The Role of Multitargeted Therapies in the Adjuvant Setting in Renal Cell Carcinoma

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1 european urology supplements 7 (2008) available at journal homepage: The Role of Multitargeted Therapies in the Adjuvant Setting in Renal Cell Carcinoma Jan Roigas * Department of Urology, Campus Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, D Berlin, Germany Article info Keywords: Adjuvant therapy Angiogenesis PDGF Renal cell carcinoma Sorafenib Sunitinib VEGF Abstract The annual incidence of renal cell carcinoma (RCC) is approximately 2% in Europe and this figure continues to rise. This can largely be attributed to greater success in detecting small renal masses (<4 cm). There has been a corresponding increase in the rate of surgical treatment for small tumours. However, earlier identification and radical intervention has not led to a reduction in mortality among patients with RCC. The options for nephrectomy have expanded beyond radical procedures and now encompass laparoscopic techniques that offer potential advantages in both perioperative and postoperative settings. In addition, the introduction of multitargeted receptor tyrosine kinase inhibitors has improved the prognosis for many patients with advanced RCC. This review explores how improvements in surgical techniques and the potential value of using multitargeted receptor tyrosine kinase inhibitors in the adjuvant setting might provide an opportunity to improve the prognosis of patients with a diagnosis of RCC. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel ; Fax: address: jan.roigas@charite.de. 1. Introduction In 1969, Charles J. Robson and colleagues published a paper describing what was to become regarded as the gold standard for renal cell carcinoma (RCC) radical surgery [1]. Techniques described include early ligation of the renal artery and vein, complete removal of the perinephric envelope, and surgical extirpation of the lymphatic field. Although this standard has remained valid for decades, urologists now need to question whether this gold standard remains relevant given the continual advances being made in surgical techniques and our improved knowledge of prognostic indicators. Analysis of the Surveillance Epidemiology and End Results (SEER) database, which contains information on >34,500 patients, demonstrates that the rising incidence of RCC observed over the past few years can be attributed largely to an enhanced ability to detect small renal masses (<4 cm) [2]. In Europe, and the rest of the world, the annual incidence of RCC is approximately 2% [3]. The number of surgical interventions for small renal masses has increased accordingly, but earlier identification and radical intervention has not led to a corresponding reduction in mortality among patients with RCC. Hollingsworth et al [2] concluded that current treatment for RCC should not change, /$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 64 european urology supplements 7 (2008) but further research is needed into why early identification and intervention were not affecting mortality rates. The surgery described by Robson no longer remains the gold standard for the management of small tumours, and options for surgical intervention now extend to open partial nephrectomy, laparoscopic tumour nephrectomy, and even laparoscopic partial nephrectomy [2]. There have also been significant developments in medical therapy for RCC in recent years; the introduction of multitargeted tyrosine kinase inhibitors, such as sunitinib, for the treatment of metastatic RCC has led to improved patient outcomes [4]. The use of such agents in the adjuvant setting warrants consideration as a way of improving the mortality rate. This review discusses whether advances in the options for surgical and medical intervention provide an opportunity to improve prognosis in patients with RCC. 2. Optimising surgical procedures 2.1. Adrenalectomy and lymph node dissection A change in attitude to adrenalectomy and lymph node dissection, as laid out in the gold standard procedure of Robson et al [1], has occurred recently in light of recent clinical evidence, contributing to a paradigm shift in the surgical management of RCC. Siemer et al [5] reported outcomes from 1635 patients who underwent nephrectomy. In 1010 of these patients, ipsilateral adrenalectomy was also performed. However, metastases in the adrenal gland were found in just 5.5% of cases and 5-yr disease-free survival (DFS) did not differ between those with or without adrenalectomy (75% vs. 73%, respectively). The study helped to define the situations in which adrenalectomy should be considered; these include findings on the preoperative computed tomography (CT) scans, the presence of large or upper pole tumours, and cases where stage T3 T4 tumours are suspected [5]. The clinical relevance of lymph node dissection in localised disease was assessed in a study by Pantuck et al [6]. Of 900 patients undergoing nephrectomy for unilateral RCC, 495 had localised disease, and survival in the 238 patients who underwent lymph node dissection was not significantly different from the 257 patients with no lymphadenectomy ( p = 0.42). The authors concluded that regional lymph node dissection offered limited information on the stage of the tumour and offered no benefit either in decreasing disease occurrence or improving survival levels and was, therefore, unnecessary in patients with clinically negative lymph nodes. However, in the case of suspect findings on the CT scan or if suspicions are raised intraoperatively, then lymph nodes should be removed Partial nephrectomy The European Association of Urology (EAU) guidelines recommend partial nephrectomy as standard care for tumours <4 cm (stage T1a) [3]. This procedure has the advantage of complete tumour resection while preserving function; however, technical feasibility is a concern and largely depends on the characteristics of the tumour, especially its location. In certain cases, laparoscopic transperitoneal or retroperitoneal tumour nephrectomy, an EAU guideline-approved procedure for T1 T2 renal tumours, can provide an option if partial nephrectomy is not technically feasible. The rates of 5-yr DFS for partial nephrectomy have been shown to be similar to those achieved with radical procedures in patients with tumour sizes <4 cm[7]. The authors of this study concluded: Patients with a small renal tumour have similar preoperative morbidity, pathological stage and outcome regardless of treatment with partial or radical nephrectomy. Therefore, partial nephrectomy remains a safe alternative for tumours of this size. Further support for good outcomes with open partial nephrectomy is provided by Fergany et al [8], who assessed long-term postoperative kidney function and survival in a series of 400 patients who had a tumour in a solitary kidney and who underwent open surgical partial nephrectomy. They reported 5-yr and 10-yr cancer-specific survival rates of 89% and 82%, respectively. Satisfactory long-term renal function was achieved in 95.5% of patients. Although several studies have shown significantly better survival in patients who had a partial nephrectomy for tumours <4 cm compared with >4 and <7 cm [9,10], recent data suggest that similar benefits may be seen in tumours >4 and <7 cm[11 14]. In these studies, patients with tumours >4 cm who underwent a partial nephrectomy were safely treated without adversely affecting recurrence or death from cancer (5-yr survival ranged from 93.8% to 94.9% with tumours >4 and <7 cm) [11 14]. Furthermore, the EAU guidelines recognise that partial nephrectomy is appropriate treatment for tumours up to 7 cm [3]. Evidence in the literature suggests that the surgeon s decision should be based on the location of the tumour and technical feasibility rather than tumour size alone [12]. However, because these more challenging procedures

3 european urology supplements 7 (2008) may be associated with an increased risk of morbidity, it is important to counsel patients when deciding whether a partial nephrectomy or radical laparoscopic nephrectomy is the most appropriate treatment. Patients selected for partial nephrectomy to remove small tumours that are found incidentally often have good performance status and, therefore, may experience improved postoperative recovery and health-related quality of life [15]. Nonetheless, several complications are related to this procedure, including urinary fistula, perinephric urinoma, and arteriocalyceal fistulas [15], and partial nephrectomy has been associated with marginally higher complication rates than radical nephrectomy [15,16]. Interestingly, Patard et al found no significant differences in medical or surgical complication rates when comparing partial nephrectomy for tumours 4 cm with tumours >4 (tumours 4 cm: surgical complication rates 10.8%, medical complication rates 12.3%; tumours >4 cm: surgical complication rates 8.7%, medical complication rates 10.8%) [17]. Most complications that occur following partial nephrectomy can be managed in a conservative way to minimise impact on the perioperative outcome [15]. Recent studies have found that partial compared with radical nephrectomy did not alter duration of hospital stay [15,17] or procedure costs; however, partial nephrectomy did preserve renal function and improve overall quality of life [15] Emerging surgical techniques Laparoscopic partial nephrectomy Laparoscopic partial nephrectomy is an emerging option combining the advantages of partial nephrectomy with those of a minimally invasive procedure. However, it is an advanced form of laparoscopic surgery requiring a high degree of skill and is therefore confined to centres with considerable laparoscopic experience. Gill et al have published a retrospective analysis of 200 partial nephrectomies, divided equally between laparoscopic and open procedures [18]. The study included patients with a solitary renal tumour of 7 cm. The open procedure was superior to the laparoscopic procedure in terms of patients who had a positive surgical margin (0% vs. 3%, respectively, p = 0.1). The laparoscopic procedure was also associated with a higher rate of major intraoperative complications (5% vs. 0%, p = 0.02) and, although there were no significant differences in overall postoperative complications, renal/urologic complications were more common in the laparoscopic group (11% vs. 2%, p = 0.01). Table 1 lists some of the comparative perioperative and postoperative outcomes for the two procedures, which suggest that the laparoscopic procedure has significant advantages in terms of morbidity and recovery time. However, of particular note is the increased ischaemia time with the laparoscopic procedure, and continuing efforts to reduce this time must be made to ensure optimal maintenance of renal function. Encouraging data have also been published on comparative long-term outcomes with laparoscopic and open partial nephrectomy. Permpongkosol et al reported similar 5-yr survival rates for the laparoscopic and open interventions (93.8% vs. 95.8%, respectively), although the numbers of cases were relatively small (85 and 58 cases, respectively) [19] Ablation techniques For some patients, ablation techniques, including cryoablation, radiofrequency ablation (RFA), and high-intensity focused ultrasound (HIFU), represent new and alternative surgical options that have shown encouraging results. These techniques are minimally invasive treatment options with limited morbidity and are being investigated in patients for whom invasive, open, or laparoscopic partial nephrectomy is undesirable as a result of an increased risk of surgical complications [20,21]. EAU guidelines recommend ablation techniques for patients with small peripheral tumours who are not suitable candidates for open or laparoscopic surgery [3]. By far the most promising therapy is renal cryoablation, which, although technically challenging, is safe and has resulted in good outcomes for patients (overall survival %) [20]. However, until further data become available cryoablation is only suitable for small (<4 cm) solid renal tumours in older patients who are at high surgical risk [20]. RFA and HIFU are both experimental procedures and until robust long-term data become available these techniques should remain Table 1 Perioperative and postoperative outcomes for open and laparoscopic partial nephrectomy [18] Laparoscopic surgery (n = 100) Open surgery (n = 100) Tumour size, cm * Operation time, h * Blood loss, ml * Ischaemia, min * Morphine equianalgesic, mg * Hospital stay, d * Recovery, wk * * p < 0.05.

4 66 Table 2 Prognostic algorithms, nomograms, and models for stratification of RCC outcome [34,35] Reference Target population Tumour subtype Prognostic variables Prognostic outcome Accuracy Yaycioglu et al, 2001 [36] Preoperative, localised RCC All Symptoms, tumour size Recurrence 65% Cindolo et al, 2003 [37] Preoperative, localised RCC All Symptoms, tumour size Recurrence 67% Kattan et al, 2001 [38] Postnephrectomy, localised RCC All TNM stage, tumour size, histology, Recurrence 75% symptoms Sorbellini et al, 2005 [39] Postnephrectomy, localised RCC Clear cell TNM stage, tumour size, nuclear grade, histologic necrosis, microvascular invasion, symptoms Recurrence 82% Frank et al, 2003 [40] Postnephrectomy, localised RCC Clear cell Positive surgical margins, TNM stage, size, grade and necrosis Frank et al, 2002 [41] Postnephrectomy, localised RCC Clear cell TNM stage, tumour size, nuclear grade, necrosis Zisman et al, 2001 [42] Postnephrectomy, all stages All TNM stage, nuclear grade, performance status (UISS) Zisman et al, 2002 [44] Postnephrectomy, all stages All TNM stage, nuclear grade, performance status, metastases (UISS) Karakiewicz et al, 2007 [43] Postnephrectomy, all stages Clear cell, chromophobe, papillary TNM stage, tumour size, symptom classification Leibovich et al, 2003 [46] Postnephrectomy, metastatic Clear cell Lymph node status, constitutional symptoms, metastasis location, histology, TSH level Motzer 2004 [47] Postnephrectomy, metastatic All Anaemia, corrected calcium level, performance status Recurrence (site-specific) Abdominal, 81%; thoracic, 83%; bone, 80% Disease-specific survival 85% Disease-specific survival 86% at 2 yr, 82% at 5 yr (reported by Karakiewic [43]) Disease-specific survival 73% (reported by Cindolo [45]) Disease-specific survival 87 89% Overall survival 67% Overall survival Not reported european urology supplements 7 (2008) Accuracy from area under curve; 50% accuracy would be expected from chance alone and 100% is perfect prediction [34]. UISS = University of California, Los Angeles (UCLA) Integrated Staging System; RCC = renal cell carcinoma; TNM = tumour, nodes, metastases; TSH = thyroid-stimulating hormone.

5 european urology supplements 7 (2008) second-line options for localised renal tumours or those patients for whom a partial nephrectomy is undesirable [20] Treatment approaches for locally advanced and metastatic RCC Advances in our understanding in cancer pathology have laid the foundation for investigating the benefits of integrating therapeutic modalities, particularly in locally advanced and metastatic RCC. Indeed, combining treatment modalities has been associated with improved treatment outcomes for patients with locally advanced RCC and metastatic RCC [3,22 24]. Because surgery is the most effective form of treatment for RCC, the surgeon aims to remove the entire tumour [25], which in some cases includes removal of the venous thrombus in the venous system or radical nephrectomy in the metastatic setting. Removing a tumour that has extended into the intrahepatic vein (T3 in the Mayo classification) is both technically challenging and demanding. Despite technologic advancement, this procedure involves considerable morbidity and mortality. Furthermore, patients with venous system involvement are at a greater risk of recurrence [25]. Itis generally accepted that patients presenting with T3 RCC require a multidisciplinary approach to maximise treatment outcomes and survival [3,22]. The EAU guidelines suggest that selected patients undergoing a nephrectomy to treat T3 RCC might experience improved progression-free survival if combined with adjuvant therapy [3]. Selecting patients who are most likely to derive benefit from adjuvant therapy is crucial for positive outcomes. Therefore, prognostic algorithms and nomograms are a valuable tool to aid identification of those patients who are most likely to benefit from adjuvant therapy in the setting of a clinical trial (Table 2). Previous studies have shown that patients with locally advanced disease who receive cytoreductive surgery combined with immunotherapy experience improved survival: survival at 2 yr following nephrectomy plus immunotherapy 36% [23] and 41% [24]; survival at 2 yr following nephrectomy alone 32% [24]; and survival at 2 yr following immunotherapy alone 0% [24]. In metastatic disease, treatment is often considered as palliative unless all tumour deposits are removed and surgery is combined with systemic treatment [3]. The EAU guidelines recommend tumour nephrectomy for patients with metastatic disease with good performance status when combined with interferon-a (IFN-a) [3]. Indeed, Haferkamp et al reported that patients with metastatic disease who underwent surgery and received interferon- and interleukin-based immunotherapy had significantly higher median survival than those who had surgery alone (13.5 mo compared with 5.2 mo, respectively) [23] Role of nephrectomy in the era of multitargeted therapy The emergence of multitargeted therapies, with response rates that exceed those achieved with cytokine therapy [4,26], has prompted the question of whether nephrectomy will indeed be required in many patients or if there is a place for combining multitargeted therapy with surgical techniques. Clues to the potential utility of multitargeted agents in this setting come from the cytokine era. Flanigan et al combined the results of two randomised trials and assessed the survival of 331 patients with synchronous RCC undergoing either cytoreductive nephrectomy plus IFN-a 2b or IFN-a 2b alone [27]. Median survival was 13.6 mo for the combined therapy group versus 7.8 mo for group receiving IFN-a 2b alone. This represents a 31% decrease in the risk of death with combined therapy ( p = 0.002). A pertinent question today is whether or not the unprecedented activity of multitargeted therapies in RCC might obviate the need for nephrectomy in certain patients. Currently there are no data to support such an approach and nephrectomy continues to be the standard of care in patients with synchronous RCC. However, there remains both a clinical and scientific rationale for the use of multitargeted therapy in the adjuvant setting. 3. Multitargeted therapy 3.1. Multitargeted therapies improve progression-free survival in metastatic RCC Advances in our understanding of molecular biology have led to the development and approval of several angiogenesis inhibitors and targeted therapies for the treatment of metastatic RCC. Sunitinib, sorafenib, and temsirolimus have shown promising clinical activity [4,26,28]. Indeed, the survival benefit gained with these therapies in phase 3 clinical trials has been so compelling that these agents are now recommended in the updated EAU guidelines for treatment of metastatic RCC [3]. The accompanying article by Patard discusses the major finding of these

6 68 european urology supplements 7 (2008) pivotal phase 3 clinical trials [29]. These targeted therapies may become an exciting new treatment strategy in the adjuvant setting for patients with metastatic RCC. Furthermore, there may also be a role for these therapies in the neoadjuvant setting as discussed by the accompanying article by Albers [30] An emerging option for the adjuvant setting? Patients with recurrent disease following nephrectomy have micrometastatic disease at the time of surgery, and there is a 35 65% recurrence rate in patients with locally aggressive tumours [31]. Effective adjuvant therapy may reduce the risk of relapse in these patients. Data on the use of cytokines in the adjuvant setting is scarce and largely negative. In a randomised trial, 247 patients with metastatic RCC were assigned to receive either adjuvant IFN-a 2b or observation after radical nephrectomy [32]. The 5- yr overall and event-free survival probabilities were not statistically significant ( p = for overall, and p = for event-free survival with the log-rank test; Fig. 1). The authors concluded that IFN-a 2b could not be indicated after radical nephrectomy for RCC, although a protective effect in a small group of metastatic lymph node category pn2/pn3 patients suggested the possibility of some positive activity in this setting. Whereas cytokines induce immunologic responses, multitargeted agents such as sunitinib directly inhibit kinases that control the activity of important receptors involved in angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR). This is potentially an important difference given the highly vascular nature of RCC [33]. Clinical trials in patients with metastatic RCC have demonstrated that orally administered multitargeted therapies have activity in this setting and are associated with an acceptable tolerability profile [4,26]. However, arguments against the use of such agents in early RCC are based particularly on whether angiogenesis is a defining factor in micrometastatic disease. Also unclear is the length of time for which multitargeted therapies would need to be administered to achieve an optimal protective effect Clinical trials of multitargeted therapies in the adjuvant setting At the time of writing, three clinical trials are ongoing to test the rationale for multitargeted Fig. 1 No benefit of cytokines as adjuvant therapy in RCC [32]. Reprinted with permission from the American Society of Clinical Oncology. therapies as adjuvant therapy in RCC. The first, Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC), will assess the effectiveness of 1 yr of adjuvant sunitinib therapy (cycles of 50 mg/d for 4 wk followed by 2 wk off therapy) compared with placebo in patients with high-risk RCC as defined by the UCLA Integrated Staging System (UISS). This trial aims to recruit approximately 230 patients and the end point is DFS. The second trial, Adjuvant Sorafenib Sunitinib Unfavourable Renal Cell Carcinoma (ASSURE), will assess the effect of adjuvant sunitinib (50 mg/d for 4-wk on, 2-wk off therapy for a total of 9 cycles), sorafenib (400 mg twice daily for 6 wk for a total of 9 cycles), or placebo in patients with nonmetastatic RCC. The ASSURE trial was designed to include potentially curable patients at the highest risk for recurrence based on existing postoperative nomograms. This large Eastern Cooperative Oncology Group (ECOG) head-to-head trial aims to accrue >1300 patients and will have DFS at 5 yr as its primary end point. This important trial will answer a number of questions in addition to the effect of multitargeted therapies on survival. The trial will examine whether any effects extend to patients with non clear-cell carcinomas. End points relating to surgical techniques have also been incorporated, and any significant differences in outcomes in patients who have open versus laparoscopic surgery should be identified. Additionally, the data provided by the trial should enable markers to be identified that help to predict the likelihood of relapse. A longer-term trial aims to elucidate the duration of drug exposure necessary to achieve optimal reduction in the risk of recurrence with multitargeted therapy. The Sorafenib with Placebo in

7 european urology supplements 7 (2008) Patients with Resected Primary Renal Cell Carcinoma (SORCE) phase 3 trial is a three-arm study that will compare 3 yr of sorafenib therapy (400 mg twice daily), 1 yr of sorafenib therapy plus 2 yr placebo therapy, and 3 yr of placebo therapy in patients with resected primary RCC and no residual disease, but who are at intermediate or high risk of relapse (Leibovich score 3 8). As with the other two trials, the primary end point is DFS. Urologists will await the results of these three trials in the hope that the role of adjuvant therapy in RCC can be redefined and that, for the first time in the history of RCC treatment, patients can be offered an adjuvant therapy that extends DFS. 4. Conclusions Surgery remains the standard of care for localised RCC and also remains the best chance of achieving cure. For T1a disease, open partial nephrectomy is recommended, if technically possible. Although laparoscopic tumour nephrectomy is a standard procedure for T1 T2 disease, the emerging laparoscopic partial nephrectomy (when feasible) has not been standardised and, at the time of writing, remains the remit of experienced centres only. The role of multitargeted therapy in the management of localised RCC remains to be defined, and until evidence appears to the contrary, nephrectomy will continue to be recommended. Ongoing clinical trials of multitargeted therapy in the adjuvant setting will provide the data necessary to ascertain the extent to which this approach represents a feasible new dimension in the treatment of RCC. Acknowledgements The author would like to acknowledge Innovex Medical Communications for writing and editorial assistance provided in the preparation of this paper. The content of this article is based on that presented at a Pfizer Inc. supported satellite symposium held at the 22nd European Association of Urology Congress, Berlin, Germany. 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