Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress?

Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.     

Current status of studies on targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) is regarded as one of the most refractory malignancies. A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC. Over the past 20 years, a nonspecific immunotherapy, with cytokines, has been employed as the gold standard for therapy of metastatic RCC. However, with scientific development and clinical testing of new drugs, targeted molecular cancer therapy has become a focus of interest. At the same time, with a better understanding of RCC,the treatment method has converged on anti-vascular endothelial growth factor (VEGF) and related molecular-targeted pathways.A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC. For example sorafenib and sunitinib were approved, in 2005 and 2006 respectively, by the U.S. FDA for treating advanced RCC. In this report, issues such as the importance of VEGF in RCC and the studies of bevacizumab,sunitinib and sorafenib in treating metastatic RCC etc., are reviewed.     

Surgical management of renal cell carcinoma

Renal cell carcinoma (RCC) is a relatively rare malignancy, although the incidence appears to be increasing. RCC remains resistant to chemotherapy and curative therapy is limited to surgical resection of localized tumors. Recently there has been an expansion of the indications for nephron sparing approaches to patients with localized tumors. Likewise, the management of locally advanced tumors and the indications for cytoreductive surgery in the setting of metastatic RCC have been clarified by recent studies. Herein, we discuss the role of surgery for the management of localized and metastatic RCC.     

Combination therapy for renal cell cancer: what are possible options?

Antiangiogenic therapy has shown promise in the treatment of patients with renal cell carcinoma (RCC). Two classes of antiangiogenic drugs, the anti-vascular endothelial growth factor antibody bevacizumab and the tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, have shown efficacy in patients with RCC and are approved by the US Food and Drug Administration for treatment of this cancer. In practice, the clinical benefit of antiangiogenic drugs in RCC has been heterogeneous, and in patients who do respond, benefits are modest and/or short-lived. To improve efficacy, combination targeted therapy has been attempted, but with either very limited additional efficacy or nontolerable toxicities. Recent advances in the molecular understanding of tumor angiogenesis and mechanism of resistance, along with the rapid development of targeted drug discovery, have made it possible to further explore novel combination therapy for RCC.     

转移性肾癌的靶向治疗

转移性肾癌是一种对于传统化、放疗较不敏感的不可治愈性疾病。虽然免疫治疗对部分患者具一定疗效，但疗效通常并不持久，且治疗可能导致严重的毒副作用。随着近年来对肾癌生物学及分子发病机制的加深理解，针对使用多种靶向治疗药物治疗肾癌的研究取得了可喜的成果。无论针对初治或以往治疗失败的患者，靶向治疗均显示出高于传统治疗的优越性。此外，治疗的耐受性非常良好，并不影响患者的生存质量。本综述将依据最新的临床证据，着重围绕目前主要的治疗进展加以分别阐述，同时简单概括相关的治疗靶点信息，力求使读者在基础和临床两方面对转移性肾癌的靶向治疗获得较为深刻的认识。     

VEGF-targeted therapy in metastatic renal cell carcinoma

PURPOSE: To review the biology of renal cell carcinoma (RCC) and the clinical results of vascular endothelial growth factor (VEGF) blockade in metastatic RCC. METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation, and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken. RESULTS: VHL tumor suppressor gene inactivation is observed in the majority of clear cell RCC cases, leading to VEGF overexpression. Therapy with agents directed against the VEGF protein or the VEGF receptor have demonstrated initial clinical activity in metastatic RCC. CONCLUSIONS: Therapeutic targeting of VEGF in RCC has strong biologic rationale. Substantial clinical activity has been reported in initial clinical trials with VEGF-targeting agents. Further investigation is needed to optimally use these agents for maximal clinical benefit.     

协同致死在肾细胞癌中的研究进展

肾细胞癌（renal cell carcinoma,RCC）是常见的癌症之一,常采用手术结合靶向和免疫治疗为主的综合治疗。但因靶向治疗的客观缓解率有限和免疫治疗的耐药性增加等问题,RCC亟需全新的治疗手段。目前协同致死理论在RCC的研究领域中取得重大突破,特别是在高突变率的基因包括VHL、PBRM1、SETD2等的RCC中,许多研究证实RCC中存在切实可行的协同致死伴侣。此外协同致死筛选方法及液体活检的开展,将为RCC患者精准化、个体化治疗提供新的思路。本文就协同致死在RCC方面的研究进展和机遇挑战进行综述。     

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.     

肾癌的靶向治疗

 目前转移性肾癌是最难治的恶性肿瘤之一。基于肾癌发生的分子机制的阐明，从而导致发展有希望治疗靶点的新药。在临床研究中，舒尼替尼和索拉芬尼是治疗晚期或转移性肾癌有明显的效果和可处理的毒性，它属于口服的多靶点酪氨酸激酶抑制剂，抑制血管内皮生长因子受体与血小板衍生的生长因子受体和C-KIT受体酪氨酸激酶。这两种药很快批准作为第二线药物治疗肾癌，并将用作第一线治疗。舒尼替尼或索拉芬尼作为单剂治疗与联合方案治疗肾癌值得进一步研究     

What is standard initial systemic therapy in metastatic renal cell carcinoma?

Historically, systemic therapies for metastatic renal cell carcinoma (RCC) have met with minimal success. Recently, an improved understanding of cancer biology has been translated into therapies that target pathways critical for RCC growth and survival and produce more robust clinical impact. The risks and benefits of several approaches to systemic therapy in metastatic RCC are reviewed. The need for chronic therapy of novel agents and potential for toxicity raise questions in regard to the timing of therapy and value of combination therapy over sequential single agents. Further insight into the biology of response, resistance, and toxicity is needed to allow for rational patient selection and enhanced application of systemic therapies. As new standard therapies for metastatic RCC emerge, clinical trial conduct remains a priority to further optimize patient outcome.     

肾细胞癌靶向治疗研究现状

肾细胞癌被认为是最难治的恶性肿瘤之一。由于对肾细胞癌分子发病机制研究的进一步深入,在晚期肾细胞的治疗中出现了一系列成功范例。在过去20年,非特异性免疫治疗被认为是晚期肾细胞癌治疗标准。近年,随着分子靶向药物的研发和临床使用,肿瘤的分子靶向治疗已成为肿瘤治疗的研究热点,同时由于对肾细胞癌进一步了解,肾细胞癌的治疗已开始转向抗-血管内皮生长因子及其相关通路研究,大量的临床研究试验,证明了分子靶向治疗在晚期肾细胞癌的疗效,其中Sorafenib(索拉非尼)和Sunitinib(舒尼替尼)分别于2005年和2006年经美国FDA批准用于晚期肾细胞癌。本文将围绕VEGF在肾细胞癌的重要性和Bevacizumab(贝伐单抗)、Sunitinib和So-rafenib治疗晚期肾细胞癌研究进展等问题进行简要阐述。     

The future of tyrosine kinase inhibitors: Single agent or combination?

The past 3 years have delivered positive phase 3 trial results for sorafenib, sunitinib, temsirolimus, and bevacizumab in renal cell carcinoma (RCC). The benefit of these therapies has been best defined as either first-line therapy or following cytokine therapy in patients with clear cell RCC. In light of the differences in the molecular targets of each agent, there is reason to believe that sequential single-agent therapy or regimens combining these agents could extend the benefits observed in the reported randomized trials. However, to date, few data have been reported supporting either strategy. A careful consideration of the specific mechanism of action of each agent provides a basis for considering the optimal therapeutic strategies for incorporating each of these agents into the management of metastatic RCC.     

Novel targets and therapies for metastatic renal cell carcinoma

For the past 20 years, the systemic treatment of metastatic renal cell carcinoma (RCC) has been limited primarily to cytokines, with few patients showing benefit. However, recent advances in understanding the pathobiology of RCC have led to the identification of novel therapeutic targets for this disease. Drugs specifically designed to inhibit these targets have been developed, with several showing superior efficacy over traditional cytokine therapy. Moreover, these agents are well tolerated and have improved the span of progression-free, and in some cases, overall survival. As a result, between December 2005 and January 2006, two of these targeted therapies--sunitinib (Sutent) and sorafenib (Nexavar)--were approved by the U.S. Food and Drug Administration for the treatment of advanced RCC. The authors review the clinical trials that have focused on these two drugs as well as those concentrating on two other promising agents, bevacizumab (Avastin) and temsirolimus. The ways in which these novel drugs are changing the standard of care for metastatic RCC and the future directions of RCC clinical trials are also discussed.     

Cytogenetic characterization of renal cell carcinoma in von Hippel-Lindau syndrome

We report the case of a 26-year-old man with von Hippel-Lindau syndrome (VHL) and two renal cell carcinomas (RCC), one of which was studied cytogenetically. Chromosomal analysis of the RCC showed a translocation that involved chromosomes 3 and 8 with subsequent loss of the derivative chromosome 8. The patient's peripheral lymphocytes showed a normal karyotype that indicated that there was not a constitutional chromosomal translocation. This is the third reported case of RCC in a patient with VHL in which loss of a portion of the short arm of chromosome 3 (3p) has occurred. Similar chromosomal changes that involve 3p have been reported in both familial and sporadic cases of RCC and have led to speculation that a tumor suppressor gene may be located in this region. Cytogenetic characterization of renal tumors could assume increasing significance in the diagnosis and classification of RCC and potentially may guide therapy. These studies may also lead to a better understanding of the biologic behavior of RCC and result in more informed patient evaluation and counseling.     

Patients with Metastatic Renal Cell Carcinoma with Long-Term Disease-Free Survival After Treatment with Sunitinib and Resection of Residual Metastases

A complete response (CR) to therapy in patients with metastatic renal cell carcinoma (RCC) is rare but has been achieved in a minority of patients using high-dose interleukin-2. Surgical CR after partial response to immunotherapy in metastatic RCC has been anecdotally reported, although the low overall response rate to cytokines precludes this procedure in the majority of patients. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Clinical efficacy has been demonstrated, with high objective response rates observed in a variety of solid tumor types, including RCC. Herein, we report 2 cases of patients with cytokine-refractory metastatic RCC who received sunitinib and achieved sufficient decrease in tumor burden to permit subsequent surgical resection, resulting in long-term CR.     

Patients with metastatic renal cell carcinoma with long-term disease-free survival after treatment with sunitinib and resection of residual metastases

A complete response (CR) to therapy in patients with metastatic renal cell carcinoma (RCC) is rare but has been achieved in a minority of patients using high-dose interleukin-2. Surgical CR after partial response to immunotherapy in metastatic RCC has been anecdotally reported, although the low overall response rate to cytokines precludes this procedure in the majority of patients. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Clinical efficacy has been demonstrated, with high objective response rates observed in a variety of solid tumor types, including RCC. Herein, we report 2 cases of patients with cytokine-refractory metastatic RCC who received sunitinib and achieved sufficient decrease in tumor burden to permit subsequent surgical resection, resulting in long-term CR.     

Von Hippel–Lindau: How a rare disease illuminates cancer biology

Von Hippel–Lindau (VHL) disease is a rare autosomal dominant syndrome (1/36,000 live births) with highly penetrance that predispose to the development of a panel of highly vascularized tumors (model of tumoral angiogenesis). Main manifestations include central nervous system (CNS) and retinal haemangioblastomas, endolymphatic sac tumors, clear-cell renal cell carcinomas (RCC), phaeochromocytomas and pancreatic neuroendocrine tumors. RCC has become the first potential cause of mortality and VHL disease is the main cause of inherited RCC. The disease is caused by germline mutations in the VHL tumor-suppressor gene that plays a major role in regulation of the oxygen-sensing pathway by targeting the hypoxia-inducible factor HIF for degradation in proteasome. VHL has also major HIF-independent functions, specially in regulation of primary cilium, extracellular matrix and apoptosis. Somatic inactivation of the VHL gene is the main molecular event in most sporadic RCC and the treatment of advanced RCC has been revolutionized by targeted therapy with drugs that block angiogenesis. These drugs are now in first line in metastatic sporadic RCC and have shown promising results for RCC, pancreatic neuroendocrine tumors and malignant pheochromocytomas in VHL patients.     

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。     

Treatment of metastatic renal cell carcinoma

Purpose  To review the treatment of metastatic renal cell carcinoma (RCC), including the use of new targeted therapies. Methods  A search of MEDLINE (1966 to August 2008) and American Society of Clinical Oncology Meeting abstracts (2005 to May 2008) was preformed using the search terms bevacizumab, everolimus, interferon-alfa (IFN-α), interleukin-2 (IL-2), sorafenib, sunitinib, temsirolimus, and RCC. Articles most pertinent to the treatment of metastatic RCC are reviewed. Results  The treatment of metastatic RCC has undergone a paradigm shift over the past 5 years from biologic response modifiers to new targeted therapies. Historically, response rates for the biological response modifiers, aldesleukin (IL-2), and IFN-α were approximately 15%. Recently, three targeted agents, sorafenib, sunitinib, and temsirolimus have been approved for the treatment of RCC. Additionally, bevacizumab has been investigated and shown to increase progression free survival in RCC. IL-2 remains the only agent to induce complete, durable remissions; however, many patients are not eligible for this therapy. Newer agents (sorafenib, sunitinib, and temsirolimus) have shown to be superior to IFN-α or placebo and bevacizumab combined with IFN-α has shown activity when compared to IFN-α alone. Unlike IL-2, the greatest benefit obtained with targeted therapies is in achieving stable disease (SD). Despite their benefit, targeted therapies have never been compared with each other in clinical trials and choosing the most appropriate agent remains challenging. To date, the optimal sequence or combination of treatments has not been defined; however, everolimus has recently demonstrated activity in patients progressing on targeted therapy. Conclusions  IL-2 remains the most active regimen in inducing complete responses; however, its use is accompanied by substantial morbidity and is limited to those with a good performance status. Targeted therapies are also efficacious in the treatment of RCC, with the major benefit being induction of SD. Future research will better define the sequencing of therapies, as well as, explore the activity of novel combination regimens.     

Pathologic complete response in renal cell carcinoma brain metastases treated with stereotactic radiosurgery

Renal cell carcinoma (RCC) is often regarded as a radiation-resistant tumor. However, radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole-brain irradiation has been used to treat brain metastases from RCC. To date, there have been no clinical pathologic correlative findings before and after RT. Herein, we present a case of a patient with brain metastases from RCC treated with SRS. The diagnosis of clear-cell RCC was made in 2001 after right radical nephrectomy. He was also found to have lung metastases at diagnosis. He presented with neurologic symptoms in 2004, and magnetic resonance imaging showed 3 brain lesions with a significant amount of edema consistent with brain metastases. The largest lesion caused a midline shift and was surgically resected. Pathology revealed metastatic RCC. The other 2 smaller brain lesions were treated at 20 Gy respectively with shaped-beam SRS using the BrainLab Novalis® system. No whole-brain irradiation was delivered. However, the patient had difficulty weaning off his steroids, and a magnetic resonance imaging performed 6 months after SRS was read as “progression of the lesions.” He then underwent resection of both the irradiated brain lesions. Pathologic examination revealed necrotic tissues without any viable tumor identified. The patient has since been doing very well, now 18 months after SRS and 5 years from the Initials diagnosis. This is the first reported case that demonstrates that precise high-dose radiation in the form of SRS can cause significant tumor cell death (pathologic complete response) in radiation-resistant brain metastases from RCC. This finding also provides a rationale to deliver stereotactic body RT for primary and metastatic RCC extracranially. A prospective clinical trial using stereotactic body RT for primary and metastatic RCC is under way.