Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 98–112 (DOI: 10.1159/000355906)

Successes and Limitations of Targeted Therapies in Renal Cell Carcinoma Marc Pracht  · Dominik Berthold Medical Oncology Unit, Department of Oncology, CHUV, Lausanne, Switzerland

Abstract Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are © 2014 S. Karger AG, Basel showing very promising results.

Introduction

Renal cell carcinoma (RCC) represents the sixth most frequent cancer in developed countries [1]; there are about 209,000 new cases of RCC and more than 102,000 deaths worldwide. This corresponds to about 2–3% of all malignant tumors in the adult [2].

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Epidemiology

Table 1. Genetic abnormalities, oncogenic pathways and prevalence associated with sporadic RCC RCC subtype

Genetic abnormality

Oncogenic pathway

Prevalence (sporadic RCC)

Hereditary predisposition syndrome

ccRCC

VHL

VHL/HIF/VEGF PI3K/AKT/mTOR

70–85%

Von Hippel-Lindau disease

Papillary type 1 RCC

cMET

cMET/RAF/MEK/ERK

Hereditary papillary RCC

Papillary type 2 RCC

fumarate hydratase

VHL/HIF/VEGF PI3K/AKT/mTOR

10–15% → 60–75% type 1 → 40% type 2

Hereditary leiomyomatosis and RCC

Chromophobe RCC

BHD1

cKIT/RAF/MEK/ERK

Successes and limitations of targeted therapies in renal cell carcinoma.

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α...
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