Selecting Patients for Cytoreductive Nephrectomy in Advanced Renal Cell Carcinoma

Who and When

Axel Bex; Tom Powles

Disclosures

Expert Rev Anticancer Ther. 2012;12(6):787-797. 

In This Article

Abstract and Introduction

Abstract

Renal cell carcinoma presents with metastatic disease in approximately 30% of patients at the time of diagnosis. Cytoreductive nephrectomy (CN) of the primary tumor in the face of metastatic disease is part of a multimodality approach including systemic therapy that is based on evidence from randomized trials in the cytokine era. Data from the pretargeted therapy era showed that CN had a clear role in metastatic renal cell carcinoma, increasing life expectancy by approximately 6 months. The substantial improvement in outcomes reported for targeted therapy has challenged the previous role of CN. However, despite the absence of data from Phase III trials, available evidence suggests that some patients may benefit substantially from CN in the era of targeted therapy. This review summarizes current arguments for CN and how to best select patients for surgery. Ongoing trials are key in generating evidence towards a personalized approach to debulking nephrectomy.

Introduction

Although renal cell carcinoma (RCC) accounts for only 3% of all adult malignancies, there are approximately 60,000 new cases of kidney cancer and 26,000 deaths each year in the EU.[1]

Metastatic disease is present in up to 30% of patients at the time of diagnosis, and almost 95% of these have multiple sites affected.[2] Metastatic RCC (mRCC) is one of the most chemotherapy-resistant malignancies, and is associated with a poor prognosis.[3] Prior to the introduction of VEGF-targeted agents, systemic treatment options for mRCC were limited to cytokines such as IL-2 and IFN-α. Cytoreductive nephrectomy (CN) was part of a multimodality treatment for patients with synchronous metastatic disease, the primary tumor in place and a good performance status (PS). The rationale of CN for mRCC was based on evidence from two randomized trials. Both trials followed similar designs and eligibility criteria. In the Southwest Oncology Group (SWOG) trial 8949[4] and the European Organization for the Research and Treatment of Cancer (EORTC) trial 30947,[5] patients with a performance score of 0–1 were prospectively randomized to CN followed by IFN-α versus IFN-α without surgery. In both studies, a statistically significant improvement in overall survival (OS) was documented for CN prior to IFN-α therapy. However, the benefit in OS following CN in these trials was limited and did not exceed 6 months in a combined analysis.

Both trials also revealed that CN should not be used indiscriminately. Rather, patients should be selected for surgery along certain prognostic risk factors that are associated with prolonged OS. PS has been established as one of the most important factors and the Memorial Sloan–Kettering Cancer Center (MSKCC) risk score, which incorporates five clinical factors for assessment of response to therapy and survival, is commonly used to select patients for treatment.[6] Other criteria include significant tumor burden of the primary tumor, absence of significant comorbidity, absence of CNS metastasis and low risk of surgical morbidity.[7]

With the rare exception of a few patients with solitary metastasis, CN alone cannot achieve cure in metastatic patients and is generally viewed as part of a multimodality management that combines surgery and systemic therapy.

The introduction of drugs that target angiogenesis has improved treatment of mRCC. Currently approved agents include receptor tyrosine kinase inhibitors (TKIs), VEGF-antibodies and mTOR inhibitors.

The increased activity of targeted therapy, both in terms of outcome and response at metastatic sites and the primary tumor, renewed the controversy of the role of CN in patients with primary mRCC.[8] It is argued by those in favor of medical therapy alone that, due to the more effective treatment, CN would not change clinical outcomes in mRCC patients. They suggest that these patients ultimately die of their disease despite targeted therapy. In addition, responses in the primary tumor, which are as low as 6% (by Response Evaluation Criteria in Solid Tumors [RECIST]) in some series, support this view. Others feel that CN prolongs survival and that a period of presurgical targeted therapy in selected patients may help to identify those who suffer from early progression and may not benefit from surgery.[9,10] This is often referred to as presurgical targeted therapy and is controversial.

This review summarizes the current evidence for CN. In contrast to systemic treatment, where the need to individualize therapy has long been recognized, the discussion regarding surgery had been rather dogmatic. As a consequence, the question has been more focused on asking the indiscriminate 'yes' or 'no' to debulking nephrectomy, rather than the personalized 'in whom' and 'when'. Although the results of randomized trials are lacking, current evidence may enable us to make the first steps in making these decisions. Therefore, this review will focus on how to best select patients that are likely to derive a benefit from a multimodality approach including surgery.

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