actually use these drugs in various clinical settings, such as the presurgical setting, the adjuvant setting, sequential administration and combined administration, in addition to cytokines. Therefore, we need more elaborate studies to obtain the optimal treatment methods to maximize the effect of such agents to extend overall survival while maintaining quality of life of metastatic renal cell carcinoma patients. In this article, we reviewed the issues related to the current status of pharmacotherapy available for metastatic renal cell carcinoma.     

Targeted Therapies in Metastatic Renal Cell Carcinoma: Overview of the Past Year

During the past half-decade, clinical trials have permitted major progress in treatment of metastatic renal cell carcinoma with the first generation of targeted therapies (bevacizumab, sunitinib, sorafenib, everolimus, and temsirolimus). New targeted agents such as axitinib, tivozanib, and dovitinib, all of which are tyrosine kinase inhibitors, have been developed in treatment of metastatic renal cell carcinoma. In the same time, more information regarding mechanism of disease and drug resistance shed light on new targets and new potent agents. We report an overview of the more relevant data published over the past year, which may modify the therapeutic landscape of kidney cancer in the near future.     

Cancer immunotherapy: A paradigm shift in the treatment of advanced urologic cancers

The recent resurgence of immunotherapy has transformed the therapeutic field of advanced urologic cancers. In this seminars issue, we evaluate the role of emerging and recently approved immunotherapeutic agents in advanced prostate, urothelial, and renal cell carcinoma. In each of these fields, we discuss recent regulatory approvals as well as promising ongoing clinical trials. Finally, we discuss incidence and management of immune related adverse events specifically associated with PD-1/PD-L1 inhibitors.     

Immunotherapy for metastatic renal cell carcinoma: A brief history,current trends,and future directions

Recent innovations in systemic therapy for metastatic renal cell carcinoma (mRCC) have occurred at a break-neck pace. In the 1980s, nontargeted cytokine-mediated immunotherapy was the systemic therapy of choice. Based on improvements in tolerability and patient outcomes, targeted antiangiogenic agents supplanted cytokines in the early 2000s. During the last decade, the most recent innovation has come in the form of immune-checkpoint inhibitors (ICIs), a form of immunotherapy that enhances immune-mediated tumor cell destruction. ICIs improve on all prior iterations of systemic therapies and have become the first-line therapy for many mRCC indications. ICIs have been shown to increase overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response rate (CRR) in mRCC patients. We reviewed the recent trends associated with ICI management of mRCC, their immune-related adverse events, and cost implications.     

Current Status of Targeted Therapy in Metastatic Renal Cell Carcinoma

Over the past few years, considerable advances in the understanding of the pathology and underlying molecular pathways in renal cell carcinoma (RCC) have been translated into the development of targeted therapeutics for this disease. Clear-cell RCC is characterised by the inactivation of the von Hippel-Lindau tumour suppressor gene, resulting in the dysregulation of hypoxia response genes, overproduction of vascular endothelial growth factor, which promotes tumour angiogenesis, proliferation, and metastasis. Novel multitarget tyrosine kinase and angiogenesis inhibitors have achieved a benefit in progression-free and overall survival in patients with advanced RCC in recent prospective randomised trials. This review will describe the most relevant clinical data with the new molecular-targeted agents in RCC and provide an overview of current indications for these compounds.     

Current status of targeted therapy for advanced renal cell carcinoma

The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-α]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions.     

Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy

Renal cell carcinoma is the most common malignant tumor originating from the kidney. Compared with other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiotherapy. However, it is well known that renal cell carcinoma represents one of the most immune‐responsive cancers and several immunotherapeutic strategies have been investigated in the management of renal cell carcinoma with variable degrees of success. The development of immunotherapy with α‐interferon or high‐dose interleukin‐2 is the best established treatment, and is associated with durable disease control. Although the lack of defined antigens in renal cell carcinoma has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma for more than 30 years. At present, there are three types of cell‐based vaccines in renal cell carcinoma treatment: autologous tumor‐cell vaccines, genetically modified tumor vaccines and dendritic cell‐based vaccines. A further type is peptide‐based vaccination with tumor‐associated antigens as possible targets, such as carbonic anhydrase IX, survivin and telomerase that are overexpressed in renal cell carcinoma. In the present article, we review data from completed clinical trials of vaccine therapy, and discuss future trials to assess the current knowledge and future role of vaccine therapy for renal cell carcinoma in the era of recently developed targeted therapy.     

Update on the medical treatment of metastatic renal cell carcinoma

CONTEXT: Metastatic renal cell carcinoma (mRCC) has long been treated only by immunotherapy with good results only in a small population of patients. In recent years, major improvements in treatment possibilities have occurred with the advent of anti-angiogenic drugs. In the past 2 yr, pivotal phase III trials have confirmed this major breakthrough by increasing the progression-free survival rates and/or overall survival rates provided by sunitinib, sorafenib, and bevacizumab, and more recently by the mTOR (mammalian target of rapamycin) inhibitors temsirolimus and everolimus. OBJECTIVE: To update the previous review on smart drugs published in the European Journal in 2006 (Patard JJ, et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006; 49:633-43). EVIDENCE ACQUISITION: Critical review of published literature 2006-2008 (Pubmed website search words: renal cell carcinoma and/or targeted therapy and prospective trials) and more recent meeting abstracts (American Society of Clinical Oncology 2007). Quality assessment included prospective phase I-III trials and critical evaluations with low numbers of patients, retrospective analyses, and slide presentations of meeting abstracts. EVIDENCE SYNTHESIS: This review presents the current situation and provides more recent data on sequential treatment, the association of targeted drugs, and the treatment of non-clear-cell histologies. CONCLUSIONS: Treatment of mRCC with targeted therapy centers on at least two major pathways: angiogenesis and mTOR involving inhibiting drugs that may be used alone, in combination, or sequentially.     

肾细胞癌靶向治疗预后相关因素研究进展

肾细胞癌（RCC）是泌尿系统常见的恶性肿瘤之一。分子靶向治疗是通过干预肿瘤细胞信号传导通路,抑制肿瘤的生长。相比于传统的细胞冈子治疗手段．肾癌靶向治疗效果更好。但是目前对肾癌靶向治疗的预后仍缺乏有效判断手段,本文结合最新研究综述了RCC靶向治疗预后密切相关的影响冈素研究现状及进展。     

Palliative und supportive Therapie des Nierenzellkarzinoms

At the time of diagnosis, 25-30% of all patients with renal cell carcinoma already present with metastatic disease. Furthermore, 20-30% of patients with renal cell carcinoma will have progressive disease despite radical nephrectomy with complete tumor resection.In this review, we discuss the current therapeutic options for patients with metastatic renal cell carcinoma: These include palliative radical nephrectomy, surgery of metastasis, tumor embolisation and medical treatment options (e.g. immunotherapy, chemotherapy and targeted therapy), as well as supportive pain treatment.