Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

Metastatic Renal Cell Carcinoma: Pathogenesis and the Current Medical Landscape

ContextRenal cell carcinoma (RCC) represents a worldwide epidemiologic burden. Patients with metastatic disease usually have poor prognosis, and traditional treatments are often ineffective.ObjectiveThis review describes the epidemiology and pathogenesis of metastatic RCC (mRCC) and highlights the unmet clinical need for effective, targeted treatments.Evidence acquisitionMedical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.Evidence synthesisThere were approximately 200 000 new kidney cancer cases worldwide in 2002, and the disease's incidence is increasing in the United States and parts of Europe. The occurrence of RCC can be either sporadic or familial, and risk factors include smoking, obesity, and hypertension. RCC can be asymptomatic, and 25–30% of patients will present with metastatic disease at the time of diagnosis. Patients with mRCC usually have a poor prognosis, and estimates for their 5-yr survival range between 0% and 20%. Traditional therapies—namely, cytokines or chemotherapy—have limited efficacy in the majority of patients. Recently, the emergence of novel targeted therapies has provided new treatment options with increased efficacy. Clinical trials with these agents have highlighted a need to accurately assess activity and efficacy end points such as progression-free survival, which may be a useful surrogate for overall survival.ConclusionsDespite substantial progress in our understanding and treatment of mRCC in recent years, its incidence is increasing, and the disease is still considered incurable. The increasing accuracy of diagnosis and prognosis and the development of novel targeted agents are vital for the effective management of mRCC.     

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。     

Angiogenesis and angiogenic inhibitors in renal cell carcinoma

In most patients with renal cell carcinoma (RCC) of clear cell subtype, there is inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, which leads to a proangiogenic state with overexpression of vascular endothelial growth factor (VEGF). This molecular level knowledge has led to the development of multiple antiangiogenic therapies directed against the VEGF protein or the VEGF receptor. These therapies have significant clinical activity in metastatic RCC. Therefore, a therapeutic strategy based on targeting VEGF in RCC has a sound molecular basis and therapy with VEGF-targeting agents has significant clinical activity. To further improve efficacy, future research should focus on better identification of patients who will most benefit from such therapy. We reviewed the published literature regarding angiogenesis, the VHL gene, VEGF biology, and antiangiogenic therapies in metastatic RCC. This article reviews the role of angiogenesis in RCC and summarizes data regarding antiangiogenic therapy in metastatic RCC.     

Treatment of Advanced and Metastatic Renal Cancer: A Revolution?

ContextA significant proportion of patients with renal cell carcinoma (RCC) will experience recurrence or tumour progression after surgical treatment. Nowadays, several treatment options, including immunotherapy and targeted therapies, are available for management of advanced and metastatic RCC.ObjectiveThis paper aims to give an overview of the current treatment options for patients with advanced and metastatic RCC.Evidence acquisitionThis paper is based on a presentation given at the 6th Meeting of the European Society of Oncological Urology 2009, held in Istanbul, Turkey. Data were retrieved from recent review articles, original articles, and abstracts on the treatment of advanced and metastatic RCC.Evidence synthesisThe potential role of adjuvant vaccines in treatment of patients with advanced RCC after nephrectomy has been suggested. With regard to the newly developed targeted agents for treatment of metastatic clear-cell RCC, sunitinib and bevacizumab plus interferon-α (INF-α) seem promising as first-line therapy for good- and intermediate-risk patients. Temsirolimus appears to be effective as first-line treatment in metastatic RCC (mRCC) patients with poor prognosis. Sorafenib and everolimus should be considered as second-line therapy in mRCC patients. Some targeted therapies have also demonstrated clinical activities in patients with metastatic non–clear-cell RCC. Although grade 1 and grade 2 treatment-related adverse events were common with targeted therapies, most were manageable. The effect of targeted agents in earlier stage disease is currently under investigation. Cytokine therapy was associated with a modest survival benefit in mRCC. A combined analysis, however, suggested that cytoreductive nephrectomy might improve survival in patients with mRCC treated with interferon immunotherapy.ConclusionsMore research on the use of adjuvant vaccines in treating patients with advanced RCC is warranted. Although the management of metastatic disease has undergone a revolution in recent years, a lot of questions still need to be answered.     

Treatment of metastatic renal cell carcinoma and renal pelvic cancer

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of molecular targeted drugs have revolutionized the treatment for patients with metastatic RCC (mRCC). Multi-targeted tyrosine kinase inhibitors (sorafenib and sunitinib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have recently shown superiority over interferon-α or placebo. However, while the molecular targeted drugs have demonstrated encouraging results, these drugs have also sometimes induced unexpected adverse events. Control of adverse events is important to obtain the maximum effectiveness and sustain quality of life for patients. Because renal pelvic cancer has many similarities in pathogenesis with urinary bladder cancer, the same chemotherapeutic regimen is often proposed for patients with metastatic renal pelvic cancer. Combined chemotherapy with gemcitabine and cisplatin is now widely considered to be first-line chemotherapy against these metastatic diseases; however, there are still unresolved problems with this treatment, including the limited survival benefit. To select new therapeutic modalities, a more profound understanding of the molecular biology of renal pelvic cancer is crucial. The purpose of this review is to summarize the current evidence supporting the role and activities of new chemotherapeutic agents and to reveal potential future directions in the management of mRCC and renal pelvic cancer.     

Current Treatment in Advanced Renal Cell Carcinoma (RCC): Impact of Targeted Therapies in the Management of RCC

Renal cell carcinoma (RCC) is a highly resistant tumour for which there are currently no therapies that are effective across all patient subgroups. Recently, there has been an increased understanding of the molecular pathophysiology underlying RCC. The von Hippel–Lindau/hypoxia–inducible factor pathway has been strongly implicated in RCC. Several key molecules of this signalling pathway, including vascular endothelial growth factor, platelet-derived growth factor, epidermal growth factor, and the mammalian target of rapamycin have been identified. The recognition that these molecules play a pivotal role in tumour angiogenesis and tumour cell proliferation has led to the development of novel targeted agents for therapeutic intervention. This article discusses the efficacy of standard treatments for RCC and describes targeted agents that are currently being evaluated in clinical trials. Whilst the results from trials of epidermal growth factor receptor inhibitors have generally been disappointing, bevacizumab, sorafenib, sunitinib, and temsirolimus have shown potential in clinical trials. To date, both sorafenib and sunitinib are well tolerated and have demonstrated activity in phase 3 trials in patients with advanced or metastatic RCC, whilst temsirolimus has shown activity in a subgroup of poor-prognosis patients with advanced RCC.     

Metastatic non-clear cell renal cell carcinoma: current therapeutic options

Non-clear cell (ncc) renal cell carcinoma (RCC) accounts for approximately 25% of all patients with metastatic RCC. It is refractory to standard immuno(chemo)therapy and, to date, no specific trials have been reported to evaluate the efficacy of novel targeted drugs in the different subtypes of metastatic nccRCC. We review all available data from subgroup analyses of the global sorafenib and sunitinib expanded access programmes, current phase-III trials, and smaller multi- and single-centre studies focusing on the activity of targeted agents in these specific and rare RCC subtypes. Both sorafenib and sunitinib have significant activity in metastatic nccRCC, but the efficacy of each agent seems to vary between different nccRCC forms. Preliminary clinical data for temsirolimus appear to be promising but more extensive and long-term data are awaited. With the advent of novel therapeutic options, specific controlled multicentre trials are urgently needed to define their exact value and efficacy for treating the historically resistant nccRCC forms. The medium-term aim should be to tailor the most advantageous therapy for each patient with respect to his/her individual RCC subtype and physical condition.     

‘CELLO SCROTUM’ HOAX

Renal cell carcinoma (RCC) is among the most resistant tumours to chemotherapy, radiotherapy and hormonal therapy. Cytokine therapy is effective in a small subset of patients, but it is associated with substantial toxicity and rarely benefits patients with extensive tumour burdens or adverse prognostic factors. Since 2005, clinical trials have shown significant clinical benefits for five molecularly targeted therapies in patients with advanced RCC. These agents constitute two mechanistic classes: (i) angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) ligand (bevacizumab, in combination with interferon‐a) or VEGF receptors (sunitinib, sorafenib); and (ii) inhibitors of the mammalian target of rapamycin (mTOR) signalling (temsirolimus, everolimus). This review assesses the mechanistic distinctions and functional overlaps of these classes of agents, and discusses key characteristics of their respective clinical efficacy and side‐effect profiles in patients with RCC, some of which might affect patient selection and treatment strategies. Current research is designed to optimize the use of these agents, as well as the development of new investigational therapies within these mechanistic classes. The differences and synergies are particularly important for understanding the best ways to integrate VEGF/VEGF receptor inhibitors and mTOR inhibitors for combination or sequential treatment of patients with advanced RCC.     

Molecular Marker for Predicting Treatment Response in Advanced Renal Cell Carcinoma: Does the Promise Fulfill Clinical Need?

Renal cell carcinoma (RCC) is largely diagnosed incidentally on imaging taken for unrelated reasons. The management of localized lesions is primarily extirpative with excellent results. Treatment of advanced RCC has evolved over recent years with the use of targeted therapies such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and antibody-mediated therapies. The treatment response to these targeted therapies is highly variable, with no clear clinical method of identifying patients who will benefit from or not tolerate therapy. The field of molecular markers has evolved significantly in the last decade, with a multitude of markers identified that predict treatment response and drug toxicity. The following review critically evaluates those molecular markers that have been assessed for their utility in predicting treatment response in patients with advanced/metastatic renal cell carcinoma (mRCC). Identifying the ideal treatment for these patients will improve responses to therapy, minimize morbidity, and save significant healthcare dollars.     

Clinical effect and future considerations for molecularly-targeted therapy in renal cell carcinoma

Vascular endothelial growth factor (VEGF) pathway activation leads to the angiogenic phenotype of renal cell carcinoma (RCC). Several different strategies targeting various aspects of this pathway have emerged as standard therapy in metastatic RCC. Bevacizumab, a VEGF ligand-binding antibody, sunitinib and sorafenib, small molecule inhibitors of the VEGF receptor, as well as temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) have all shown substantial clinical activity in metastatic RCC. Several relevant clinical aspects have also emerged with use of these agents such as defining resistance, measurement of response, and combination therapy.     

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.     

Active targeted therapy for metastatic collecting duct carcinoma of the kidney: a case report and review of the literature

Collecting duct carcinoma (CDC) is a rare and aggressive renal cell carcinoma (RCC) with extremely poor prognosis, which has been shown to have a poor response to several kinds of systemic therapy. Targeted agents have greatly changed the therapeutic landscape in advanced RCC. Nonetheless, patients with CDC are always excluded from the prospective trials with targeted therapies due to its rarity. We present a case of metastatic CDC that responded favorably to the multiple tyrosine kinase inhibitor, sorafenib, achieving a partial response in both lungs and retroperitoneal lymph nodes metastases. We also reviewed the limited number of reports of metastatic CDC treated with targeted agents and found that 33.33 % (4/12) of patients had favorable clinical activity. These suggest that targeted therapy should be considered for the treatment of metastatic CDC and its prospective evaluation is encouraged.     

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.     

Looking Ahead in Renal Cell Carcinoma: Integrating New Agents in the Armamentarium of the Urologist

Urologists play a pivotal role in many aspects of the care of patients with renal cell carcinoma (RCC). However, until recently, in some European countries, they have rarely been involved in the systemic treatment of this disease or in the design of clinical trials. This is undoubtedly set to change with the emergence of new oral, molecularly targeted therapies for RCC. Sorafenib (Nexavar^®; Bayer Healthcare, West Haven, CT, USA) is one such therapy, which has already been shown to be efficacious and well tolerated for the treatment of RCC. Although targeted agents show great promise for the treatment of RCC, their precise role in the treatment of metastatic disease, and in adjuvant and neoadjuvant settings has yet to be defined. Drawing from their extensive experience of RCC, urologists will be instrumental in the design and application of clinical studies to define the role of targeted therapies in all settings of RCC and, ultimately, to integrate targeted therapies into clinical practice. Through increased understanding of the molecular pathways involved in RCC, research into diagnostic and prognostic markers, and commitment to clinical trials, urologists can be at the forefront of this progress.     

Continued Progress in the Treatment of Advanced Renal Cell Carcinoma: An Update on the Role of Sunitinib

ContextRenal cell carcinoma (RCC) constitutes approximately 2–3% of all cancers worldwide. Approximately a third of patients diagnosed with RCC present with metastatic disease (mRCC) and in about a third of patients with localized disease, RCC recurs following treatment. Metastatic renal cell carcinoma (mRCC) is associated with poor survival rates, and until recently, cytokines were the only treatment options for mRCC.ObjectiveThe rationale for the use of targeted agents in mRCC is reviewed, and the key challenges to optimizing treatment are discussed.Evidence acquisitionClinical data on the safety and efficacy of targeted agents in mRCC, practical therapy management, and patient stratification strategies are reviewed.Evidence synthesisThe development of targeted agents, including sunitinib, sorafenib, temsirolimus, and bevacizumab (given with interferon-α [IFN-α]) has dramatically changed the outlook for patients with mRCC and improved survival rates. Sunitinib has demonstrated clinical efficacy for mRCC in phase 2 and phase 3 trials and in an expanded-access study. Sunitinib is now a reference standard of care for the first-line treatment of patients with mRCC.As with the other targeted agents, sunitinib treatment is associated with a particular profile of adverse events (AE). Management of AEs is critical, as tolerability can affect adherence to therapy and limit clinical benefit. The development of practical strategies to support the optimal use of targeted agents is essential.In addition, prognostic factors such as tumor histology affect treatment outcome. Patient stratification into risk groups based on prognostic factors allows optimal treatment selection. A treatment algorithm, based on patient stratification and the available clinical data for the targeted agents, may facilitate the optimal choice of treatment for patients with mRCC.ConclusionsThis supplement reviews the clinical data from sunitinib studies in mRCC as well as practical therapy-management strategies and presents a treatment algorithm for mRCC. Finally, experience from the clinic is presented.     

Molecular targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide. Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy causes poor prognosis. Immunotherapy is relatively effective for RCC, but the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC. Recently, the mechanisms responsible for the growth of RCC have been clarified, and molecular targeted therapy has been developed. In this paper, we review the new molecular targeted therapeutic agents effective for RCC.     

Proposal of “cyclic therapy”, a novel treatment strategy with targeted agents for advanced renal cell carcinoma

The number of molecular targeted agents for advanced renal cell carcinoma (RCC) has gradually increased, but evidence on the optimal order of selection for such agents has not yet caught up with this trend. In addition, timing of switching molecular targeted drugs may also become an important issue for controlling the disease as types of these drugs grow in number. Based on the fact that the efficacy of a rechallenge of the drug previously used suggests the recovery of the sensitivity, a cyclic therapy in which drugs are changed before exacerbation to repeatedly administer several drugs in a rotated manner, may also be an effective sequential therapy.     

Sequence of treatment in locally advanced and metastatic renal cell carcinoma

The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-α), pazopanib, or—in poor risk patients—temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.