Elsevier

The Lancet

Volume 373, Issue 9669, 28 March–3 April 2009, Pages 1119-1132
The Lancet

Seminar
Renal cell carcinoma

https://doi.org/10.1016/S0140-6736(09)60229-4Get rights and content

Summary

Considerable progress has been made in the treatment of patients with renal cell carcinoma, with innovative surgical and systemic strategies revolutionising the management of this disease. In localised disease, partial nephrectomy for small tumours and radical nephrectomy for large tumours continue to be the gold-standard treatments, with emphasis on approaches that have reduced invasiveness and preserve renal function. Additionally, cytoreductive nephrectomy is often indicated before the start of systemic treatment in patients with metastatic disease as part of integrated management strategy. The effectiveness of immunotherapy, although previously widely used for treatment of metastatic renal cell carcinoma, is still controversial, and is mainly reserved for patients with good prognostic factors. Development of treatments that have specific targets in relevant biological pathways has been the main advance in treatment. Targeted drugs, including inhibitors of the vascular endothelial growth factor and mammalian target of rapamycin pathways, have shown robust effectiveness and offer new therapeutic options for the patients with metastatic disease.

Introduction

The management of renal cell carcinoma has undergone a transformation in the past few years. Surgical innovation has reduced morbidity and the need for surgery, and has led to approaches that have reduced invasiveness and preserve oncological effectiveness. An enhanced understanding of the underlying biology has led to substantial clinical advances in management of advanced disease. Present systemic treatment targeted at the vascular endothelial growth factor (VEGF) protein and related pathways has produced robust clinical effects in the treatment of metastatic renal cell carcinoma.

Section snippets

Epidemiology

Renal cell carcinoma accounts for 2–3% of all malignant diseases in adults. It is the seventh most common cancer in men and the ninth most common in women. Incidence worldwide is about 209 000 new cases per year and 102 000 deaths per year.1 The incidence of all stages of this cancer has increased over several years, contributing to a steadily increasing mortality rate per unit population.2, 3, 4 Active and passive cigarette smoking is an established risk factor for renal cell carcinoma with a

Presentation and diagnosis

Renal cell carcinoma is a male-predominant (2:1 ratio) disease with a typical presentation in the sixth and seventh decades of life (median age about 60 years). Patients with this cancer can present with local or systemic symptoms, although most presentations are incidental with the widespread use of abdominal imaging. Local signs and symptoms include haematuria, flank pain, or a palpable abdominal mass, all of which have negative prognostic implications. Systemic symptoms can be due to

Pathological changes

A major advance in renal cell carcinoma is the realisation that this disease is not one entity but rather a collection of different types of tumours, each derived from the various parts of the nephron and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes (figure 2).16, 24, 25, 26 Most common is clear cell disease, so named because the high lipid content in the cytoplasm is dissolved during histological preparation methods leaving a

Management of small renal masses

Small (≤4 cm) solid, enhancing (becoming brighter on CT with contrast) renal masses must be considered highly suspicious for renal cell carcinoma, although management of these lesions has caused great controversy over the past decade. The malignant potential of these lesions in the past has been assumed, the understanding of the natural history was rudimentary, and most lesions were treated surgically with radical or partial nephrectomy. Partial nephrectomy was preferred whenever there were

Surgical approaches for advanced disease

Tumours greater than 7 cm and those with locally invasive characteristics have increased potential for being malignant. About 5–10% of renal cell carcinomas extend into the venous system as tumour thrombi, often ascending the inferior vena cava as high as the right atrium. Renal cell carcinoma is still predominantly a disease for which radical extirpative surgery is not only justified but strongly indicated for locally advanced tumours. Every effort should be made to achieve total surgical

Systemic therapy for metastatic disease

Patients presenting with or having recurrent metastatic renal cell carcinoma in whom no surgical options are advisable should be considered for systemic treatment. Although several active agents now exist for treatment of metastatic disease as discussed below, their general inability to produce durable complete responses necessitates chronic treatment in most patients, and thus benefits must be weighed against the overall burden of treatment, including acute and chronic toxicity, time, and

Immunotherapy

Aldesleukin (interleukin-2) and interferon have been the standard of care for patients with metastatic renal cell carcinoma until recently. Despite the use of these agents for more than 20 years, the effectiveness of these two drugs is still controversial. Several important studies have defined the use of immunotherapy in this disease. Bolus high-dose intravenous aldesleukin initially generated great enthusiasm,97 yet a benefit versus low-dose cytokine regimens was not shown in subsequent

Targeted therapy

The premise of targeted therapy in oncology is the fundamental reliance of tumour cells on biological pathways to which drugs inhibiting those pathways can be applied. An increased understanding of the underlying molecular biology of renal cell carcinoma has established the VEGF and mammalian target of rapamycin (mTOR) pathways as relevant therapeutic targets. The pathogenesis of this tumour was elucidated by the discovery of the VHL gene from study of families with von Hippel-Landau syndrome.

Sunitinib

Sunitinib (Sutent, Pfizer, New York, NY, USA) is a small-molecule inhibitor of the tyrosine-kinase portion of the VEGF family of receptors.120 Patients (n=169) with renal cell carcinoma who had progressed after previous cytokine-based treatment were given sunitinib 50 mg orally four times per day for 4 weeks on followed by 2 weeks off in phase II trials; these patients showed an investigator-assessed objective response rate of 45%, median duration of response was 11·9 months, and median

Temsirolimus

Temsirolimus (Torisel, Wyeth, Collegeville, PA, USA), is an inhibitor of mTOR, a molecule implicated in several tumour-promoting intracellular signalling pathways.129, 130, 131 Regulation of the activation of the mTOR pathway is mediated through a series of complex signalling interactions that link growth factor receptor signalling and other cell stimuli, phosphoinositide-3 kinase activation, and activation of the Akt/protein kinase-B pathway (figure 5 cell stimuli). On stimulation of a cell by

Management strategies for metastatic carcinoma

With the availability of several treatment options, each with a slightly different profile of risk and benefit, there are various options for initial treatment. The choice of treatment approach requires appreciation of the risks and benefits of the drugs discussed and knowledge of the limitations of the present data. The goal for every patient with metastatic renal cell carcinoma on presentation is to maximise overall therapeutic benefit, which means delaying for as long possible a lethal

Conclusions

Renal cell carcinoma has become a model for solid tumours in which an improved understanding of biological pathways has led to systemic treatments that have greatly improved patient outcomes. To move these advances further forward will require integration of surgical and systemic treatments to attain complete remissions, and an increased understanding of the biology of renal cell carcinoma to identify the clinical and molecular phenotype of response and resistance, and to uncover novel targets.

Search strategy and selection criteria

We searched the National Library of Medicine (PubMed; 1980 to present) using the search terms “renal cell carcinoma,” “renal carcinoma”, or “kidney cancer” with further limits defined as published in the past 5 years, studies in adults, and core clinical journals in English. We retrieved 804 articles. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles

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