Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies

Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment.     

The clinical potential of temsirolimus in second or later lines of treatment for metastatic renal cell carcinoma

An impressive variety of targeted therapies has been approved for the treatment of metastatic renal cell carcinoma (mRCC). Despite promising progress, there are still unmet clinical needs. The optimal sequence of these agents in the therapeutic setting has not yet been determined. Most available data address first- and second-line therapy of clear cell RCC. The mTOR inhibitor temsirolimus has been approved for first-line treatment of mRCC, and there are new data addressing the use of temsirolimus in later therapeutic lines. Temsirolimus has discerning features compared with other currently registered drugs, such as its intravenous administration route–providing predictable bioavailability and adherence to treatment–and potential benefit in nonclear cell histologies. Here, we review the available literature on temsirolimus, with reference to data also available for everolimus, to determine its clinical potential in mRCC.     

Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma

Targeted agents have substantially improved patient outcomes in metastatic renal cell carcinoma (mRCC) and have now replaced cytokines as standard of care. Despite the clinical benefits observed, resistance to targeted agents has been shown to develop after a median of 5-11months of treatment. Furthermore, a small subset of patients does not experience any clinical benefit from targeted therapy. Two general modes of resistance have been proposed: intrinsic (pre-existing) and evasive (adaptive). Evasive resistance is thought to be the mechanism involved when patients progress after initial clinical benefit. It has been suggested that upregulation of alternative pro-angiogenic factors and/or downregulation of angiostatic factors may be involved. Several strategies have been shown to enable clinical benefit in patients who have experienced disease progression during prior therapy. These strategies include: adjusting the dose of the drug, combination therapy or switching to an alternative agent, with or without a different mechanism of action. Improvements in our understanding of the mechanisms of resistance associated with targeted agents and refinement of management strategies may help to improve patient outcomes further. In this article, we review the available evidence supporting mechanisms of resistance to targeted agents in mRCC, with a focus on tyrosine kinase inhibitors, and consider the potential management strategies which may allow further clinical benefit to be achieved.     

Sunitinib for the treatment of metastatic renal cell carcinoma

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor approved multinationally for the first- and second-line treatment of metastatic renal cell carcinoma (mRCC). The recommended dose of sunitinib is 50 mg per day for 4 weeks followed by 2 weeks off-treatment (Schedule 4/2). In a phase III trial in 750 patients with mRCC who had not received prior treatment, sunitinib demonstrated superior efficacy to interferon-α for the first-line treatment of mRCC. Sunitinib doubled progression-free survival compared with interferon-α; furthermore, median OS with sunitinib was greater than 2 years. As a result, sunitinib is now considered a reference standard of care for first-line mRCC treatment in patients at favourable or intermediate prognostic risk and is recommended in treatment guidelines. Additionally, results from an expanded-access programme, in a broad, heterogeneous patient population, confirmed the efficacy of sunitinib. Sunitinib has a distinct and predictable profile of adverse events, most of which are manageable with standard medical interventions. Therapy management strategies, including optimisation of dose and treatment duration and adverse event management can help patients achieve optimal efficacy with sunitinib in clinical practice. To further improve outcomes in patients with mRCC, current trials are evaluating sequencing or combination of targeted agents. The use of sunitinib as adjuvant therapy after nephrectomy and as neoadjuvant therapy is also being assessed. This paper provides an in-depth critical review of sunitinib, with particular focus on the data supporting the use of sunitinib for mRCC.     

Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma

The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.     

转移性肾细胞癌生物治疗的现状及展望

由于肾细胞癌（renal cell carcinoma, RCC）的内在抵抗性,使得其对放、化疗均不敏感,生物治疗成为转移性肾细胞癌（metastatic renal cell carcinoma, mRCC）患者唯一的选择。随着对RCC的进一步了解,小分子靶向药物治疗已逐步取代了以往的细胞因子疗法。近年来,新型免疫疗法成为RCC生物治疗研究的热点;小分子靶向药物治疗和新型免疫疗法在RCC治疗中显示出极大的优势,提高了患者的生存时间和生活质量,但是反应率低、耐药、副反应等问题也随之出现。为RCC患者提供个体化治疗,让患者从治疗中得到更大的益处是临床工作者努力的目标。     

Current options for the treatment of locally advanced and metastatic renal cell carcinoma: focus on sunitinib

Recent developments in molecular biology have increased our understanding of the biology and genetics of renal cell carcinoma (RCC) and identified pathways for novel targeted therapy. Several targeted therapies are now available that show promising activity in this disease. Sunitinib, an oral multitargeted tyrosine kinase inhibitor (TKI), has recently been approved for first-line treatment of metastatic RCC (mRCC) and is the new reference standard for the treatment of clear-cell disease. Three other promising TKIs are temsirolimus, approved for the treatment of advanced RCC, sorafenib, approved for the treatment of patients with advanced RCC who have failed or are considered unsuitable for cytokine therapy and bevacizumab, effective in combination with immunotherapy for first-line therapy of mRCC. Several other agents are under investigation as single-agent or combination therapy for mRCC. These include the TKIs axitinib, pazopanib, everolimus, erlotinib, gefitinib and lapatinib. Use of these agents is leading to the development of treatment paradigms that will transform the management of mRCC.     

Adjuvant Therapy for Renal Cell Carcinoma: Past,Present, and Future

At the present time, the standard of care for patients who have received nephrectomy for localized renal cell carcinoma (RCC) is radiographic surveillance. With a number of novel targeted agents showing activity in the setting of metastatic RCC, there has been great interest in exploring the potential of the same agents in the adjuvant setting. Herein, we discuss the evolution of adjuvant trials in RCC, spanning from the immunotherapy era to the targeted therapy era. Pitfalls of current studies are addressed to provide a context for interpreting forthcoming results. Finally, we outline avenues to incorporate promising investigational agents, such as PD‐1 (programmed death‐1) inhibitors and MNNG transforming gene inhibitors, in future adjuvant trials.     

Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents

The medical treatment of metastatic renal cell carcinoma (mRCC) has undergone a paradigm shift during the last decade with the approval of five drugs targeting vascular endothelial growth factor (VEGF) or its receptors (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and of two drugs inhibiting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway (temsirolimus and everolimus). Median survival has now reached 2 years in mRCC patients receiving first-line targeted treatment. A considerable body of work was conducted on the identification of prognostic factors of survival in the earlier era of immunotherapy of mRCC. The current challenge is to pursue this work on biomarkers of prognosis for targeted therapy and, even more importantly, to identify predictive factors of response to such therapy. This review provides an overview of recent key work on prognostic and predictive factors in patients with advanced clear cell RCC treated with VEGF-targeted agents.     

New systemic treatment options for metastatic renal‐cell carcinoma in the era of targeted therapies

Advances in understanding the biology and genetics of renal‐cell carcinomas have led to the development of novel targeted therapies for the treatment of metastatic renal‐cell cancer. Previously the systemic approaches were limited to cytokine therapies that were modest in their clinical benefits and at the expense of significant toxicities. Investigational treatments with allogeneic bone marrow transplantation were equally toxic and resulted in significant morbidity and mortality. The development of targeted therapy has revolutionized the treatment of metastatic renal‐cell cancer with more meaningful outcomes. This review aims to provide a detailed discussion of the clinical benefits of targeted therapies such as sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, and some of the newer agents in clinical trial development. The efficacy of these compounds in terms of response, survival and clinical benefit are explored as well as their toxicities. The role of surgery in metastatic renal‐cell carcinoma is reviewed in the context of cytoreductive therapy and resection of solitary and oligometastatic disease. Ongoing studies in the adjuvant setting following curative resection are also reviewed. The availability of targeted therapies has led to their rapid adoption as frontline therapy over traditional cytokine therapy, thus bringing more optimistic and hopeful therapeutic options in a condition where historically, systemic treatments have been relatively unsatisfactory and disappointing.     

Bevacizumab in combination with IFN-α in metastatic renal cell carcinoma: the AVOREN trial

Metastatic renal cell carcinoma (mRCC) is tumor resistant to all cytotoxic agents. During the last decade, effective targeted therapies emerged including sunitinib, pazopanib and the combination of bevacizumab with IFN-α. The use of bevacizumab plus IFN-α combination in mRCC is supported by the AVOREN trial. Although the primary end point of the AVOREN trial was overall survival, progression-free survival was used to evaluate efficacy and served as the basis of regulatory submission owing to the advent of targeted agents that probably resulted in the prolongation of overall survival in both experimental and control arms. The doubling of median progression-free survival in the AVOREN trials (from 5.4 to 10.2 months) is remarkably similar compared with the results of Phase III trials with sunitinib and pazopanib. Bevacizumab plus IFN-α is the only combined regimen currently used in mRCC and serves as a comparator in the trials combining bevacizumab with other agents.     

Multidisciplinary management of metastatic renal cell carcinoma in the era of targeted therapies

The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy.     

转移性肾细胞癌分子靶向治疗进展

肾细胞癌是我国泌尿生殖系统最常见的肿瘤之一。约30%的肾细胞癌患者在就诊时或手术后可能出现转移,预后差。转移性肾细胞癌对放疗与化疗均不敏感。转移性肾癌的分子靶向治疗已经取得了显著进展。现将最新的相关进展进行总结。     

Molekulare Therapie beim Nierenzellkarzinom

Molecular or targeted tumor therapy (small molecules) has resulted in unusual progress in the treatment of metastatic renal cancer (mRCC). Targeted therapies aim to attack, more or less specifically, deregulated intracellular signal transduction, such as proliferation, differentiation, and apoptosis. Thus, these therapies are expected to have high efficacy with lower side effects than classic chemotherapy. Elucidation of the crucial role of the von Hippel-Lindau tumor suppressor gene in upregulating growth factors associated with angiogenesis has identified specific targets for novel therapeutic strategies in mRCC. Two different drug classes are available: monoclonal antibodies (first component in mRCC: bevacizumab) that target surface molecules, and intracellular-acting small molecules, especially tyrosine kinase inhibitors (first components in mRCC: sorafenib, sunitinib, and temsorilimus). All modalities have specific benefits but also limitations and have resulted in greater progression-free periods and overall life expectancy in mRCC. They were the first new drugs to be approved for treating advanced or metastatic RCC in the past 10 years. These drugs provide novel perspectives for drug treatment in mRCC. Currently, the optimal combination and sequence of drugs is being explored in RCC clinical studies. A plethora of agents likely to have clinical activity are currently in the development pipeline. Today there are more than 160 drugs targeting renal cancer, from those in early preclinical development to marketed drugs. Many unanswered questions still remain, particularly concerning the efficacy of targeted agents in patients with low-risk RCC; the optimal sequence and combination of therapies for first-line, second-line, and third-line treatment; and the efficacy of this strategy in adjuvant settings.     

Considerations for the Design of Future Clinical Trials in Metastatic Renal Cell Carcinoma

Metastatic renal cell carcinoma (mRCC) remains incurable in most cases, and there is a need to improve outcomes through clinical research, which will include development of novel molecularly targeted or immunotherapeutic agents. There are also many remaining questions regarding the optimization of currently available regimens, including the utility of dose escalation, the benefit of combination therapy, and the optimal sequences of therapies. Addressing these clinical questions will require careful planning and the inclusion of novel elements in trial designs. Future trials should include molecular phenotyping and selection of patients most likely to benefit from targeted therapies. In this article, we consider lessons learned from previous trials in mRCC and discuss how these lessons might be implemented in the design of future trials that focus on clinically useful questions and provide results that can be readily interpreted. The ultimate aim of the next generation of mRCC trials will be rapid cost-effective identification, testing, and approval of agents that can improve prognosis in this challenging disease.     

Personalizing prophylactic surgery in cancer: current practice and future perspectives from new genome-wide association studies

Recurrence rates of approximately 35–65% after nephrectomy in patients with localized or locally advanced renal cell carcinoma clearly underline the need for adjuvant treatment modalities. Adjuvant treatment with cytokines, hormonal treatment and radiotherapy has not shown survival benefit. The only Phase III trial revealing significant prolongation of progression-free survival was published in 2004. In this trial, targeting the immune system using an autologous tumor-cell vaccine provided clinical efficacy, but as yet, no standard adjuvant therapeutic approach is available. Recent advances in understanding the molecular biology of renal cell carcinoma led to the development of several targeted agents showing antitumor efficacy and prolongation of progression-free survival in patients with metastatic kidney cancer, but to date, no data are available regarding their applicability and efficacy in the adjuvant setting. However, controlled trials applying these drugs in the adjuvant setting have already started and, hence, the question is raised as to whether there is still a role for vaccination immunotherapy in the era of targeted therapies. In this paper, results from current Phase III trials and other relevant studies regarding adjuvant treatment in renal cell carcinoma are reviewed with special interest on adjuvant vaccination therapies, particularly regarding future options of this therapeutic approach.     

Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence

Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.     

Evaluation of patients with metastatic renal cell carcinoma after failure of first-line treatment

The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.     

Optimisation of sunitinib therapy in metastatic renal cell carcinoma: adverse-event management

Reliance on cytokine therapy for the treatment of metastatic renal cell carcinoma (mRCC) has been all but eliminated by the introduction of novel targeted agents. Several of these agents, including the receptor tyrosine kinase inhibitor sunitinib, have demonstrated efficacy in the treatment of mRCC. Sunitinib treatment is generally well tolerated, and is associated with a low incidence of grade 3 or 4 adverse events. However, a distinct pattern of novel adverse events associated with sunitinib treatment has been identified. These events require monitoring and management to help reduce their frequency, severity, clinical significance and nature. This article summarises the most important adverse events observed during sunitinib treatment and suggests measures to manage the event, while also helping patients to sustain an optimal treatment schedule and gain maximum clinical benefit from sunitinib.     

Molecularly targeted therapy in renal cell carcinoma

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.