Recent Developments in Research on Kidney Cancer: Highlights from Urological and Oncological Congresses in 2007

european urology supplements 7 (2008) 494 507 available at www.sciencedirect.com journal homepage: www.europeanurology.com Recent Developments in Research on Kidney Cancer: Highlights from Urological and Oncological Congresses in 2007 Jean-Jacques Patard a, *, Toni K. Choueiri b, Eric Lechevallier c, Nicolas Mottet d a CHU Pontchaillou, Rennes, France b Dana Farber Cancer Institute, Brigham and Women s hospital Harvard Medical School, Boston, MA, USA c Hôpital Salvator, Marseille, France d Clinique Mutualiste, St. Etienne, France Article info Keywords: Angiogenesis inhibitors Bevacizumab Partial nephrectomy Radical nephrectomy Renal cell cancer Sorafenib Sunitinib Temsirolimus Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: This paper communicates the major new findings on renal cell carcinoma (RCC) that were presented at the 2007 annual meetings of the European Association of Urology (EAU), American Urological Association (AUA) and American Society of Clinical Oncology (ASCO) and discussed during a closed meeting in September 2007. Methods: The most relevant new findings were selected by urological experts in the field of RCC. Results: Although laparoscopic partial nephrectomy (LPN) is a promising technique, it may be associated with additional postoperative morbidity and prolonged warm ischemia time (WIT) compared with open PN. WIT is the strongest modifiable risk factor to avoid decreased renal function after PN. LPN is not recommended in patients with a unique/solitary kidney. However, PN should be preferred to radical nephrectomy whenever PN is technically feasible, because data suggest that overall survival is decreased in patients with small renal tumours who underwent a radical nephrectomy. Conclusions: Additional data have been accumulated regarding targeted therapies. The efficacy of sunitinib and sorafenib as first- and secondline therapy, respectively, has been confirmed. Prognostic factors have been identified for both therapies. Although, sorafenib was not superior to interferon-a as first-line treatment, dose escalation with sorafenib could be an interesting approach. Bevacizumab improves progressionfree survival when combined with interferon-a as first-line therapy. New drugs as well as drug combinations are now being investigated. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. CHU Pontchaillou, Service d Urologie, Rue Henri le Guillou, 35033 Rennes Cedex, France. Tel. +33 2 99284270; Fax: +33 2 99284113. E-mail address: jean-jacques.patard@univ-rennes1.fr (J.-J. Patard). 1569-9056/$ see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2008.01.001

european urology supplements 7 (2008) 494 507 495 1. Introduction Although renal cell carcinoma (RCC) is relatively rare, it is one of the most lethal urological malignancies. RCC represents the third leading cause of death among genitourinary malignancies and the tenth leading cause of overall cancer death in the United States [1]. In the European Union in 1998, approximately 30,000 patients were diagnosed and approximately 15,000 died of RCC [2]. Most RCCs are discovered incidentally during the initial nephrological workup. Probably because of increased use of imaging (eg, ultrasound, computed tomography [CT]) theincidenceofrcchadincreasedoverthepastyears by approximately 2% per year [2,3]. This development has been accompanied by a stage migration towards the detection of smaller, more organ-confined tumours and a shift in treatment strategies (ie, increased use of nephron-sparing surgery, minimally invasive techniques and tissue-ablative approaches) [4]. Despite the increased detection of incidental tumours, the mortality from RCC has remained stable [2]. Prognosis for RCC varies considerably depending on the disease stage at diagnosis. The American Cancer Society estimates that those diagnosed with organ-confined tumours have a very good prognosis with a 90.4% 5-year survival rate. For patients with locally advanced disease, the 5-year survival rate is still 61.7%. However, when RCC is present in the metastatic form (which is the case in about 25 30% of all cases), it is associated with a very poor 5-year survival rate: only 9.5% [1]. Although RCC represents a heterogeneous group of diseases, most of the current research efforts are focused on clear-cell RCC (CCRCC), which represents about 75% of all human renal epithelial neoplasms[5]. A better understanding of the molecular biology of CCRCC has led to several novel and promising therapeutic approaches for patients with metastatic RCC (mrcc), as well as to the initiation of many clinical trials, some of which will be discussed in this paper. This manuscript presents the most relevant new data on RCC presented at the European Association of Urology (EAU), the American Urological Association (AUA), and the American Society of Clinical Oncology (ASCO) 2007 annual meetings. These data were selected by the authors of this paper and discussed during a closed meeting in Brussels, September 2007. 2. Diagnostics and outcome prediction 2.1. Percutaneous biopsy of renal masses guided by CT Over the past years, increased use of imaging has led to an increased detection of smaller-size renal tumours. These tumours can be treated with lessinvasive surgery or even with active surveillance. However, it is important to correctly identify and diagnose these tumours to make appropriate treatment decisions. Schmidbauer and colleagues [6] evaluated whether CT may aid in the percutaneous biopsy of renal masses. A total of 96 patients with RCC underwent CT guided core biopsy. In 69 patients the lesion was surgically removed and available for histology. Twenty-seven patients underwent radiofrequency ablation or cryoablation. Mean tumour size was 3.6 cm. Biopsy showed RCC in 74% and benign histology in 23% of patients. Accuracy of CTguided biopsy for RCC was 100%, for Fuhrman grade 75%, and for histological subtype 87%. CT-guided, percutaneous, preoperative renal tumour biopsy thus has a high diagnostic accuracy. Although it is still too early to draw conclusions, CT-guided biopsies could become increasingly important in managing small renal masses in the future. 2.2. Natural history of small renal tumours A multicentre Canadian trial evaluated the natural history of patients with incidental RCC [7]. A total of 100 patients with newly diagnosed T1aN0M0 were enrolled from August 2002 until September 2006. Patients were managed with active surveillance, which included serial imaging every 3 mo in year 1 and every 6 mo from year 2 onwards. Mean followup was 10 mo. The mean tumour diameter at diagnosis was 2.1 cm. Over the mean follow-up of 10 mo, the average tumour growth rate was 0.14 cm/yr, which did not differ statistically from zero growth ( p=0.07). Two patients progressed but were managed conservatively because of morbidity. One patient died because of an unrelated cause and no patients developed metastatic disease. It was concluded that the majority of small tumours are indolent with a low malignant potential. Patients with small indolent tumours could be managed conservatively with serial imaging and surgery could be avoided. However, the following study, which was presented at the AUA annual meeting, suggests that even small tumours may have a significant metastatic potential [8]. The authors argued that, although observational urological studies indicate that the risk of distant metastasis of small renal tumours is negligible, these studies may underestimate the true rate of metastasis in small renal tumours because of selection bias, that is, patients with mrcc are not referred to the urologist. The Surveillance, Epidemiology and End Results (SEER) database is not subject to this selection bias and was

496 european urology supplements 7 (2008) 494 507 Fig. 1 Metastatic potential of small renal tumours [8]. increased growth kinetics during active surveillance are likely to possess unfavourable pathological features and warrant surgical intervention. Taken together, these results suggest that tumour size alone is not a sufficient indicator for predicting outcome of small renal tumours. Indeed, very small tumours represent a heterogeneous group. If lowgrade tumours could be considered for active surveillance, high-grade tumours should be managed by active therapy. Rapidly growing tumours should also be considered for active therapy, even if a clear threshold remains to be defined. analysed from 1998 to 2003 to determine the risk of metastases in patients with small renal tumours (<4 cm) [8]. Metastasis was defined as cases with distant disease or regional disease by virtue of lymph node involvement. A total of 10,420 patients with renal cancer were included. The overall rate of distant metastases for all tumour sizes was 18.3%. As tumour size increased, the rate of metastases also increased (Fig. 1). It was concluded that even small renal cancers have a significant metastatic potential. A subset of patients may have aggressive disease despite small tumour size. In light of the significant risk of metastases in these tumours, these patients should be managed with active treatment instead of active surveillance. Patients with small renal tumours are commonly managed conservatively [9]. Those with increased tumour growth on radiography are treated with delayed therapy. Crispen et al [10] assessed the influence of nuclear grade on linear tumour growth and tumour doubling time in 28 patients with pathologically proven CCRCC, who were managed with 12 mo of active surveillance before definitive treatment. Median tumour size at baseline was 2.3 cm and did not differ between low-grade and high-grade tumours. Median growth rate for individual lesions was 0.24 cm/yr and median doubling time of pathological RCC was 26.9 mo. Linear growth rate and tumour-doubling time did not correlate with tumour size at baseline. However, there was a statistically significant difference in linear growth rate between low-grade (I II) and high-grade (III IV) tumours: 0.21 vs. 0.72 cm/yr, respectively ( p = 0.0049). In addition, the doubling time of highgrade tumours (17 mo) was statistically significantly shorter than that of low-grade tumours (31 mo; p = 0.015). This study thus shows that high-grade CCRCC has an increased linear growth and decreased doubling time compared with low-grade CCRCC when managed with delayed treatment. It also suggests that small tumours demonstrating 2.3. Age as a determinant of RCC-specific mortality after nephrectomy A European, multicentre cohort study evaluated the effect of age on RCC-specific mortality [11]. A total of 3727 patients treated with radical nephrectomy (RN) were included in the study. Univariable and multivariable Cox regression analyses were performed with gender, TNM stage, tumour size, Fuhrman grade, symptom classification, and histological subtype as covariates. The median overall survival (OS) was 13.5 yr. Age was analysed as a continuously coded variable as well as a cubic spline to allow for nonlinear effects. It was shown that older age, coded as either a continuous variable or a cubic spline, was a statistically significant predictor of RCC-specific mortality in univariate analyses (both p < 0.001). Likewise, age coded as either a continuous variable or a cubic spline was an independent predictor of RCC-specific mortality in multivariate analyses (both p < 0.001). Thus, younger patients had a significantly better RCCspecific mortality than older patients in both types of analyses. It was therefore concluded that young age is associated with better survival regardless of TNM stage, Fuhrman grade, tumour size, histological subtype, and symptom classification. This finding also suggests that age should be included in all future prognostic models. 2.4. Impact of histology on cancer control after nephron-sparing surgery At the EAU 2007 annual meeting, a multicentre, retrospective study was presented that evaluated the impact of the histological subtype of RCC on cancer control after partial nephrectomy (PN) [12].A total of 807 patients were included in the study: 574 men (71%) and 233 women (29%). Clear-cell, papillary, and chromophobe RCC were presented in 73%, 21%, and 6% of patients, respectively. Mean tumour size did not differ significantly between the three

european urology supplements 7 (2008) 494 507 497 Table 1 Histological subtype has no impact on cancer control after partial nephrectomy [12] Clear cell Histological subtype Papillary Chromophobe Mean tumour size (cm) 3.3 3.3 3.6 Multifocality (%) 14.7 12.7 4.1 Local recurrence 3.4 1.9 2.1 (% of patients) Cancer-related death (% of patients) 5.6 3.2 2.2 groups (Table 1). In addition, multifocality was not found to be significantly increased in papillary tumours (Table 1). Furthermore, the local recurrence rate and the risk of cancer-related death were independent from the histological subtype ( p = 0.6 and p = 0.3, respectively; Table 1). It was concluded that PN can achieve good cancer control regardless of histological subtype when tumours are properly selected. 2.5. Inferior vena cava wall invasion by a tumour thrombus There are still many controversies about the prognostic importance of inferior vena cava (IVC) invasion and also regarding prognostic indicators in this setting. Zini et al [13] performed a retrospective chart-review study to determine whether IVC wall invasion can be predicted preoperatively and whether the prognosis of patients with RCC is less favourable when a tumour thrombus invades the IVC wall. The records of 39 consecutive patients with RCC and a thrombus in the IVC were examined. Invasion of the IVC wall by a thrombus was present in 51% of patients. The mean IVC antero-posterior diameter and mean ostium renal vein diameter were statistically significantly smaller when the IVC wall was not invaded compared with when it was invaded ( p < 0.05). The IVC antero-posterior diameter and ostium renal vein diameter cut-off values to predict wall invasion with a sensitivity of 90% were 18 mm and 12 mm, respectively. It was also shown that IVC wall invasion statistically significantly affected recurrence ( p = 0.031) and cancerspecific survival time ( p = 0.002). Thus, an IVC antero-posterior diameter >18 mm and an ostium renal vein diameter >12 mm suggest invasion of the IVC wall with a sensitivity of 90%. In addition, the prognosis of patients with RCC and an IVC thrombus seems to depend on whether the thrombus invades the IVC wall. Therefore, information regarding IVC wall invasion should be systematically recorded in pathological reports. 2.6. Prognosis and survival of synchronous bilateral RCC Synchronous bilateral RCC is rare; therefore, there are few studies describing it and there are few data on its prognosis. A European study retrospectively evaluated databases from eight international academic centres to identify patients with N0M0 synchronous bilateral RCC [14]. Among 10,337 patient charts reviewed, a total of 118 patients with N0M0 synchronous bilateral RCC were identified. Bilateral CCRCC was the most common (73% of patients) and bilateral papillary RCC the second most common (16% of patients) histological subtype. Patients with synchronous bilateral N0M0 RCC were compared with those with unilateral N0M0 RCC. There were no statistically significant differences between both groups with respect to Eastern Cooperative Oncology Group (ECOG) performance status, T stage, and Fuhrman grade. However, bilateral tumours were more frequently multifocal (54% vs. 16%, p < 0.001), and the patients more frequently had a positive family history of RCC (9% vs. 3%, p = 0.04). Patients with N0M0 synchronous bilateral RCC and unilateral RCC had a similar prognosis with respect to disease-specific ( p = 0.61) and OS time ( p = 0.90). It was therefore concluded that patients with N0M0 synchronous bilateral RCC have a similar prognosis as patients with N0M0 unilateral RCC. Family history of RCC and multifocality were more common among patients with N0M0 synchronous bilateral RCC. 2.7. Which factors predict decreased renal function outcome after PN? PN allows for greater preservation of renal parenchyma and function compared with RN. However, although it has been suggested that age, preoperative renal function, and comorbidity contribute to change in renal function after PN, the effect of factors such as tumour and surgery characteristics have not yet been well studied. A study evaluated 1049 patients who underwent PN between 1999 and 2005 [15]. Median preoperative serum creatinine was 1.0 ng/ml and glomerular filtration rate (GFR) 75.9 ml/min. Median tumour size was 3 cm. Median operative time and median warm ischemia time were 232 and 25 minutes, respectively. Median postoperative serum creatinine was 1.1 ng/ml and GFR 65.3 ml/min. Multivariate analysis was performed to evaluate which factors determined a low postoperative GFR. This analysis showed that renal function was decreased in patients undergoing PN in a solitary kidney or with bilateral disease (Table 2). Renal function was also decreased with increasing

498 european urology supplements 7 (2008) 494 507 Table 2 Factors predictive of decreased glomerular filtration rate after partial nephrectomy [15] Risk factors Tumour in solitary kidney <0.0001 Bilateral disease 0.035 Increasing tumour size 0.0381 Increasing age at surgery 0.0018 Increasing warm ischemia time <0.0001 Decreasing preoperative glomerular filtration rate <0.0001 Surgical approach 0.8 Tumour depth 0.5 Operative time 0.9 tumour size, increasing age at surgery, increasing warm ischemia time and decreasing preoperative GFR (Table 2). Surgical approach (open vs. laparoscopic surgery), tumour depth (central vs. peripheral), and operative time did not significantly affect renal function. It was concluded that warm ischemia time is the strongest modifiable risk factor for decreased renal function after PN; thus, efforts should be made to limit warm ischemia time in both open and laparoscopic PN. 3. Conservative surgery 3.1. Laparoscopic PN for small renal tumours The increased detection of small renal tumours has also led to an increase in the use of PN. PN is commonly performed for tumours <4 cm[2]. It can be performed both open and laparoscopically. Over the years laparoscopic PN has increasingly been performed, but it is questioned if outcomes and complication rates are comparable to open PN. At the urological congresses, several studies were presented that evaluated laparoscopic PN. In a large study that was also recently published, Gill et al [16,17] compared the early postoperative outcomes for 1800 patients with a single renal tumour 7cm who underwent open (n = 1,029) or laparoscopic PN (n = 771). Data were collected both retrospectively and prospectively at three centres. Compared with open surgery, laparoscopic PN was associated with a statistically significantly shorter operating time, reduced operative blood loss, and shorter hospital stay (all p < 0.0001). However, it was also associated with a statistically significantly longer ischemia time, increased rate of postoperative complications (particularly urological complications), and an increased number of subsequent procedures (all p < 0.0001). The risk of intraoperative complications was comparable for both procedures, and renal functional outcomes were comparable 3 mo after p laparoscopic and open PN: 97.9% and 99.6% of renal units retained function, respectively. Three-year cancer-specific survival for patients with a single ct1n0m0 RCC was similar: 99.3% for laparoscopic PN and 99.2% for open PN. It was concluded that early results of laparoscopic PN in patients with a single RCC 7 cm are promising. It offers the advantages of less operative time, reduced operative blood loss, and a shorter hospital stay. However, laparoscopic PN is also associated with additional postoperative morbidity compared with open PN. Another smaller study that was presented at the EAU 2007 annual meeting specifically looked at morbidity of laparoscopic versus open PN [18]. In this single-centre, prospective study, 248 patients underwent laparoscopic (n = 84) or open (n = 164) PN between 1987 and 2005. In contrast to the previously discussed study, the postoperative complication rate of laparoscopic PN did not exceed the rate of open surgery. In addition, no statistically significant difference was found in the presence of surgical margins. As discussed above, the 3-yr cancer-specific survival rate for laparoscopic PN looks very promising. In a single-centre study with a median follow-up of 5.7 yr, Lane et al [19] evaluated the outcomes of laparoscopic PN in 56 patients with a localised tumour (average tumour size, 2.9 cm). RCC was confirmed in 37 cases (66%). Table 3 presents the outcomes of this study. No distant recurrences occurred and a 2.7% rate of local recurrence was found. Five-year overall and cancer-specific survival rates were 86% and 100%, respectively. It was concluded that, on the basis of the results of this single-centre study, laparoscopic PN is an established alternative to open PN. Warm or cold ischaemia may be performed to achieve a satisfactory haemostasis in laparoscopic PN. A study previously discussed [15] concluded that warm ischaemia time should be kept as short as possible to prevent damage to the kidney. As an alternative to warm ischaemia, cold ischaemia may also be performed. In a single-centre study, laparo- Table 3 Five-year outcome data after laparoscopic partial nephrectomy [19] Local recurrence (% of patients) 2.7 Distant recurrence (% of patients) 0 Death from renal cell cancer (% of patients) 0 Death of other causes (% of patients) 14 New onset abnormal renal function (% of patients) 4.1 New onset chronic renal insufficiency (% of patients) 2.0 Loss of kidney (% of patients) 1.8 Overall survival (%) 86 Cancer-specific survival (%) 100

european urology supplements 7 (2008) 494 507 499 scopic PN was performed under cold ischaemia by using a renal artery perfusion method [20]. A total of 28 patients were included between 2000 and 2006 with a mean tumour size of 2.67 cm. Mean ischaemia time was 40.8 min and mean estimated blood loss was 241 ml. Two postoperative complications occurred (pancreatitis and pulmonary embolism). A mean calculated postoperative split MAG3 (mercapto acetyl tri glycine) clearance was significantly lower on the operated side. However, postoperative peak concentrations were similar for the operated and nonoperated kidneys. This finding suggests preservation of the function of the renal unit that was under cold perfusion ischaemia. There was a decrease in the calculated creatinine clearance in the immediatepostoperative period followed by an improvement 3 mo after surgery with stable function thereafter. In a median follow-up of 4 yr, no local recurrence or systemic progression occurred. It was therefore concluded that cold ischaemia for laparoscopic PN using arterial perfusion is a safe and feasible method. It could constitute a viable alternative for complex renal tumours in which long ischaemia time is anticipated. However, more experience is required before this procedure can be considered safe and effective, and a standard of care. 3.2. Robotic partial nephrectomy Although laparoscopic PN has many advantages, it may also be hampered by technical difficulties such as problems with intracorporeal suturing and limited haemostasis. Austrian investigators [21] presented their 5-yr experience with robotic PN using the DaVinci 1 system in 26 patients with small RCC. The robotic surgery was successfully completed in all but one patient requiring open conversion. Mean operative time, including the robot setup, was 147 min, which decreased with surgical experience; the last 10 cases had a mean operative time of 112 min. Mean cold ischaemia time was 33 min and warm ischaemia time was 23 min. Average hospital stay was 5.4 d. None of the patients required intraoperative transfusions. There was no urine extravasation or urinoma requiring further interventions. In one patient a positive resection margin was found requiring subsequent nephrectomy for local recurrence. Another patient developed local recurrence after 2 yr, leaving an oncological success (lack of disease recurrence) of 93%. It was concluded that robotic PN is a valid approach for treatment of patients with small renal tumours. However, further experience is warranted for determining the respective place of robotic PN versus conventional LPN. 3.3. Laparoscopic and open PN in patients with a single tumour <7 cm in a solitary kidney The unique/solitary kidney represents the perfect model for addressing the impact of a surgical technique on renal function outcome. Laparoscopic PN is feasible in patients with a solitary functioning kidney, but as discussed previously it may also be associated with a longer warm ischaemia time and increased risk of postoperative complications [16,17]. Astudy[22] presented at the AUA 2007 annual meeting evaluated the postoperative and early renal functional outcomes of patients undergoing laparoscopic or open PN for a tumour in a solitary functioning kidney. A total of 221 patients with a single sporadic renal tumour 7 cm in a solitary kidney underwent open or laparoscopic PN between 1999 and 2006. Table 4 displays the outcomes of this study. Median tumour size was somewhat larger in the patients treated with open surgery. Median warm ischaemia time was longer, and postoperative complications, urological complications, and chronic renal failure occurred more often in patients treated with laparoscopic PN. It was therefore concluded that, although laparoscopic PN is technically feasible for a single tumour in a solitary kidney, warm ischaemia time is longer and complication rates are higher compared with open PN. Therefore open PN may be the preferred operative approach for patients with a single tumour in a solitary kidney and other patients at high risk for chronic kidney disease. The results of this study obviously question the efficacy of laparoscopic PN in preserving renal function. This issue will have to be extensively addressed in further well-conducted studies. Table 4 Laparoscopic vs. open partial nephrectomy (PN) in patients with a single renal tumour =7 cm in a solitary kidney [22] Open PN (n = 189) Laparoscopic PN (n = 32) Median tumour size (cm) 3.9 2.8 Median warm ischaemia 21 30.5 time (min) Transfusion (% of patients) 8 6 Postoperative complications 24 45 (% of patients) Urological complications 10 15 (% of patients) Chronic renal failure (% of patients) 2 9

500 european urology supplements 7 (2008) 494 507 3.4. Enucleation for small renal tumours With the increasing evidence that the size of tumour margins does not matter, the concept of tumour enucleation is now being revisited. Data on the use of this technique in small renal tumours are limited to only a few studies. Pertia and Managadze [23] presented the results of a single-centre study in 44 patients who underwent elective nephron-sparing surgery by means of enucleation from 1997 to 2001. Median follow-up was 71 mo. Median tumour size was 3.7 cm. Within the first 30 d of treatment, there was no perioperative mortality and bleeding was not observed. One patient (2.7%) experienced urinary leakage. Local recurrences were not observed. Fiveand 7-yr cumulative survival rates were 97.7% and 95.4%, respectively. Five and 7-yr cancer specific survival rates were 100% and 97.6%, respectively. The authors concluded that tumour enucleation is a safe and acceptable approach compared with conventional PN. 3.5. PN in T1b and pt3 RCC Although PN is commonly reserved for renal tumours < 4 cm, its use for tumours 4 7 cm is more controversial. A single-centre retrospective study [24] evaluated the outcomes of PN for 68 patients with renal tumours of 4 7 cm (T1b RCC). Forty percent of these patients presented with imperative, 16% with relative, and 44% with elective indications. After a median follow-up of 37.9 mo, 4.4% of these patients experienced a local recurrence, 2.9% a locoregional recurrence, and 4.7% distant metastases. Five-year clinical progression-free survival (PFS) was 83%, 5-yr cancer-specific survival was 97%, and 5-yr OS was 70.8%. In patients with elective indications, renal function was preserved, whereas in patients with imperative and relative indications renal function was decreased. This small single-centre study thus shows that PN for T1b RCC is surgically feasible and demonstrates excellent cancer-specific survival. Local cancer control was achieved in a large number of patients, with the preservation of renal function in patients with elective indications. Trinh et al [25] evaluated the outcome of PN in patients with pt3 RCC. A total of 91 patients with pt3 RCC treated with PN were compared with a matched cohort of 215 controls who were treated with RN for pt3 tumours. Patients in both groups had comparable characteristics: Most tumours were CCRCC and most were Furhman grade II and III; nodal and distant metastases occurred in 3% and 9% of patients, respectively. The rate ratio between cancer-specific survival of PN and RN was 1.0 (logrank p = 0.7). PN thus results in a similar cancerspecific survival as RN in patients with pt3 RCC. This study suggests that, when a total excision of the primary tumour has been performed, it is not necessary to propose a RN, even though the tumour is classified as pt3 on final pathology. In other words, tumour biology is at the forefront regardless of surgical technique (radical vs. partial nephrectomy). 3.6. Repeat PN on the same kidney Patients with hereditary RCC with tumours approaching 3 cm are commonly treated with PN. However, these patients often need repeat surgery on the same renal unit for new tumours to delay or avoid dialysis and its associated morbidity. A retrospective chart review of 51 cases of repeat PN on the same renal unit in 47 patients with RCC from 1992 to 2006 was performed by Johnson et al [26]. The median procedure time was 7.5 h with a median resection of three solid lesions. The median size of the largest lesion was 3.5 cm. Thirty-three percent of cases were performed in patients with a solitary renal unit, and 6% of cases were performed laparoscopically. The median blood loss was 1800 ml, and 65% of the patients received intraoperative transfusions. In addition, 9.8% of patients required postoperative transfusions. Intraoperative and postoperative complications occurred in 21% and 23% of cases, respectively. Three patients had a loss of the renal unit. The authors conclude that repeat PN is a feasible treatment modality. However, it must be acknowledged that operative morbidity was especially high in this setting. Nowadays, noninvasive techniques such as radiofrequency ablation should be regarded as viable alternatives to such difficult and challenging procedures. 3.7. RN in patients with small renal tumours Recently it has been shown that the performance of RN in patients with small renal tumours is a significant risk factor for the development of chronic kidney disease [27]. Patients with chronic kidney disease have an increased risk of cardiovascular (CV) and overall mortality. Two studies presented at the AUA 2007 annual meeting compared the effect of RN versus PN on mortality in patients with small renal tumours. Huang and coworkers [28] analysed the SEER database to evaluate whether RN is associated with an increased risk of CV events and death compared with PN. A cohort of 3146 patients who were surgically treated for renal tumours <4 cm (pt1a) diagnosed between 1995 and

european urology supplements 7 (2008) 494 507 501 2002 was identified. A total of 81% of these patients underwent RN and 19% PN. Median follow-up was 48 mo. In unadjusted analysis, RN was associated with an increased risk of CV events (hazard ratio [HR], 1.19; p < 0.01). Five-year OS was 75% in patients treated with PN versus 68% for patients treated with RN ( p < 0.001). RN was associated with an increased risk of death for any cause compared with PN, controlling for age, gender, race, marital status, general comorbidity and pre-existing CV disease (HR, 1.29; p < 0.001). It was therefore concluded that RN is associated with a significantly increased risk of overall mortality and a trend towards increased CV events in patients with RCC <4 cm. Another study presented at the AUA compared RN with PN with respect to OS in patients with small RCC: In a retrospective study [29], 648 patients with RCC <4 cm who underwent RN or PN between 1989 and 2003 were identified. At last follow-up 146 patients died from any cause and 502 patients were still alive with a median follow-up of 7.1 yr. RN and PN were performed in 290 and 358 patients, respectively. Among patients <65 yr (n = 327), RN was statistically significantly associated with an increased mortality rate from any cause compared with PN (risk ratio, 2.16; 95% confidence interval [95%CI], 1.12 4.19; p = 0.02). This increased risk of mortality from any cause for RN patients persisted after adjusting for preoperative creatinine, ECOG performance status, and histology. This study thus suggests that RN may be associated with a decreased survival in patients <65 yr with small RCC compared with PN. 4. Systemic therapy 4.1. Targeted therapies and surgery: Preliminary studies The oxindol tyrosine kinase inhibitor sunitinib is a small molecule with antitumour and anti-angiogenic activity that selectively multitargets inhibition of platelet-derived growth factor (PDGFR), vascular endothelial growth factor (VEGFR), KIT, and FLT3 [30]. Sunitinib has been shown to shrink tumour size and reduce time to progression as first-line therapy in patients with mrcc [31]. In a preliminary study, Thomas et al [32] investigated the activity of sunitinib in primary renal tumours in patients with unresectable RCC with or without distant metastases to assess tumour shrinkage and conversion to resectable disease. A total of 15 patients with unresectable RCC were treated off-protocol with sunitinib 50 mg on days 1 28 of a 42-d cycle between February and November 2006. Initial mean radiographic renal tumour size was 10.9 cm. Side effects were observed in 87% of patients, but no patients discontinued sunitinib therapy because of toxicity. Systemic disease progression was evident in 33% of patients. From these preliminary results, it was concluded that administration of sunitinib in patients with unresectable RCC is feasible. Further follow-up is needed to assess the effect of sunitinib on primary tumour size. Another preliminary study presented at the AUA 2007 annual meeting evaluated the feasibility of laparoscopic salvage nephrectomy after targeted neoadjuvant therapy for mrcc [33]. A total of 21 patients with mrcc underwent neoadjuvant therapy with either bevacizumab or sorafenib and underwent laparoscopic salvage nephrectomy. The median operative time was 3.15 h and the estimated blood loss was 162 ml. The patients were hospitalised for 2 d. A median of 19 lymph nodes were removed. There were no intraoperative or postoperative complications. Follow-up was too short to assess responses. From these early results, it was concluded that laparoscopic salvage nephrectomy after targeted neoadjuvant therapy is a safe and feasible approach for carefully selected patients with mrcc. 4.2. Sorafenib Sorafenib is an oral multikinase inhibitor that has activity against Raf-1 serine/threonine kinase, B- Raf, VEGFR-2, PDGFR, FLT-3, and c-kit [30]. Sorafenib has shown antitumour activity as second-line therapy for mrcc in phase 2 trials [34]. Very recently, the phase 3, randomized, double-blind, placebo-controlled trial comparing sorafenib and placebo after failure of prior systemic therapy has been published [35]; the final results regarding OS were published at the ASCO 2007 annual meeting [36]. A total of 905 patients with advanced CCRCC were randomised to receive continuous oral sorafenib 400 mg twice daily (bid; n = 451) or placebo (n = 452) added to best supportive care [35]. At January 2005, the median PFS was 5.5 mo for sorafenib and 2.8 mo for placebo, with an HR sorafenib/placebo of 0.44 ( p < 0.01). On the basis of this statistically significant benefit on PFS of sorafenib versus placebo, patients were unblinded to their study medication in May 2005 and could cross over from placebo to sorafenib. A total of 216 patients taking placebo crossed over to sorafenib. When the final ITT analysis was performed (in September 2006), sorafenib did not demonstrate a significant benefit over placebo with regard to OS. However, a secondary analysis censoring the pla-

502 european urology supplements 7 (2008) 494 507 Table 5 Sorafenib is not superior to interferon-a as firstline treatment of advanced renal cell carcinoma [37] Sorafenib (n = 97) Interferon-a (n = 92) Complete/partial 5 9 response (%) Disease control rate (%) 79 64 Median progression-free survival (mo) 5.7 5.6 ( p = 0.5) cebo crossover data showed a statistically significant benefit in OS for sorafenib (17.8 mo) versus placebo (14.3 mo; HR, 0.78; 95%CI, 0.62 0.97; p = 0.0287). It was therefore concluded that sorafenib may prolong OS in second-line therapy compared with placebo in patients with advanced RCC. In the same phase 3 trial, the effect of sorafenib on VEGF and svegfr2 was also analysed. It was shown that, after sorafenib treatment, VEGF levels were increased and svegfr2 levels were decreased [36]. With the use of a Cox proportional hazard model, it was shown that VEGF was an independent prognostic factor for PFS ( p = 0.014) and OS. It was concluded that patients with high baseline VEGF levels have a poorer prognosis and are more likely to benefit from treatment with sorafenib. Up to now, sorafenib has only been studied as a second-line therapy for patients with mrcc. Szczylik et al [37] presented the results of the first randomized, phase 2 trial evaluating first-line treatment with sorafenib (oral 400 mg bid; n = 97) versus interferon-a (IFN-a; 9 MU three times a week; n = 92) in 189 previously untreated patients with advanced RCC. Table 5 displays the outcomes of this study and shows that sorafenib was not superior to IFN-a as first-line treatment of advanced RCC. The phase 2 and 3 studies described above demonstrated that sorafenib is effective as second-line therapy with limited toxicity when taken at a dose of 400 mg bid [34 36]. A phase 2, single-centre study evaluated dose escalation of sorafenib in patients with mccrcc with no more than one prior therapy [38]. Data on 44 patients were available; 19 patients received prior therapy. These 44 patients received sorafenib 400 mg bid for 1 mo. The dose was escalated to 600 mg bid in the next month in 41 patients, and 32 patients continued with sorafenib 800 mg bid thereafter. Complete response was achieved in 16% of patients, partial response in 39% of patients, and stable disease in 20% of patients. PFS was 8.4 mo and OS 11.4 mo. The results of this small, single-centre study demonstrate that dose escalation of sorafenib has promising antitumour activity. However, further studies are needed to confirm these results. 4.3. Sunitinib Two phase 2 trials have shown efficacy of sunitinib in mrcc as second-line therapy [39,40]. Very recently the New England Journal of Medicine published the results of a phase 3 trial evaluating sunitinib as first-line monotherapy [31]. A total of 750 untreated, good- and intermediate-risk patients (according to the Memorial Sloan-Kettering Cancer Center [MSKCC] risk group categorisation [41]) with mccrcc were randomised to sunitinib (6-wk cycles: 50 mg orally once daily for 4 wk, followed by 2 wk off) and IFN-a; (6-wk cycles: subcutaneous injection 9 MU three times weekly). The updated results presented at the ASCO 2007 annual meeting showed that the median PFS was longer for patients treated with sunitinib (11 mo) than for those treated with IFN-a (4 mo; p < 0.000001) [42]. The objective response rate was also statistically significantly higher for patients treated with sunitinib (46%) versus those treated with IFN-a (12%; p < 0.000001). On the basis of these results, it was concluded that sunitinib is the reference for firstline treatment of mccrcc with significant improvements in objective response rate and PFS compared with IFN-a. In this phase 3 trial, the prognostic factors for PFS with sunitinib were also evaluated [42]. It was shown that baseline factors that predicted longer PFS with sunitinib were haemoglobin = lower limit of normal ( p = 0.0043), corrected calcium = 10 mg/dl ( p = 0.001), ECOG score = 0 ( p = 0.0005), number of metastatic sites = 0 or 1 ( p = 0.0064), and time from diagnosis to treatment = 1 yr ( p = 0.0002). These risk factors may be used to predict which patients have a longer PFS with sunitinib. 4.4. Predictors of response to VEGF-targeted therapy in mrcc Because of the positive results of the phase III trials, therapy targeted against VEGF pathways (e.g. sunitinib, sorafenib) has become more important in the treatment of patients with mrcc. Identification of patients who are more likely to benefit from this therapy may aid in patient selection for therapy and in interpretation of the results of clinical trials. The group of Choueiri [43] presented at the ASCO 2007 annual meeting the results of a prospective study evaluating clinical factors associated with outcome in mrcc patients treated with VEGF-targeted therapy. This study was also recently published in Cancer [44]. A total of 120 patients with mrcc were treated with bevacizumab, sorafenib, sunitinib, or axitinib. Forty-one patients (34%) achieved an objective

european urology supplements 7 (2008) 494 507 503 Fig. 2 Impact of number of risk factors present in patients treated with systemic therapy on progression-free survival [43,44]. response. The median PFS for the whole group was 13.8 mo. Multivariate analysis identified the following independent adverse prognostic factors for PFS: time from diagnosis to current treatment <2 yr, baseline platelet count >300 K/ml, baseline neutrophil count >4.5 K/ml, baseline corrected serum calcium <8.5 or >10.0 mg/dl, and initial ECOG performance status >0. With the use of these adverse prognostic factors, three risk groups were formed on the basis of the number of prognostic factors present for PFS: a favourable risk group possessing zero to one prognostic factor, an intermediate-risk group possessing two prognostic factors, and a poor-risk group possessing three to five prognostic factors. Fig. 2 displays the median PFS time per risk group and shows that the median PFS decreased with the number of risk factors present. The identification of these prognostic factors for PFS in patients with mrcc treated with VEGF-targeted therapies may aid to select those patients who will respond to VEGF-targeted therapies in clinical practice. In addition, these factors can be incorporated into stratification schemes for clinical trials using VEGF-targeted therapy and for interpretation of the results of clinical trials evaluating VEGFtargeted therapy. In another study, Choueiri et al [45] evaluated whether von-hippel Lindau (VHL) mutation status could predict objective response to VEGF-targeted therapy. In patients with RCC, VHL is often mutated, but it is unknown whether there is any relation with response to VEGF-targeted therapy. Therefore, a retrospective study in 123 patients with mrcc treated with sunitinib, sorafenib, axitinib, or bevacizumab was performed. The objective response rate was 36.5% for the whole group. VHL mutation was found in 48% of patients. Patients with a VHL mutation had an objective response rate of 41%, whereas those without a VHL mutation had an objective response rate of 31% ( p = 0.34). However, patients with certain types of severe mutations that are predicted to result in a loss of the VHL protein function (loss of function mutations) had a response rate of 51% compared with 41% in patients with wildtype VHL. In multivariate analyses the presence of a loss of function mutation was an independent prognostic factor associated with an improved objective response rate ( p = 0.03), even after correcting for ECOG performance, haemoglobin, corrected calcium, lactate dehydrogenase (LDH), prior radiation, prior therapy, and number of metastatic sites. It was therefore concluded that patients with a VHL loss of function mutation may be more likely to respond to VEGF-targeted therapy, although patients with wildtype VHL had a non-negligible response to these agents. However, this observation needs to be confirmed in further research. In addition, studies identifying biomarkers relevant to response to VEGFtargeted therapy in mrcc are also needed. 4.5. Bevacizumab/IFN-a versus placebo/ifn-a as first-line treatment in mrcc Bevacizumab is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF [30]. It has been shown to improve time to progression compared with placebo in patients with refractory mrcc [46]. A randomized, double-blind phase 3 trial evaluated the efficacy and safety of bevacizumab + IFN-a (n = 327) versus placebo + IFN-a (n = 322) in patients with mccrcc [47]. The addition of bevacizumab to IFN-a statistically significantly increased objective response rate: 12.4% for placebo + IFN-a versus 30.6% for bevacizumab + IFN-a ( p < 0.0001). Complete response rates were 2% and 1%, and partial response rates were 11% and 30% for placebo + IFN-a and bevacizumab + IFN-a, respectively. PFS was also statistically significantly improved with bevacizumab + IFN-a: placebo + IFN-a versus bevacizumab + IFN-a: 5.4 mo versus 10.2 mo, respectively ( p < 0.0001). It was concluded that bevacizumab improves PFS when combined with IFN-a as first-line therapy in mrcc. Therefore, the combination of bevacizumab and IFN-a should be considered as a possible alternative to sunitinib as first-line therapy. 4.6. Effect of tyrosine-kinase inhibitors in metastatic papillary and chromophobe RCC CCRCC is the most common type of renal cancer. Papillary RCC is the second most common type

504 european urology supplements 7 (2008) 494 507 Table 6 The tyrosine-kinase inhibitors sunitinib and sorafenib may be effective in chromophobe metastatic renal cell carcinoma (RCC) but seem to have minimal activity in papillary RCC [48] Overall response rate (%) Progression-free survival (mo) Chromophobe RCC (n = 12) Papillary RCC (n = 41) 25 4.8 0.07 9.3 6.6 0.07 Table 7 In patients with papillary and chromophobe renal cell carcinoma, treatment with sunitinib resulted in a longer progression-free survival than treatment with sorafenib [48] Progression-free survival (mo) Overall response rate (%) Sunitinib (n = 20) Sorafenib (n = 33) 11.9 5.5 0.002 15 6 0.3 (accounting for 10 15% of all cases), and chromophobe RCC is the third most common type (accounting for about 5% of cases) [1]. The tyrosine-kinase inhibitors sorafenib and sunitinib have shown antitumour activity in mccrcc. However, their activity in papillary and chromophobe mrcc has not yet been evaluated. A multicentre study evaluated the effect of sunitinib or sorafenib in 53 patients with mrcc, 62% of whom were previously treated [48]. A total of 77% of these patients had papillary mrcc and 23% chromophobe mrcc. These patients were treated with either sunitinib (38% of patients) or sorafenib (62% of patients). Overall response rate and PFS were higher in patients with chromophobe RCC than in those with papillary RCC (Table 6). Overall response rate and PFS were also higher in patients treated with sunitinib than in patients treated with sorafenib (Table 7). It was concluded that tyrosine-kinase inhibitors may be effective in chromophobe mrcc but seem to have minimal response in papillary p p mrcc. Despite that conclusion, prolonged PFS can be observed in papillary RCC. 4.7. Temsirolimus Temsirolimus is a specific inhibitor of mammalian target of rapamycin, a serine/threonine kinase that plays a key role in cell-cycle regulation [30]. At the ASCO 2006 annual meeting, the results of a directcomparative, phase 3 trial between temsirolimus, IFN-a, and their combination in patients with advanced RCC as first-line therapy were presented [49]. Patients with stage IV or recurrent RCC who met at least three of the following poor prognosis criteria were enrolled: (1) less than 1 yr from initial diagnosis to randomisation; (2) Karnofsky performance status of 60 or 70; (3) haemoglobin less than limit of normal; (4) corrected calcium higher than 10 mg/dl; (5) LDH higher than 1.5 times the upper limit of normal; and (6) more than one metastatic disease site. A total of 626 patients were randomised to IFN-a (up to 18 MU subcutaneously three times weekly; n = 207), temsirolimus (15 mg/wk; n = 209), or combined therapy (temsirolimus 15 mg/wk and IFN-a 6 MU three times weekly; n = 210). In this study, temsirolimus demonstrated a statistically significant longer OS ( p = 0.0069) and PFS ( p = 0.0001) compared with IFN-a. At this year s ASCO meeting, the results of a post hoc subset analysis of this trial evaluating the influence of tumour histology on OS and PFS in patients treated with temsirolimus or IFN-a were presented [50]. In both treatment arms, about 81% of patients had CCRCC and 19% had other histology (13% indeterminate, 6% non-clear cell). Of those patients with additional cell subtype data, 75% showed papillary histology. For patients with CCRCC, median OS and PFS were longer for those treated with temsirolimus than for those treated with IFN-a (HR, 0.82 and 0.76, respectively; Table 8). For patients with other tumour histologies, median OS and PFS were also longer for those treated with temsirolimus versus IFN-a (HR, 0.49 and 0.38, respectively; Table 8). The authors concluded that temsirolimus is of benefit in patients with CCRCC as well as in patients with other tumour histologies. Table 8 Temsirolimus improves survival in advanced clear cell and papillary renal cell carcinoma [50] Clear cell Other histology Interferon-a (n = 170) Temsirolimus (n = 169) Interferon-a (n = 36) Temsirolimus (n = 37) Median overall survival (mo) 8.2 10.6 4.3 11.6 Median progression-free survival (mo) 3.8 5.5 1.8 7.0