Understanding the Importance of Smart Drugs in Renal Cell Carcinoma

european urology 49 (2006) 633–643

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Review – Kidney Cancer

Understanding the Importance of Smart Drugs in Renal Cell Carcinoma Jean-Jacques Patard a,c,*, Nathalie Rioux-Leclercq b,c, Patricia Fergelot c a

Department of Urology, Rennes University Hospital, France Department of Pathology, Rennes University Hospital, France c Department of Oncogenomic, UMR 6061-CNRS, Rennes 1 University, France b

Article info

Abstract

Article history: Accepted January 10, 2006 Published online ahead of print on February 2, 2006

Objective: To understand the mode of action of the currently most investigated new drugs in renal cell carcinoma (RCC) and ultimately to analyze what should be the role of the urologist in this new therapeutic era. Methods: A comprehensive review of the peer-reviewed literature was performed on the topic of molecular pathways involved in RCC angiogenesis, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR) and targeted molecular therapy for RCC. Results: Von Hippel-Lindau (VHL) disease has provided a model for understanding that the early inactivation of the VHL gene was responsible for accumulation of hypoxia-inducible factor and therefore activation of hypoxia-inducible genes such as VEGF, platelet-derived growth factor, erythropoietin, carbonic anhydrase IX and tumor growth factor a. The fact that such VHL inactivation also was found in up to 70% of sporadic RCC has been the rationale for developing new drugs targeting VEGF, VEGFR, platelet-derived growth factor receptor and tyrosine kinase receptors that are required for intracellular transduction. Conclusion: Initial results from phase 2 trials in metastastic disease are very promising. There is a strong rationale for initiating adjuvant trials with those kind of agents in patients with high-risk localised tumors. Urologists who have a good understanding of prognostic parameters in localised RCC particularly should be involved in such new approaches. # 2006 Elsevier B.V. All rights reserved.

Keywords: Renal cell carcinoma Neoplasm metastasis VEGF Neovascularisation Pathologic Angiogenesis inhibitors

* Corresponding author. Department of Urology, Rennes University Hospital, CHU Pontchaillou, Rue Henri le Guillou, 35 033 Rennes, France. Tel. +33 2 99 28 42 70; Fax: +33 2 99 28 41 13. E-mail address: [email protected] (J.-J. Patard).

1.

Introduction

In addition to significant changes in diagnosis and surgical management of renal cell carcinoma (RCC)

that have occurred in the past 20 years [1], dramatic progress has been made in understanding the genetic basis of RCC. Specific genes responsible for von Hippel-Lindau disease (VHL), as well as for

0302-2838/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.01.016

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hereditary papillary renal carcinoma, hereditary leiomyomatosis renal cancer and Birt-Hogg-Dube´ syndrome, have been identified. Furthermore, this discovery has been a key step in understanding that VHL inactivation was present not only in VHL disease but also in sporadic RCC tumors. Recently, new rationally designed therapies with smart drugs targeting pathways involved in signal transduction and angiogenesis have been developed successfully. The objective of this study is to provide an overview of the key molecular pathways that are involved in sporadic RCC in order to understand the mode of action of the currently most investigated new drugs and, ultimately, to analyze what should be the role of the urologist in this new therapeutic era.

2. Familial RCC as a model for understanding molecular targets in RCC VHL disease is a rare autosomal dominant cancer syndrome caused by germline mutations or deletions in a tumor suppressor gene, the VHL gene. Renal tumors which appear in 35% to 45% of affected individuals are bilateral, multifocal and uniformly of the conventional histological type [2]. In 1988, linkage analysis of VHL kindreds mapped the VHL locus to chromosome 3p25 [3]. Subsequently, an international consortium isolated the VHL gene that was characterised as a tumor suppressor gene [4]. The VHL gene fits the description of a Knudson 2-hit tumor suppressor gene [5]. Patients inherit a defective tumor suppressor gene from one parent in every cell (‘‘one hit’’), but do not have tumors until their remaining allele becomes mutated or deleted (‘‘second hit’’). Interestingly, in a high percentage of sporadic conventional RCCs, one copy of the VHL gene is inactivated by mutation and the other copy is lost by deletion [2,6,7]. The VHL gene encodes a protein (pVHL) of 213 amino acid residues [8,9]. pVHL is the substrate recognition component of a ubiquitin ligase complex that targets a protein transcription factor, hypoxiainducible factor (HIF), for proteolysis [10]. pVHL binds to 2 transcription factors, elongin B and C [11,12]. Elongins B and C, when bound to elongin A, constituted a trimeric transcriptional elongation complex called elongin/SIII [13]. As described above, the pVHL complex targets a protein called hypoxia-inducible factor 1a (HIF-1a) for ubiquitin-mediated degradation [14]. HIF-1 binds to DNA as a heterodimer consisting of an a-subunit (HIF-1a) and a b-subunit (HIF-1b). The a-subunits normally are degraded rapidly in the presence of oxygen, whereas the b-subunits are present con-

stitutively [15]. HIF-1a controls the transcription of a number of downstream genes. Under normoxic conditions, the VHL elonginC/B-Cul2 complex targets HIF-1a, leading to their polyubiquitination and proteasomal degradation [16,17]. Under hypoxic conditions as well as VHL gene inactivation, the pVHL complex does not degrade HIF-1a that accumulates in the nucleus, leading to subsequent over-expression of genes that are critical for tumor angiogenesis (vascular endothelial growth factor [VEGF]), glucose transport (GLUT1, GLUT3), glycolysis (6-phosphofructose 2-kinase), pH control (the carbonic anhydrase family), epithelial proliferation (platelet-derived growth factor [PDGF], transforming growth factor a [TGF-a]), erythropoietin (EPO), cell migration and homing (CXCR4) and for apoptosis (Bid, Bax, Bad) [16]. Among genes that are under HIF-1 control, carbonic anhydrase IX (CA IX) is particularly important in RCC. CA IX is a trans-membrane enzyme that plays a role in intra and extra cellular pH regulation. It has been hypothesised that CA IX may allow RCC tumors to accommodate to acidic and hypoxic environment, thereby allowing cancer cells to further proliferate and metastasise [18–21]. A low CA IX expression is correlated with clinical outcome and pathological features [19]. Targeting CA IX currently is explored both in metastatic and adjuvant setting [22]. A link between HIF-1a and cell cycle control also has been demonstrated via up- or down-regulation of cell cycle proteins. Thus, it has been shown that over-expression of HIF-1a induced by hypoxia was paralleled by down-regulation of the cyclin-dependent kinase inhibitor p27. In the same way, reduction or absence of p27 abrogated the hypoxia-induced G1 checkpoint, also suggesting that p27 is a key regulator of G1/S transition in hypoxic cells [23,24]. Finally, there are two active forms of HIF-a called HIF-1a and HIF-2a [25]. Evidences now exist that HIF2a is the oncogenic form of HIF-a [26–28]. In particular Smith et al. recently have identified TGF-a as a HIF-2a specific target. [29,30], which confirms that HIF-2a differs from HIF-1a in its ability to activate specific targets that are involved in oncogenic growth of RCC cells. These data support the concept that EGFR is also an important therapeutic target for VHL-defective renal cancer. All the molecular consequences of VHL inactivation are summarised in Fig. 1.

3. VEGF as a key molecule in tumor angiogenesis Tumor development requires angiogenesis induction. VEGF or VEGF-A and related molecules such as

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Fig. 1 – VHL/HIF pathway and target genes. In normoxic conditions, the HIF-a subunit degradation depends on hydroxylation and binding to pVHL forms with elongin B, C, Cul2 and Rbx1, the E3 ubiquitin ligase complex. HIF-1a and HIF-2a are expressed constitutively either in case of hypoxia or pVHL alteration. HIF-a stabilisation leads to up-regulation of target genes such as VEGF and PDGF. HIF2a activates TGF-a and, thus, is considered the oncogenic form of HIF-a.

VEGF-C and VEGF-D are potent pro-angiogenic factors involved in tumor growth and metastasis. Their intra-cellular signalling pathway, through specific receptors (VEGFRs) with tyrosine kinase (TK) activity, provides interesting targets for antiangiogenic designed drugs. 3.1.

The VEGF family

VEGF (VEGF-A) is a homodimerised glycoprotein whose gene was cloned in 1989 and includes 8 exons coding for a 206 amino acid sequence [31,32]. By alternative splicing of exons 6 and 7, several transcripts are generated; the produced peptides differ by their ability to bind to heparin and heparan sulfate proteoglycans, forming the extracellular matrix. Until now the 189, 183, 165, 148, 145, 121,162 and 165b VEGF splice forms had been described [33,34] (Fig. 2). The VEGF forms that are over-expressed in physiologic as well as in pathologic angiogenesis are VEGF 121, 165 and 189. Homodimerised VEGF 189 is bound predominantly to the extracellular matrix, whereas VEGF 121 and 165 are found mainly in soluble forms. VEGF 165 appears to be essential by its abundance and its functional role. A co-expression of 121, 165 and 189 VEGF splice forms has been found to be associated with high stage, as well as with high vessels count and density, in RCC [35]. Interestingly, VEGF165b,

635

Fig. 2 – Predicted structures of VEGF pre-mRNA and splice forms; exons are not drawn to scale.

which has been found to be down-regulated in RCC [34], is associated with a slow tumor growth rate and seems to correspond to a splice form inhibiting VEGF 165 activity [36]. In addition, some regulators of VEGF bio-disponibility, such as ADAMTS1, a metalloprotease with the ability to bind and sequestrate VEGF 165, have been identified [37]. Two other members of the VEGF family, which are structurally and functionally associated, play an important role in tumor angiogenesis: VEGF-C [38] and VEGF-D [39]. Although these members have a central domain of homology with VEGF called VHD, which contains the cystine knot motive that characterises the VEGF family, they differ from VEGF by the presence of propeptides at their extremities. VEGF-C expression is stimulated by growth factors such as PDGF and EGF but not by hypoxia. Finally it has been suggested through preclinical models that these factors could have important implications in metastatic spreading [40]. Bevacizumab, which is a humanised monoclonal antibody directed against VEGF, recognises all forms of VEGF. 3.2.

VEGF receptors

Three specific receptors of the VEGF family have been identified: VEGFR1 (Flt-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). These receptors have TK activity related to platelet-derived growth factor receptor (PDGFR). VEGF 121 and 165 bind to VEGFR-1, whereas VEGFR-2 is associated with 121, 145, 165 VEGF forms, VEGF-C and VEGF-D. VEGFs C and D bind with VEGFR-3. VEGFRs and their ligands are presented in

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Fig. 3 – Homodimerised VEGFRs and their respective ligands. Binding of ligand homodimers to the transmembrane receptor activates its dimerisation and signal transduction. VEGFR2 is essential for endothelial blood cells proliferation in tumors, whereas VEGFR3 mediates the lymphatic vessels development. The role of VEGFR1 in tumor angiogenesis is not well defined.

Fig. 3. The role of VEGFR-2, which is expressed mainly at the surface of endothelial cells of blood vessels and to a lesser extent on lymphatic vessels, appears to be essential for differentiation, proliferation and vascular permeability [41–44]. VEGFR-3 is expressed on lymphatic vessels and on tumor blood vessels [45]. VEGFR-3 has been correlated positively with VEGF-C in renal tumor lysates [46]. 3.3. VEGF production and molecular mechanisms regulating VEGF expression

VEGF expression is controlled by complex regulation mechanisms including cytokines, growth factors and hormones [47]. VEGF over-expression commonly found in renal tumors can be explained by 3 mechanisms: hypoxia, VHL gene inactivation and stimulation of the Raf-MAPK and PI3-AKT/mTOR pathways. HIF plays an important role in all three mechanisms. [48]. Cell hypoxia stimulates VEGF production by HIF activation of mRNA synthesis and by two translational mechanisms leading to increased protein production. One of the translational mechanisms involves the stabilisation of the VEGF mRNAs through the binding of a protein factor on a determined portion of the 30 untranslated region (30 UTR) [49]. The HuR mRNA binding protein has been identified as one of these factors [50]. A second mechanism that is supposed to be preferentially used in case of hypoxic stress involves the 50 untranslated region (50 UTR) through the CUG codon [51]. A recent study has

shown that the nature of the transcript could control recognition of the initiation codon by the translational machinery, suggesting that hypoxia could favour production of soluble VEGF 121 and 165 forms by tumors cells via transcripts translation [52]. As previously mentioned, VHL tumor suppressor gene inactivation is a key mechanism in tumor angiogenesis stimulation. Molecular consequences of the genetic alterations of the VHL gene include activation of the VEGF gene attributable to the constitutive expression of HIF as well as to the loss of inhibition of the transcription factor Sp1 [53]. Another mechanism is the stabilisation of the VEGF mRNA [54]. A recent study suggests that the association between VHL and HuR protein could favour mRNA degradation. Conversely, in hypoxia conditions, the absence of VHL could lead to mRNA stabilisation through HuR binding to 3’UTR [55]. Genetic variations such as single nucleotide polymorphism (SNP) may account for differences in the basal level of plasma VEGF, the mechanism of which remains unclear [56]. It also is possible that polymorphisms may influence VEGF increase in pathological conditions, but whether specific alleles could influence binding of HuR protein on 30 UTR or alternative splicing events is unknown. Both Raf-MAPK and PI3-AKT/mTOR pathways are involved in VEGF activation in cooperation with HIF [57]. Ras oncogene activation has been described in RCC [58,59]; PTEN, a tumor suppressor gene, frequently is silenced in RCC [60]. PTEN regulates Akt and then mTor activity. It has been hypothesised that Ras could induce VEGF gene transcription through the protein kinase C z (PKC z). Raf as well as PI3-kinase could activate PKC z [61]. Sorafenib and CCI-779 (temsirolimus) target the Raf and mTOR pathways, respectively (Fig. 4). 3.4.

VEGF as a marker

As noted above, the VEGF pathway is essential for understanding RCC biology. VEGF-A is considered a key component of tumor neo-vascularisation, and VEGF-C and -D potentially are involved in tumor spreading. These findings provide a rationale for using VEGF measurement as a prognostic marker. In the era of anti-angiogenic treatments in metastatic as well as in high-risk localised disease, having reliable markers either for prognostication or patient selection, or for treatment monitoring has become an important issue. Few studies on VEGF as a marker in RCC are available [62]. Only soluble forms of VEGF 121 and 165 have been studied. An alternative interesting approach would be to measure soluble VEGFR-2 [63]. Serum VEGF levels seem

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4.1.

Fig. 4 – Summary of molecular mechanisms involved in angiogenesis and tumor growth. New anti-angiogenic molecules and their targets are indicated both in endothelial and tumor cells.

to be associated with stage and grade in RCC; however, an inverse correlation between VEGF mRNA levels and serum VEGF measurements has been found. In addition, VEGF 121 mRNA levels were decreased in locally advanced tumors, compared with metastatic or small localised tumors [64,65]. Such a decrease in transcript levels had been noted previously in highly proliferative RCCs [66]. This finding could be due to an activation of 121 and 165 VEGF forms translation, leading to a reduced mRNA half-life. Finally, an increased interest for circulating VEGF also is due to the recent observation that plasma VEGF is increased in animals bearing tumors after treatment with anti-VEGFR-2 monoclonal antibody. Although the mechanism is not well understood, this rapid and transient increase after treatment could be a surrogate in treated patients for determining the optimal dose schedule in each individual [67].

4. Clinical results with new anti-angiogenic drugs in metastatic RCC At least five major anti-angiogenic drugs currently are being investigated intensively. Primary clinical results available to date are summarised in Table 1. These new drugs were investigated first as secondline treatments in metastatic disease. Initial results are very promising, and phase 3 results are pending. A large number of new trials consisting of first-line approaches or drug combinations are either planned or ongoing. The mechanisms of action of these drugs are summarised in Fig. 4.

637

Bevacizumab

Bevacizumab is a recombinant humanised monoclonal antibody directed against VEGF, which recognises all VEGF isoforms and has a prolonged half-life (17–21 days). Yang et al. have reported recently their results from a randomised phase 2 trial that compared 40 patients with refractory metastatic RCC receiving placebo with 37 patients receiving 3 mg/kg bevacizumab and 39 patients receiving 10 mg/kg bevacizumab [68]. Time to progression (4.8 months) was increased significantly in patients receiving high-dose bevacizumab, compared with those receiving placebo (2.5 months) ( p = 0.001). The probabilities of being progression-free for patients receiving high-dose antibody, low-dose-antibody, and placebo were 64%, 39% and 20%, respectively, at 4 months, and 30%, 14% and 5% at 8 months. The trial was stopped after interim analysis because of observed differences in progression-free survival among groups. Crossover from placebo to bevacizumab was allowed, and no survival difference was detected between groups (13.3 vs 15.1 vs 15.5 months). Treatment generally was well tolerated; hypertension, malaise and proteinuria were the most common side-effects in patients receiving high-dose antibody. A variety of associations between bevacizumab and other drugs currently is being investigated. Although targeting EGFR by monotherapy generally has been disappointing [69,70], Hainsworth et al have published recently their results in 63 patients with metastatic clear-cell RCC receiving bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. The treatment generally was well tolerated. At 8 weeks of treatment, 25% of the patients experienced an objective response, and an additional 61% of the patients had stable disease (SD). Survival rates at 1 and 2 years were 78% and 44%, respectively [71]. In a study comparing bevacizumab alone and bevacizumab with thalidomide, similar toxicity and progression-free survival were found in both groups [72]. However combined blockage of VEGF, EGFR and PDGF by bevacizumab, erlotinib and imatinib in 21 patients with metastatic disease showed only 9% partial response and 61% SD in addition to a significantly higher toxicity [73]. Two, ongoing phase 3 trials in previously nontreated patients is comparing interferon a or interferon a plus placebo and interferon a plus bevacizumab (CALGB 90206 and BO17705). Finally, many other associations with bevacizumab and other drugs, such as high-dose intravenous interleukin 2 (Il-2), subcutaneous outpatient regimens of IL-2,, sorafenib, sunitinib and CCI-779, are planned.

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Table 1 – Primary clinical results currently available with new targeted therapies in metastatic RCC Treatment

RR (%)

SD (%)

RR + SD (%)

TTP/PFS (mo)

Reference

Bevacizumab Bevacizumab and erlotinib

a

39 (10 mg/kg) 63

10 25

64 61

74 86

4.8 11

[68] [71]

Sunitinib Trial 1 Trial 2

63 106

40 44

28 23

68 67

8.7 8.1

[76] [77]

384a 111 52 37

2 33 46 19

78 / 40 46

80 51 86 65

6 5.8 / 5.3

[83] [88] [91] [93]

Sorafenib CCI-779 (temsirolimus) AG013736 PTK787/ZK222584

No. of patients

RR: Response rate; SD: Stable disease; TTP: Time to progression; PFS: progression-free survival. Includes only treated patients.

a

4.2.

SU11248 (sunitinib)

Sunitinib is an oxindol TK inhibitor. It is an oral, small molecule with anti-tumor and anti-angiogenic activity that selectively multi-targets inhibition of PDGFR, VEGFR, KIT and FLT3 [74,75]. Recently, the results of two phase 2 trials as second-line therapies in metastatic RCC have been reported. The two trials included 63 and 106 patients, respectively. The main treatment-related adverse effects in both trials were fatigue (38%, 28%), diarrhoea (24%, 20%), nausea (19%, 13%) and stomatitis (19%, 14%). Grade 3/4 laboratory abnormalities such as neutropenia, anemia, thrombocytopenia and hyperlipasemia were observed in 13% and 16%, 10% and 6%, 0% and 6%, and 21% and 17% in the two trials, respectively. Response rates measured by Response Evaluation Criteria in Solid Tumors (RECIST) had never been observed to date in second-line treatment in the era of immunotherapy. Overall response rate was 40% and 44%, respectively, and SD
3 months was achieved in 28% and 23% of the cases, respectively. Overall 66% of the patients were considered to have a clinical benefit from the treatment. Time to progression was 8.7 and 8.1 months, respectively; overall median survival time was 16.4 months in trial 1, whereas it was not reached in trial 2 [76,77]. A phase 3 trial comparing sunitinib and interferon a in first-line treatment for metastatic RCC has been completed recently. Results will be available shortly. An impressive number of trials combining sunitinib with gefitinib, bevacizumab, gemcitabine, capecitabine or interferon are either planned or currently open. 4.3.

BAY 43-9006 (sorafenib)

Sorafenib is an oral multikinase inhibitor that has been shown to have an anti-tumor activity in

human xenograft RCC models. Although sorafenib was thought originally to be an inhibitor of Raf-1 serine/threonine kinase [78], activity against B-Raf and other TK receptors including VEGFR-2, PDGFR, FLT-3 and c-Kit was subsequently established [79]. After the recommended dose of 400 mg given orally twice daily was established in a phase 1 trial [80], two phase 2 trials showed a significant clinical activity of BAY 43-9006 in RCC. Among 397 patients with a variety of advanced refractory solid tumors who were included in a phase 2 discontinuation study, a 42% response rate along with a 50% SD was obtained in 89 patients with metastatic RCC [81]. Similarly in a phase 2 trial including 41 patients with RCC metastatic disease, Ahmad et al reported a 40% response rate and a 30% SD [82]. A phase 3 trial comparing sorafenib and placebo after failure of a prior systemic therapy has been completed recently in 905 patients. Enrollment ended in February 2005 and preliminary results are available in 769 patients [83]. Dose modification was noticed in 25% of patients in the sorafenib arm, including 78% for adverse events; however, treatment discontinuation in 38% of the cases was due to adverse events in only 9% of the cases. The most common side-effects were skin rash or desquamation (31%), diarrhoea (30%), hand-foot skin reaction (26%) and fatigue (18%). Hypertension (8%) and neuropathy (9%) were observed more rarely. No significant haematological or biochemical toxicity was observed. Partial response and SD were observed in 2% and 78% of the patients treated with sorafenib, resulting in a 80% clinical benefit, compared with 0% and 55% for patients in the placebo arm. Median progressionfree survival time was 24 weeks in the sorafenib arm, compared with 12 weeks in the placebo arm ( p < 0.000001). A trial comparing BAY-9005 and interferon a2a as first-line treatments is now ongoing.

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4.4.

CCI-779 (temsirolimus)

CCI-779 is a specific inhibitor of mTOR, a serine/ threonine kinase that plays a key role in cell cycle regulation. mTor is a downstream effector of phosphatidyl-inositol-3-kinase (PI3K) and Akt signalling pathways [84]. PTEN, a tumor suppressor gene that is frequently silenced via methylation in RCC, regulates Akt and then mTor activity [85]. Interestingly, mTor activation leads to increase HIF1-a, especially in VHL/ cells, and mTor inhibitors can inhibit HIF activity [86]. In phase 1 studies the most common CCI-779-related side-effects were acne, rashes, mucositis/stomatitis, asthenia and nausea [87]. Recently, in a phase 2 study including 111 patients with metastatic RCCs who had failed a previous line of treatment, Atkins et al found partial and minor response in 7% and 26% of the cases, respectively. The overall clinical benefit was 51%, median time to progression was 5.8 months and median survival time was 15 months with 26% alive at 2 years [88]. In a phase 1 study evaluating the association of temsirolimus and interferon a in 71 patients with advanced RCC, the maximal tolerated dose was 15 mg temsirolimus once weekly plus 6MU interferon a at 3 times weekly. The objective response rate was 11%, the overall clinical benefit was 41% and median time to progression was 9.1 months [89]. Finally a phase 3 study comparing interferon- a alone, temsirolimus alone and the association of both drugs has been initiated in poor prognostic patients. 4.5.

AG013736

AG013736 is a TK inhibitor that targets VEGFR-1, -2 and -3, PDGFR-B and c-Kit. In a phase 1 study evaluating 36 patients, including 6 RCCs, the main observed toxicities were hypertension (61%), fatigue (28%), nausea (19%), diarrhoea (17%), vomiting (14%), headache (14%), erythema (11%) and stomatitis (11%) [90]. In a phase 2 trial including 52 patients with measurable, metastatic RCC, a 5-mg AG013736 oral dose was given twice daily continuously until disease progression or unacceptable toxicity occurred. All patients had received a previous interferon or IL-2-based therapy. Partial response and SD were observed in 46% and 40% of the cases, respectively, resulting in an impressive 86% clinical benefit rate. Treatment was discontinued in 54% of the cases because of drug-related adverse events in only 12% of the cases [91]. Perfusion imaging studies supported a reduction in tumor permeability/blood flow during therapy [92]. A second-line monotherapy study with AG013736 in sorafenib refractory tumors is planned.

4.6.

639

PTK787/ZK222584

PTK787/ZK222584 is an oral inhibitor of VEGFR-1, VEGFR-2 and PDGFR tyrosine kinases. In 37 evaluable patients with mRCC participating in a phase 1/2 trial, a measurable response was obtained in 7 patients (19%); 46% achieved stable disease. The median time to progression was 5.5 months [93]. 5. Perspectives: the role of the urologist in the era of new targeted therapies Although preliminary results with targeted therapies in RCC are promising, a huge number of questions need to be answered: the impact of these drugs on survival and on quality of life, the more effective drug in first-line treatment, the place of combined therapies and the type of drugs that should be used in combination, the optimal secondline schedule, the mechanisms for resistance to anti-angiogenic treatments, the required modalities for predicting and evaluating response (genomics, biology, imaging) and finally the morbidity of a chronic drug administration. Clearly, classic RECIST criteria are no longer appropriate for evaluating response to anti-angiogenic drugs and ‘‘SD’’ or ‘‘clinical benefit’’ criteria are ambiguous. Further studies are needed to identify criteria that could be reliable surrogates for survival. In the metastatic setting, urologists have to establish a well-balanced partnership with medical oncologists. Urologists have to learn from the medical oncologists about the management of new specific drug toxicities that are generally moderate, such as fatigue, rash, diarrhoea, hypertension and proteinuria. There is no doubt that urologists interested in oncology will prescribe those drugs in the near future. In addition, some specific questions have to be revisited by urologists: the place of nephrectomy, the place of a second-look surgery after initial response, the place of surgery of metastases and the timing of surgery for preventing specific surgical complications attributable to tumor necrosis. Even more importantly, the urologist should have a pivotal role in adjuvant treatment. Urologists are well aware of prognostic factors in localised tumors, and prognostics systems have been established that can be useful for selecting high-risk patients [94,95]. At this time only one randomised study based on a vaccine strategy has shown positive results in preventing progression in locally advanced tumors [96]. Recently the first part of an international phase 3 trial based on a heat shock protein vaccine strategy has been completed: 818 patients with T1b,

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T2 G3-G4, T3a-c, T4N0M0 and N1-2M0 have been randomised between observation and vaccine. Results are awaited. Currently, another international, double-blind, randomised study comparing placebo and anti G250 (CA IX) antibody infusion treatment in high-risk, localised tumors is ongoing; 600 patients will be included. Finally, anti-angiogenic drugs also will be tested in the adjuvant setting. A planned phase 3 trial will compare sunitinib, sorafenib and placebo (ECOG 2805) in high-risk, localised tumors. Finally an international, randomised, double-blind, controlled phase 3 study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high- or intermediate-risk or relapse (SORCE) also is planned. The risk stratification is based on the Mayo Clinic prognostic system [97]. Undoubtedly a new era in the treatment of RCC is now open, and urologists have to be aware of the rapid progress that is ongoing. To stay up-todate, urologists have to be interested in understanding the molecular pathways that are involved in RCC and have to be strongly committed in clinical trials.

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