Medical Treatment of Advanced Renal Cell Carcinoma: Present Options and Future Directions

european urology supplements 5 (2006) 619 626 available at www.sciencedirect.com journal homepage: www.europeanurology.com Medical Treatment of Advanced Renal Cell Carcinoma: Present Options and Future Directions Francesco M. Boccardo *, Pamela Guglielmini, Laura Tacchini University and National Cancer Research Institute, Genoa, Italy Article info Keywords: Chemotherapy Immunotherapy Metastatic renal cell carcinoma Targeted therapies Abstract Objectives: This paper reviews the status of the art concerning medical treatment of advanced renal cell cancer (RCC) and new therapeutic options, namely, targeted therapies. Methods: The review was based on the most recent and relevant papers appearing in the literature. Results: Cytokines, including interferon-a (IFN-a) andinterleukin2 (IL-2) represent the treatment of choice for most RCC patients. Highdose IL-2 provides a limited but clinically relevant proportion of patients with durable response benefit. Although hormone therapy has only historical value, cytotoxic chemotherapy is an option for patients who become refractory to immunotherapies. Results achieved with cytotoxic drugs are usually poor, though 5-fluororacil, capecitabine, and gemcitabine have moderate activity coupled with manageable toxicity. Growing understanding of RCC biology has provided new targets for biologic therapies. Antiangiogenic drugs, which include monoclonal antibodies against vascular endothelial growth factor (VEGF), such as bevacizumab, or small molecules targeting VEGF receptors, such as SU011248, PTK787/2K22254, and BAY 43-9006, look promising, either alone or in combination with cytokines or cytotoxic drugs. Conclusions: The management of patients with metastatic RCC is still frustrating because the most of these patients die of their disease. Although a limited subset of patients can experience clinically meaningful benefit from IL-2 or IFN-a therapy and a limited benefit, if any, can be achieved in these patients with conventional chemotherapy, there is no other proven effective therapy for patients who do not respond or who relapse after cytokine-based treatment. Better understanding of RCC biology has provided insights on relevant signal transduction pathways, genetic mutations, and tumour susceptibilities to innate immune response resulting in novel treatment strategies that promise to affect the natural history of this lethal disease. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. National Cancer Research Institute and the University of Genoa, Largo R. Benzi 10, 16132 Genoa, Italy. Tel. +39 0105600503; Fax: +39 010352753. E-mail address: f.boccardo@unige.it (F.M. Boccardo). 1569-9056/$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.03.007

620 european urology supplements 5 (2006) 619 626 1. Introduction Renal cell cancer (RCC) accounts for about 2 3% of all solid tumours and 30,000 new cases are diagnosed each year in the United States [1]. In Italy, 5000 new cases are expected each year [2]. Tumour incidence has been increasing during the last two decades in most Western countries [3]. This trend is not likely to reflect simply an aging population and increasing detection of incidental tumours, that today account for up to 60% of newly diagnosed cancers [4,5]. Mortality is also increasing [6]. Unfortunately the high prevalence of tumours diagnosed at an early stage is not paralleled by decline in the proportion of patients who already have metastases at the onset, who represent about 30% of newly diagnosed patients. Moreover, another consistent proportion of patients, about 50%, is destined to develop metastatic disease following nephrectomy. Unfortunately, though a few patients can survive for many years, metastatic RCC is still a lethal disease in the majority of cases and no treatment can be considered as standard. 2. Immunotherapy with cytokines Innate immunity plays a role in the control of renal cancer growth. Evidence suggests that immune responses to RCC may protect patients against progression of the disease and in some cases mediate tumour regression [7]. Immunoreactive cytokines have been the mainstay of treatment of RCC for the past 20 yr. Most studies focused on interferon-a (IFN-a) and interleukin 2 (IL-2). IFN-a has a number of effects, all of which contribute to its therapeutic activity in metastatic RCC: the direct inhibition of tumour cell proliferation, the increase of the lytic activity of natural killer cells, and an increased expression of the human HLA class I on tumor cells [8]. IFN has been studied in a variety of preparations, doses, and schedules, but most studies have shown the agent to have modest antitumour activity [9]. Nonetheless, IFN-a still represents one of the therapeutic options available in the front-line treatment of metastatic RCC. This treatment is generally well tolerated and is effective in about 10 15% of patients. Patients with a long disease-free interval, prior nephrectomy, good performance status, and lung or lymph node metastatic disease are those candidates who gain the greatest benefit from IFN-a treatment. Motzer et al [10] have shown that poor response to INF-a treatment is also associated with high serum lactate dehydrogenase levels, low haemoglobin concentration, and time from initial RCC diagnosis to start of therapy of <1 yr. Whether IFN-a treatment does affect patients survival still represents an open question. A recent update from the Cochrane database concluded that INF-a provides a modest survival benefit compared to the other commonly used treatments [11]. Results of a phase 3 trial comparing INF-a in combination with vinblastine chemotherapy versus vinblastine alone reporting a median survival of 67.6 wk for the combination arm compared with 37.8 wk for patients receiving vinblastine alone are usually cited to support a survival benefit from IFN-a [12]. In the attempt to increase the therapeutic efficacy of INF-a treatment, several drugs have been combined with this cytokine, including IL-2 and other cytokines, retinoids, and cytotoxic chemotherapy. Though a few combinations appeared to improve response rates achieved with INF-a alone, no additional survival benefits have emerged from randomised trials [13 16]. IL-2 is a biologic agent that mediates its antitumour effects enhancing the growth of natural killer cells and T lymphocytes. In 1985, Rosenberg described first responses in RCC with high-dose intravenous bolus IL-2 and adoptive immunotherapy with lymphokine-activated killer (LAK) cells [17]. In the United States, IL-2 received Food and Drug Administration approval for the treatment of patients with metastatic RCC in 1992 based on the results of two phase 2 clinical trials. In these studies, which have been reported after pooling of the results [18], patients received an intravenous bolus of 600,000 720,000 IU/kg recombinant human IL-2. Objective responses were seen in 37 (15%) of the 255 patients enrolled, including 17 complete responses (7%). The median survival was 16 mo. Follow-up data on these patients accumulated at median follow-up time of >10 yr confirm the durability of these responses [19]. Although some late relapses have been observed, the response duration curve appears to have leveled off after the 30-mo time point and 60% of complete responders remain in remission. These investigators conclude that a necessary step in obtaining long-term disease-free survival for patients is to achieve documented complete remissions. Although the inpatient highdose bolus IL-2 produces favourable outcomes in a handful of patients, it is associated with significant toxic effects [18,19]. Low-dose IL-2 regimens have produced similar response and survival rates in nonrandomised phase 2 trials but responses appeared to be less durable than those seen with high-dose IL-2 [20,21].

european urology supplements 5 (2006) 619 626 621 Several trials have tested the value of high-dose IL-2 versus low-dose IL-2. However, results of these trials are not easy to interpret because some of them have compared IL-2 versus IL-2 plus IFN, whereas others have compared different schedules and routes of administration. The US National Cancer Institute (NCI) group compared response and survival rates achieved either by intravenous bolus high-dose IL-2 or by intravenous bolus lowdose IL-2. A third arm based on the administration of low-dose subcutaneous IL-2 was added following preliminary findings with subcutaneous regimens. There was a higher response proportion with highdose intravenous IL-2 (21%) versus low-dose intravenous IL-2 (13%) but no overall survival difference. The response rate of subcutaneous low-dose IL-2 (10%) was comparable to that of intravenous lowdose IL-2 but differed significantly from intravenous high-dose IL-2. Response durability and survival in completely responding patients was superior with high-dose intravenous compared to low-dose intravenous therapy [22]. These investigators concluded that until long-term follow-up of low-dose IL-2 regimens document both durable responses and survival, high-dose intravenous IL-2 remains the therapy of choice for patients with metastatic RCC who have a good performance status. Two additional studies have compared high-dose IL-2 with low-dose IL-2 combined with IFN-a [23,24]. In both studies toxicities were less frequent and severe in patients receiving low-dose IL-2 and IFN-a. However, significantly lower response rates were reported in the low-dose IL-2 arm. Although no significant difference in overall survival was observed between groups in either study, a survival benefit trend in favour of patients receiving highdose IL-2 was observed. A few studies have compared the value of INF-a versus that of IL-2. As previously reported, a French collaborative group [13] compared IL-2 versus IFN-a versus the combination of both drugs, reporting the superiority of the combination over the other two. In this study there was no difference in response and survival rates between IL-2 and IFN-a; however, the response rate observed in patients receiving IL-2 monotherapy was 6.5%, an activity rate far lower than that commonly reported for IL-2 monotherapy. More recently, the same collaborative group performed a 2 2 factorial design trial to test the impact of treatment with cytokines on survival of RCC patients with intermediate prognosis [25]. In this study patients were randomly assigned to receive either medroxyprogesterone acetate (MPA) alone or subcutaneous IFN-a or subcutaneous IL-2 or both treatments. Response rates were low in all groups and no survival benefit was observed in favour of patients treated with cytokines as compared with those receiving MPA. These investigators concluded that, at least in the group of patients selected for this trial, neither IFN-a nor IL-2 was able to have an impact on patients survival and, therefore, their study did not support the use of cytokines any longer [25]. Recent studies have tried to identify factors predictive of the response to IL-2 therapy, so that this treatment could be limited to the patients most likely to benefit from it. Prior nephrectomy and time from nephrectomy to relapse both appear to be important predictors of survival in patients receiving therapy based on IL-2 [26]. Although prognostic models for RCC based on clinical variables alone have proven useful, molecular markers as additional predictors of response and survival in patients receiving cytokine-based immunotherapy are necessary. Studies based on tissue microarray analysis have revealed that >90% of RCCs express carbonic anhydrase IX and that the high expression of this enzyme is associated with improved overall survival and higher probability of response to IL-2 based therapy [27]. 3. Other forms of immunotherapy Cellular therapy originally implied the use of LAK cells and then included tumour-infiltrating lymphocytes (TILs). Unfortunately, these approaches have not led to improved therapeutic outcomes [28]. Dendritic cells (DCs) are antigen-presenting cells that are capable of inducing primary immune responses. Several studies have examined the ability of DC-based vaccines to generate tumourspecific immune responses in patients with RCC. These studies have shown that vaccination was well tolerated and that immunologic response and disease regression could be observed in a subset of patients. These findings warrant additional investigation with this approach especially in more favourable settings [28]. Another area in the cell treatment of RCC is based on the use of allogeneic haematopoietic stem cell transplantation. This approach is aimed at developing an acute graft-versus-tumour disease. Child et al. [29] showed that nonmyeloablative allogeneic stem cell transplantation was able to induce regression of metastatic RCC in 10 of 19 patients, with 3 of the responding patients achieving a complete response and being in remission at 27, 25, and 16 mo, respectively, after transplantation.

622 european urology supplements 5 (2006) 619 626 Unfortunately, this approach is quite toxic and cannot be delivered outside specialised centres. In the study reported on by Child, 10 patients developed graft-versus-host disease and two patients died of transplantation-related complications [29]. 4. Chemotherapy Due to the frequent overexpression of the multidrug resistant (MDR) gene product P-glycoprotein, RCC is generally considered a chemoresistant tumour. Currently, there is not a standard chemotherapy regimen for RCC. Traditional cytotoxic chemotherapeutic regimens fail to affect the natural history of RCC and thus typically yield poor results. In fact, a comprehensive review on these regimens by Yagoda et al in 1995 revealed an overall response rate of 6% among 4093 patients with advanced RCC who received adequate treatment, with only a slight improvement (14.6% response rate) in a subgroup of patients who were treated with an antimetabolite (floxuridine or 5-fluorouracil) [30]. Despite the discovery of several new cytotoxic agents in the last 10 yr, the unsatisfactory state of RCC treatment was no different by the year 2000, when Ruiz et al reviewed single and multiagent phase 2 and 3 trials that had been performed between 1993 and 1998, enrolling more than 2300 patients [31]. Only a small percentage of all antiproliferative agents tested demonstrated activity. Vinblastine obtained a response rate of about 10% in various studies but with short duration and modest impact on the average survival rate. The most encouraging results have been obtained with 5-fluorouracil and gemcitabine as single agents or in combination [32]. Capecitabine has been also tested as single agent and in combination with modest activity but manageable toxicity [33]. 5. Hormone therapy It is well established that RCC expresses receptors for oestrogen, progesterone, and testosterone. Clinical and epidemiologic observations led to the conclusion that hormones may affect the growth of RCC [34]. Since the pioneering work of Bloom [35], numerous studies have investigated the clinical usefulness of these compounds, but hormonal therapy has been largely ineffective in the treatment of RCC, with <5% of patients showing an objective response to hormonal manipulations and currently this treatment modality has only historical value [36]. 6. Targeted therapies A growing understanding of the biology of RCC has indicated vascular endothelial growth factor (VEGF) as a logical therapeutic target. VEGF is a tumoursecreted cytokine with critical importance in both normal and tumour-associated angiogenesis [37], which exerts its biologic effects through the interaction with tyrosine kinase receptors present on the cell surface of vascular endothelial cells (VEGFR1, VEGFR2) or lymphatic and vascular endothelium (VEGFR3) [38]. On binding of VEGF to the extracellular domain of the receptor, dimerisation and autophosphorylation of the intracellular receptor tyrosine kinases occur and a cascade of downstream proteins is activated. In RCC, VEGF expression results from inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene, which is observed in the majority of tumours, thus identifying VEGF as a critical component of RCC tumour angiogenesis and a particularly relevant therapeutic target for this disease. Several compounds have shown antiangiogenic properties, including thalidomide, AE-941 (Neovastat), and VEGF trap. The most promising results have been achieved with neutralising antibodies against VEGF and small molecules capable of inhibiting VEGF and other growth receptor tyrosine kinases (Table 1). Bevacizumab is a recombinant human monoclonal antibody against VEGF. A phase 2 trial in which 116 patients were randomised to placebo, low-dose bevacizumab, or high-dose bevacizumab showed 10% objective response rate in the high-dose arm. However, patients in this arm demonstrated a significantly longer time to progression when compared with placebo[39]. Treatment with bevacizumab was well tolerated and no life-threatening adverse events attributable to this drug were observed [39]. In a phase 2 multicentre trial, bevacizumab was evaluated in combination with erlotinib, an antibody directed versus the epidermal growth factor receptor. Most recent results confirmed the high level of activity of this combination with a 1-yr progression-free survival rate of 52% in patients with metastatic RCC, and support continued exploration of this combination as well as other rational combinations of targeted agents [40]. The VEGF receptor is the main target of small molecules such as BAY 43-9006, SU011248, and PTK787/2K22254 [41]. BAY 43-9006 is an orally available bi-aryl urea RAF kinase inhibitor, with demonstrated inhibition of RAS-dependent human tumour xenograft models. Among other effects, activated Ras initiates the Raf/MEK/ERK pathway by binding to and activating Raf kinase. BAY 43-9006

european urology supplements 5 (2006) 619 626 623 Table 1 Efficacy of novel targeted therapies in renal cell carcinoma Drug name Target Description Phase of study Efficacy in RCC Bevacizumab VEGF Recombinant, humanised, monoclonal antibody Phase 2 study (placebo vs. low-dose or high-dose bevacizumab) Phase 3 study (IFN-a with or without bevacizumab) 116 patients enrolled: 10% ORR in high-dose arm; significantly prolonged time to disease progression compared with placebo; bevacizumab-treated patients more likely to be disease progression free at 4 mo vs. placebotreated patients. No significant effects on survival [39]. Completed enrollment. No results available yet. BAY 43-9006 VEGFR, PDGFR, RAF kinase Multi-kinase inhibitor Phase 2 study (single agent) 63 RCC patients enrolled: clinical benefit (OR + SD) achieved in 66% of patients [43]. Combination safe and well tolerated [46]. 14 of 40 planned patients enrolled: clinical benefit demonstrated in 8 patients [47]. 900 patients enrolled: clinical benefit achieved by 78% of patients, 39% survival improvement for patients receiving BAY 43-9006 [44,45]. Ongoing Phase 1 study (BAY 43-9006 + IFN-a) Phase 2 study (BAY 43-9006 + IFN-a) Phase 3 study (placebo-controlled trial) Phase 3 study (BAY 43-9006 + IFN-a vs. IFN-a alone) PTK787/2K22254 VEGFR-1, VEGFR-2, VEGFR-3 Selective tyrosine kinase inhibitor Phase 1/2 study 41 patients enrolled: clinical benefit observed in 66% of patients. OS rate at 1 yr: 63.7% [41]. SU011248 VEGFR, PDGFR, FLT3, KIT Selective tyrosine kinase inhibitor Phase 2 study Clinical benefit (PR + SD) observed in 77% of patients. Median duration of response: >10 mo. Median TTP and median OS: 16 mo [49]. Ongoing Phase 3 (SU011248 vs. INF-a) Erlotinib EGFR Small-molecule EGFR inhibitor Phase 2 study (single agent) Phase 2 study (bevacizumab plus erlotinib) 40 patients enrolled. Clinical benefit observed in 23% of patients (heavily pretreated) [50]. Median progression-free survival (all patients): 11 mo; 1-yr progression-free survival: responders (CR + PR): 80%; minor responders: 57%; stable disease: 27% [40]. RCC = renal cell carcinoma; VEGF = vascular endothelial growth factor; ORR = overall response rate; IFN-a = interferon-a; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; OR + SD = overall response + stable disease; OS = overall survival; PR + SD = partial response + stable disease; TTP = time to tumour progression; EGFR = endothelial growth factor receptor; CR + PR = complete response + partial response. has also demonstrated direct inhibition of VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor b (PDGFR-b). Given that Ras mutations are rare in RCC, the predominant antitumour mechanism of BAY 43-9006 in RCC may indeed be inhibition of VEGFR [42]. A phase 2 randomised discontinuation study with BAY 43-9006 has been performed in refractory solid

624 european urology supplements 5 (2006) 619 626 tumours, including 203 patients with metastatic RCC. Of the 63 assessable RCC patients who had reached the initial 12-wk assessment point, 25 patients (38%) achieved an objective response and 18 patients (28%) achieved stable disease [43]. These results provided the rationale for a randomised, placebo-controlled phase 3 trial of BAY 43-9006 in cytokine-refractory RCC patients. Though only a 2% response rate was observed in this prospectively controlled trial, up to 78% of the patients assigned to BAY 43-9006 showed a clinical benefit [44]. An updated analysis of this trial showed clinical benefit to translate into a survival benefit with an estimated 39% survival improvement (HR: 0.72; p < 0.01) in favour of BAY 43-9006 [45]. A preliminary evaluation of the combination of IFN-a2a and BAY 43-9006 was performed in the frame of a phase 1 study. The maximum tolerated doses were 400 mg twice a day for BAY 43-9006 and 9 MIU three times a week for IFN-a2a. At these dosages the combination was safe and moderately well tolerated [46]. In view of these preliminary results, this combination has been selected for a phase 2 study. To date, 14 of the originally planned 40 patients were enrolled, 8 of whom were evaluable for tumour response; of these, 3 patients achieved a partial response, 3 had stable disease, and 1 patient had a minor response [47]. These preliminary results are encouraging and suggest that this combination might be active also in patients previously treated with IL-2. The therapeutic value of this combination is now being tested through a large comparative trial versus IFN alone. SU11248 is a novel small molecule receptor tyrosine kinase inhibitor with direct antitumour as well as antiangiogenic activity via targeting VEGF, PDGF, KIT, and FLT3 receptor tyrosine kinases [48]. The antitumour activity against metastatic RCC has been studied in two independent single-arm trials. These trials included 169 patients with metastatic RCC and showed that SU11248 has substantial antitumour activity even when used as second-line therapy. The objective response rate of 40% coupled with a median time to progression of 8.3 mo and median survival of 16 mo observed in trial 1 are particularly encouraging when compared to prior studies of second-line therapy in RCC [49]. Phase 3 study results in untreated, metastatic RCC versus INF-a are awaited. 7. Conclusions The management of patients with metastatic RCC is still one of the most frustrating tasks because the great majority of these patients die of their disease. 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