Elsevier

European Urology

Volume 58, Issue 6, December 2010, Pages 819-828
European Urology

Platinum Priority – Collaborative Review – Kidney Cancer
Editorial by Noel W. Clarke on pp. 829–830 of this issue
Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

https://doi.org/10.1016/j.eururo.2010.08.029Get rights and content

Abstract

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.

Introduction

Renal cell carcinoma (RCC) is the most common type of renal cancer, accounting for approximately 3% of all adult malignancies and 90–95% of all kidney neoplasms [1], [2]. In the European Union (25 countries), there were over 60 000 new cases of kidney cancer and 26 000 deaths in 2006 alone [3]. Worldwide, mortality as a result of RCC currently exceeds 100 000 patients each year [4], with the incidence and mortality rate increasing by 2–3% per decade [1].

Metastatic disease is present in >25% of patients at diagnosis of RCC, and almost 95% of these have multiple sites affected [1]. The disease remains one of the most treatment-resistant malignancies and is associated with a poor prognosis [5]. Reports maintain that only approximately 23% of patients presenting with metastatic RCC (mRCC) will be alive 5 yr later [6].

Surgical intervention is the primary treatment for early-stage RCC; however, surgery alone has limited benefit in patients with metastatic disease, except for palliative reasons [1]. For advanced or metastatic disease, nephrectomy may only be curative if all metastatic deposits are excised [7]. Therefore, a combination of surgery and targeted therapy is increasingly being used for locally advanced and mRCC in an attempt to improve patient outcomes. Prior to the advent of antiangiogenic agents, systemic treatment options for mRCC were limited to cytokine therapies (ie, interleukin [IL]-2 and interferon-alpha [IFN-α]). In the past few years, a shift in the treatment paradigm for RCC has occurred with the introduction of receptor tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) antibodies, and mammalian target of rapamycin inhibitors (mTORs). Several antiVEGF therapies have been approved for use in advanced RCC in the past 5 yr. These include sorafenib, sunitinib, and pazopanib; small molecule inhibitors of VEGF receptors (VEGFRs); platelet-derived growth factor receptors (PDGFRs); c-Kit; and Flt-3 [8], [9], [10]. In addition, bevacizumab, an antiVEGF antibody, was approved in combination with IFN-α [11], [12]. Efficacy and toxicities have been extensively reported. Of note, most patients studied with these agents had clear-cell RCC, good or intermediate performance status (PS), and had undergone prior nephrectomy (85–94%).

The mTOR inhibitor temsirolimus has been approved in patients with mRCC who present with at least three of six poor prognostic risk factors, and everolimus for patients with mRCC who have failed prior antiVEGF therapy [13]. The pivotal study for temsirolimus revealed a greater benefit for temsirolimus relative to IFN-α in patients who had not undergone a prior nephrectomy, but the results do not tell us about the outcomes in the nephrectomy versus non-nephrectomy groups [14]. At this time, there are no data available to definitively guide us on the optimal integration of temsirolimus with cytoreductive nephrectomy (CN).

Collectively, these agents show superior efficacy over IL-2 and IFN-α, and have allowed for a substantial improvement in the disease treatment. This article will give an overview of approved and emerging targeted therapies for RCC and describe how they may be integrated with surgery in management of the disease.

Section snippets

Evidence acquisition

A nonsystematic review was performed based on a literature search of MEDLINE for reports on surgery, receptor TKIs, VEGF antibodies, mTORs, and cytokine adjuvant therapy relating to RCC. In addition, registries of clinical trials (eg, www.clinicaltrials.gov) were searched. Abstracts of meeting proceedings were included in the review and analysis, provided they were retrievable from the public domain, to ensure an up-to-date review of a rapidly evolving field.

Evidence synthesis

With the retrieved literature, abstracts, and clinical trial information, an evidence synthesis was performed for: 1) the combination of VEGF-targeted therapies with surgery in mRCC; 2) adjuvant use of VEGF-targeted therapy in nonmetastatic high-risk patients; 3) neoadjuvant and presurgical treatment of unresectable RCC; 4) safety of VEGF-targeted therapy in combination with surgery; and 5) new agents for the treatment of RCC that may be integrated with surgery.

Conclusions

The recent interest surrounding the multimodal approach of integrating drug therapies with surgery for the treatment of RCC is a direct response to the advent of targeted therapies with specific molecular mechanisms of action. The encouraging response data in both primary tumors and metastases suggest that this is a rational step in the evolution of RCC treatment.

Presently, we do not have definitive evidence supporting changes in the current treatment paradigms. In the absence of prospective

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