Elsevier

European Urology

Volume 60, Issue 4, October 2011, Pages 684-690
European Urology

Special Edition EAU–ICUD – Review – Kidney Cancer
ICUD-EAU International Consultation on Kidney Cancer 2010: Treatment of Metastatic Disease

https://doi.org/10.1016/j.eururo.2011.06.017Get rights and content

Abstract

Context

Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC).

Objective

This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms.

Evidence acquisition

Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature.

Evidence synthesis

Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed.

Conclusions

Increasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials.

Introduction

Renal-cell carcinoma (RCC) accounts for 2% of all cancers. In Europe, 40 000 patients are diagnosed with RCC each year, leading to 20 000 deaths [1].

One-third of patients are initially diagnosed with locally invasive or stage IV disease. Recurrence occurs in about 25% of patients having surgical resection for localized disease even though it was considered as curative. The prognosis for patients with distant disease was generally poor, with a 5-yr survival rate not >10% [2]. Until the past 4 yr, systemic treatments in patients with metastatic RCC (mRCC) have proven largely ineffective. Regarding chemotherapy or hormonal therapy, no single agent has been reported to achieve a consistent response rate in >10% of patients. Only a very small percentage of patients are likely to develop long-term disease-free survival following interferon-α (IFN-α)– and/or interleukin-2 (IL-2)–based therapy [3], [4]. At Memorial Sloan-Kettering Cancer Center (MSKCC), the overall median survival in 670 patients who were treated with chemotherapy or immunotherapy in 24 consecutive clinical trials from 1975 to 1996 was 10 mo [5].

Two key pathways are essential to the pathophysiology of the clear-cell RCC subtype: the hypoxia response pathway associated with inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and the mammalian target of rapamycin (mTOR) signalling pathway [6]. Several therapies targeting these two pathways, including sunitinib, sorafenib, temsirolimus, bevacizumab, and everolimus, are available for clinical use and have revolutionized the treatment of mRCC [7]. This article reviews current targeted treatment approaches in the first- and second-line mRCC settings, as well as modifications to existing treatment algorithms, based on recently available data.

Section snippets

Evidence acquisition

Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature. All data were reviewed and final statements were approved by experts in the field.

Current treatment approaches utilizing novel targeted agents

At present, treatment for metastatic clear-cell RCC with molecularly targeted agents can be broadly divided into the following categories: previously untreated patients, those refractory or intolerant to immunotherapy, and those who have failed treatment with VEGF-targeted therapy [2]. An important consideration that influences treatment decisions is the MSKCC prognostic risk-stratification system, which is widely used to define patient profiles and provides an indication of overall survival

Conclusions

Sunitinib monotherapy and bevacizumab in combination with IFN-α may be considered first-line treatment options in patients with metastatic or unresectable clear-cell RCC and favourable or intermediate prognosis according to MSKCC criteria (grade A). In the first-line setting, temsirolimus is recommended in patients with poor prognostic features, according to modified MSKCC criteria (grade A). Cytokines, including high-dose IL-2, remain an option for first-line treatment of highly selected

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