Urologic Oncology: Seminars and Original Investigations
Review articleA survey of therapy for advanced renal cell carcinoma
Introduction
RCC represents approximately 2% of all malignancies and 80% to 85% of kidney tumors in adults [1], [2]. The incidence is increasing worldwide and mortality exceeds 100,000 patients each year. Although localized RCC may be cured by surgery, it often arises without early symptoms, so that most patients are diagnosed when distant metastases are present and curative surgery is no longer possible [3]. Moreover, about 30% of patients eligible for radical nephrectomy will relapse after surgery. Metastatic RCC is resistant both to conventional chemotherapy and to radiotherapy; different approaches have therefore been explored since the early 1990s, focusing mainly on the modulation of immune response. Although some impressive results have been achieved, the response rate (RR) is still very low and the overall 5-year survival of patients with metastatic RCC is less than 10% [4].
There are several subtypes of RCC, but more than 80% of all tumors show a clear cell carcinoma histology. Because clear cell carcinoma of the kidney is extremely common in patients affected by von Hippel Lindau (VHL) syndrome, several investigators have studied the role of the VHL gene in the pathogenesis of RCC. The loss of function of this gene (VHL) is associated with a constitutive activation of hypoxic response resulting from up-regulation of both the HIF-1α and HIF-2α subunits of hypoxia inducible factor (HIF) [5]. Up-regulation of HIF leads to the overexpression of many genes, such as vascular endothelial growth factor (VEFG), transforming growth factor (TGF)-α, c-Met, stromal cell-derived factor (SDF)-1, chemokine receptor CXCR4, and others [6], [7].
The overexpression of VEGF has been found in the majority of RCC patients by evaluating mRNA levels and VEGF proteins in RCC tumor tissues [8]. VEGF exerts its effect by binding tyrosine kinase receptors on the cell surface, including VEGFR-1, VEGFR-2, VEGFR-3, and neuropilin receptor [9].
In the last 2 years, many drugs, which, despite their different mechanisms of action, are able to interfere with angiogenesis, have been shown to be effective in advanced RCC. The aim of this paper is to summarize the results of cytokine therapy, which was the standard option for RCC patients until the last 2 years, and to discuss the results of recent trials that have investigated newer agents.
Section snippets
Surgery
The disappointing outcome of medical treatment and radiotherapy has led to an increased use of surgery even in advanced disease in order to improve the quality of life by removing the primary tumor or to improve survival or disease-free survival (DFS) in selected patients with single or few metastases. In contrast to treatment for many other solid tumors, removal of the primary tumor is often performed in advanced RCC even in the presence of metastatic disease. Apart from anecdotal reports of a
Chemotherapy
Most conventional agents have been proved ineffective in the treatment of advanced RCC, with a response rate lower than 10% [20]. In spite of this, some of these agents, such as vinblastine (VBL), are often used in a palliative context. Only a few of the newer cytotoxic drugs have shown some effectiveness in the treatment of advanced disease. The combination of gemcitabine and capecitabine showed a RR of 15.8% in a small phase II study [21]. Moreover, gemcitabine combined with doxorubicin
Interleukin-2 and interferon-α
High-dose interleukin-2 (HD IL-2) was approved by the U.S. Food and Drug Administration for front-line treatment of advanced RCC in 1992 following publication of the results of seven phase II studies that had enrolled 255 patients affected by stage IV RCC [25]. In these studies, patients were treated with HD IL-2 (doses ranging between 600,000 and 720,000 IU/kg) by 15-minute infusion every 8 hours for up to 14 consecutive doses over 5 days, followed by a second identical cycle after 5 to 9 days
Sorafenib
Sorafenib is a multikinase inhibitor and was the first drug to be approved for the treatment of advanced RCC by the US FDA since 1992, when IL-2 was licensed for the same indication. Initially, sorafenib was shown to be a strong inhibitor of Raf [41], whose abnormal activation through the Raf/MEK/ERK pathway can promote cell proliferation. Further studies demonstrated that sorafenib is also able to block other kinases, such as VEGFR-2, VEGFR-3, platelet-derived growth factor receptor ß (PDGF-
Sunitinib
Sunitinib malate is a strong inhibitor of multiple kinases, including VEGFR type 1–3, PDGFR-α and PDGFR-β kinases, which play important roles in the pathogenesis of many tumors [50], [51]. Preclinical data have shown that in vitro, sunitinib malate is able to inhibit VEGF-related proliferation but that its anti-tumor activity might also be related to a direct antineoplastic effect [50], [52], [53].
Phase I clinical studies, although designed to investigate the maximum tolerated dose (MTD), have
Bevacizumab
Bevacizumab is a monoclonal recombinant humanized antibody that binds and neutralizes all biologically active isoforms of VEGF [58]. It has a well documented efficacy in first-line treatment of advanced colorectal cancer in combination with 5-fluorouracil, folinic acid, and irinotecan [59]; its efficacy has also been demonstrated in front-line chemotherapy of advanced breast cancer and non-small-cell lung cancer in combination with paclitaxel and carboplatin [60].
The activity of bevacizumab in
Temsirolimus and everolimus
Temsirolimus (CCI-779) is a an inhibitor of mammalian target of rapamycin (mTOR) kinase, whose abnormal activation is involved in multiple signaling pathways promoting cell growth, cell proliferation, and response to oxygen deprivation, including synthesis of hypoxia-inducible factor 1-α [64], [65], [66]. The blockage of mTOR signaling suppresses the production of multiple proteins that regulate progression through the cell cycle and angiogenesis [67], [68].
Some effect was observed in phase I
Combinations of molecular targeted agents
Once several different agents had been shown to be active, studies of combination therapy were started. At the time of writing, only preliminary results from phases I or II studies are available, mainly concerning the combination of bevacizumab with sunitinib, sorafenib, temsirolimus, and everolimus (Table 2).
The safety and MTD of the combination of sunitinib and bevacizumab was assessed in a phase I study [77]. Patients received escalating daily doses of sunitinib (25 mg, 37.5 and 50 mg) with
Non-clear cell renal cancer
Non-clear cell histologies, including papillary (pRCC), chromophobe (chRCC), collecting duct, and unclassified cell types account for 10% to 20% of all RCC. Metastatic nccRCC are characterized by resistance to systemic therapy and poor survival, with longer survival for chRCC than for pRCC or collecting duct tumors in historic data (20 vs. 5.5 months, respectively) [82].
A retrospective phase II analysis of 53 patients affected by pRCC and chRCC showed that both sunitinib and sorafenib were
The role of surgery and multimodality therapy in the era of targeted therapies
Radical nephrectomy is the treatment of choice for initial stage RCC as well as in locally advanced disease. In the latter case, the recurrence rate is very high, ranging between 50% and 85%, according to tumor stage and nodal involvement. Two large randomized trials showed that neither IFN nor IL-2 improve PFS and OS in radically resected high-risk patients [88], [89]. The availability of new active drugs might be a potentially useful option for these patients, but no adjuvant trial has been
Discussion and future directions
Our expanding knowledge of the biology of RCC has extended the range of possible targets of therapy for this cancer (Table 1). Anti-angiogenic agents and multikinase inhibitors have increased the armamentarium available for the treatment of advanced RCC. Other agents, such as mTOR inhibitors, are also receiving attention and are gaining ground in this field. As a result, a fairly wide range of choices is now available to the oncologist, implying the need for a careful evaluation of data from
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