Addenbrooke s Hospital, Cambridge, United Kingdom

Transcription

1 The Oncologist The Oncologist CME Program is located online at To take the CME activity related to this article, you must be a registered user. Genitourinary Cancer Cytoreductive Nephrectomy in Metastatic Clear-Cell Renal Cell Carcinoma: Perspectives in the Tyrosine Kinase Inhibitor Era SWETHAJIT BISWAS, a JOHN KELLY, b TIM EISEN c a Department of Oncology, Oncology Centre, Addenbrooke s Hospital, Cambridge, United Kingdom; b Department of Surgical Oncology and c Department of Oncology, University of Cambridge & Addenbrooke s Hospital, Cambridge, United Kingdom Key Words. Cytoreductive surgery Clear-cell renal cell cancer Immunotherapy Tyrosine kinase inhibitors Disclosures Swethajit Biswas: None; John Kelly: none; Tim Eisen: Consultant/advisory role: Bayer, Wyeth, Pfizer, Roche, Novartis; Honoraria: Bayer, Wyeth, Pfizer, Roche; Research funding/contracted research: Bayer, Pfizer; Ownership interest: AstraZeneca Section editors Chris Parker and Matthew R. Smith have disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. Target audience: Physicians who wish to advance their current knowledge of clinical cancer medicine in genitourinary cancer. LEARNING OBJECTIVES 1. Summarize the relationship of data on nephrectomy in metastatic RCC to immunotherapy. 2. Apply to your practice available prognostic predictive scoring systems. 3. Compare and contrast the potential benefits and costs of cytoreductive nephrectomy in the TKI era. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT Cytoreductive nephrectomy in combination with adjuvant immunotherapy is an established treatment option for selected patients with metastatic clear-cell renal cell carcinoma (mcc-rcc). Multitargeted antiangiogenic and mammalian target of rapamycin tyrosine kinase inhibitors (TKIs) are now established treatment paradigms in patients with mcc-rcc. Given that all the recent seminal TKI trials in mcc- RCC provide no evidence base for the use of cytoreductive nephrectomy in the TKI era, it is not presently clear where such a surgical approach fits into the treatment paradigm. This review summarizes the evidence for the management of mcc-rcc and outlines novel approaches to be tested within future trials if the initial proposed phase III trials in this setting, using sunitinib, are successful. Overall, two prin- Correspondence: Tim Eisen, Ph.D., F.R.C.P., Department of Oncology, Box 193, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom. Telephone: 44(0) ; Fax: 44(0) ; tim.eisen@medschl.cam.ac.uk Received May 22, 2008; accepted for publication December 15, 2008; first published online in The Oncologist Express on January 15, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Biswas, Kelly, Eisen 53 cipal questions need addressing. First, is cytoreductive nephrectomy necessary in the TKI era? Second, if so, what is the most appropriate scheduling of TKI therapy with cytoreductive nephrectomy? The Oncologist 2009;14:52 59 ABRIEF OVERVIEW OF THE TREATMENT OF METASTATIC CLEAR-CELL RENAL CELL CARCINOMA Renal-cell carcinoma accounts for 5% of epithelial cancers worldwide [1]. Up to 85% of these cancers are clearcell renal cell carcinoma (CC-RCC) and 25% of such cases represent metastatic (m)cc-rcc [2]. Dismally, the 2-year overall survival rate of patients with mcc-rcc is only 10% 20%. CC-RCCs develop as a result of activation of pseudohypoxic pathways within proximal tubule nephron cells. This mainly arises as a result of loss of function of the von Hippel Lindau tumor suppressor gene, leading to constitutive protein expression of the hypoxia-inducible factor (HIF)-2 and/or HIF-1 isoforms [3]. Historically, cytokine immunotherapies such as i.v. high-dose interleukin-2 (IL-2) and interferon (IFN)- have been the cornerstones of mcc-rcc treatment [4, 5]. However, cytokine immunotherapy has now been superseded by tyrosine kinase inhibitors (TKIs) in the first-line disease setting [6, 7], and specific TKIs have also been shown to have activity in the second-line disease setting, where either IFN- [8] or an alternative TKI [9] have been administered first line. However, no TKI has yet been shown to extend overall survival in any disease setting. Which TKI is the most appropriate therapy in the firstline disease setting is determined by categorizing mcc- RCC patients into specific prognostic groups. Mekhail et al. [10] extended the Memorial Sloan-Kettering Cancer Center (MSKCC) model at the Cleveland Clinic Foundation (CCF) for use in the era of targeted biological therapy (Table 1). This model categorizes patients into good, intermediate, and poor prognostic groups depending on the presence of any one of nine validated risk factors (Table 2). There are two seminal phase III clinical trials using TKIs in the first-line treatment of mcc-rcc. First, Motzer et al. [6] demonstrated that sunitinib is superior to IFN- in terms of progression-free survival (PFS), with a partial response rate of 40% and attainment of stable disease in a further 40% of patients within all MSKCC prognostic groups. Second, for patients in the MSKCC poor-prognosis category, Hudes et al. [7] demonstrated that temsirolimus was superior to both IFN- alone and the combination of the two drugs. In the second-line disease setting, after IFN- treatment failure, the phase III TARGET (Treatment approaches in renal cancer global evaluation trial) trial by Escudier et al. [8] demonstrated that sorafenib had a partial response rate of 10%, versus 2% for placebo (p.001), with a longer PFS time, 5.5 months with sorafenib versus 2.8 months with placebo (hazard ratio, 0.44; p.01). However, there was no demonstrable difference in overall survival. More recently, in an abstractpresented phase III trial, the oral mammalian target of rapamycin (mtor) inhibitor everolimus (RAD-001) was shown to have second-line activity compared with placebo in patients refractory to either first-line sunitinib or sorafenib, because it produced a longer time to disease progression, 4 months versus 1.9 months [9]. Furthermore, antiangiogenic therapies have been combined with IFN- immunotherapy in the first-line disease setting. The phase III AVOREN (Avastin and interferon in renal cancer: Bevacizumab plus interferon- -2a for treatment of metastatic renal cell carcinoma) study, involving nephrectomized mcc-rcc patients, demonstrated a longer PFS time, 10.2 months versus 5.4 months, with the addition of bevacizumab to IFN- (hazard ratio, 0.63; p.0001) and a higher response rate, 30.6% versus 12.4% (p.0001), but with no difference in overall survival [11] (Table 3). SELECTION OF PATIENTS FOR CYTOREDUCTIVE NEPHRECTOMY At present, there are no validated clinical prognostic nomograms to assess which patients are suitable for cytoreductive nephrectomy within the immunotherapy setting. Therefore, by default, the CCF-modified MSKCC prognostic criteria (Table 1) can be used by oncologists to guide surgical referral decisions for cytoreductive nephrectomy, particularly given that only MSKCC good-prognosis patients derive clinical benefit from IFN- [12]. Zisman et al. [13] devised a model based on the University of California Los Angeles integrated staging system used in resected primary CC-RCC patients to define prognosis in mcc-rcc patients postnephrectomy. Patients were categorized as high risk if they had Fuhrman s grade 4 tumors and a performance status score 1. Within this group, there were no survivors at 3 years postnephrectomy. Importantly however, this prognostic model remains to be prospectively validated. Pierorazio et al. [14] recently suggested the concept of the fractional percentage tumor volume (FPTV) in cytoreductive nephrectomy the percentage of tumor that the primary cancer represents within the entire tumor burden (primary plus metastasis), determined by imaging. That study demonstrated that FPTV is an independent predictor

3 54 Cytoreductive Nephrectomy in mcc-rcc Table 1. Prognostic groups in the CCF-extended MSKCC model in metastatic clear-cell renal cell carcinoma [10] CCF-extended MSKCC model prognostic category Good prognosis Intermediate prognosis n of risk factors (n 9) Median overall survival time (mos) (n 353) Abbreviations: CCF, Cleveland Clinic Foundation; MSKCC, Memorial Sloan-Kettering Cancer Center. Poor prognosis Table 2. Validated risk factors in the Cleveland Clinic Foundation extended Memorial Sloan-Kettering Cancer Center model in metastatic clear-cell renal cell carcinoma Risk Risk factor factor 1. Karnofsky score 80% 6. Prior radiotherapy 2. Corrected calcium 10 mg/dl 7. Hepatic metastasis 3. Hemoglobin Less than lower limit of local reference range 8. Pulmonary metastasis 4. Serum lactate dehydrogenase 1.5 upper limit of local reference range 9. Retroperitoneal lymph node metastasis 5. Time to first-line therapy from initial diagnosis of metastasis 12 mos Table 3. Current treatment algorithm for metastatic clear-cell renal cell carcinoma in the era of biological targeted therapies Good risk Intermediate risk Poor risk First line Single-agent immunotherapy: interferon- Sunitinib Temsirolimus plus bevacizumab, or sunitinib Second line Sorafenib (postcytokine) or everolimus (post-tki) Some data for TKI switch Few data Abbreviation: TKI, tyrosine kinase inhibitor. of disease-specific survival. For patients with 90% FPTV, the disease-specific survival duration was 11.6 months, versus 2.9 months for patients with 90% FPTV (p.002). For patients with 90% FPTV, the risk for CC- RCC death on multivariate analysis was significantly lower (hazard ratio, 0.29; p.02), and patients with 90% FPTV spent a greater proportion of time hospitalized before death. From this, it could be suggested that FPTV may represent a new stratifying criterion for future trials involving cytoreductive nephrectomy and postoperative systemic therapy. One of the fundamental prerequisites for cytoreductive surgery is that patients are selected in such a way that the morbidity of surgery does not compromise the likelihood of the patient receiving postoperative systemic therapy. Although research within this area is limited, a study by Fallick et al. [15], using IL-2 in 28 patients, demonstrated that at least one cycle of IL-2 could be administered in 93% of the 26 patients who were still eligible for IL-2 postnephrectomy if: 75% of the primary tumor was debulked, the primary tumor was predominantly of clear-cell morphology, and no central nervous system, liver, or bone metastases were present, and if patients had adequate cardiopulmonary function, no active infection, and no serious medical comorbidities. Using these particular selection criteria, there was an overall response rate of 39% and a median overall survival duration of 20.5 months. CYTOREDUCTIVE SURGERY IN THE ERA OF TKIS Certain questions remain to be addressed regarding the optimal TKI treatment paradigm in mcc-rcc. First, the feasibility and clinical utility of TKI dose escalation to improve or sustain disease response remains to be investigated, but initial studies are already showing clinical promise [16]. This could conceivably be extended into future trials involving cytoreductive nephrectomy, but only if the initial mcc-rcc trials using TKIs are positive. Second, the clinical utility of newer antiangiogenic TKIs, such as axitinib [17] and pazopanib [18], remains to be prospectively evaluated in phase III mcc-rcc trials, but could also be

4 Biswas, Kelly, Eisen 55 translated into the cytoreductive setting if these initial trials are positive. Because TKIs have a different mechanism of action than cytokine immunotherapies, it is conceivable that cytoreductive surgery may not increase the efficacy of TKIs postnephrectomy in mcc-rcc. However, if cytoreductive nephrectomy per se has a major impact on proangiogenic drive, then adjuvant TKI therapy may have a synergistic anticancer effect. For primary CC-RCC tumors, this is being currently investigated within the SORCE (A phase III randomized double-blind study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse) trial (sorafenib versus placebo) in the United Kingdom [19] and the ASSURE trial (sunitinib versus sorafenib versus placebo) in the U.S. [20]. OPERATIVE MORBIDITY FROM CYTOREDUCTIVE NEPHRECTOMY IN MCC-RCC WEIGHING THE RISK BENEFIT RATIO IN AN AGING POPULATION The Southwest Oncology Group 8949 and EORTC trials suggested that cytoreductive nephrectomy in mccmrcc 1 0 in situ 700 pts Equivalence Nephrectomy Then Sunitinib Sunitinib Figure 1. Schematic for the proposed CARMINA phase III trial assessing the role of cytoreductive nephrectomy in the treatment of metastatic clear-cell renal cell carcinoma (mcc- RCC) with sunitinib. mrcc 1 0 in situ 440 pts Nephrectomy Then Sunitinib Sunitinib Then Nephrectomy Figure 2. Schematic for the proposed European Organization for Research and Treatment of Cancer phase III trial assessing the scheduling of sunitinib therapy in the perinephrectomy setting in metastatic clear-cell renal cell carcinoma. THE RATIONALE FOR CYTOREDUCTIVE NEPHRECTOMY IN THE TKI ERA At present there is no evidence base from the three seminal TKI trials in mcc-rcc that there is a role for cytoreductive nephrectomy. However, because cytokine immunotherapy has little effect on primary tumor reduction in mcc-rcc, it is an appropriate question in the current therapeutic era to ask whether TKIs do. Although there are currently no largescale prospective TKI-based trials addressing this issue, a recent study using sunitinib and involving 17 patients demonstrated a 31% reduction in the median volume of the primary tumor accompanied by a 39% increase in the median volume of primary tumor necrosis [21]. However, patients who have an Eastern Cooperative Oncology Group (ECOG) performance status score of 1 (borderline for nephrectomy) or 1 and/or are high-risk surgical candidates should be excluded from radical nephrectomy in the mcc- RCC setting. Therefore, two fundamental questions need addressing: 1. Is cytoreductive nephrectomy clinically beneficial in the treatment of mcc-rcc with TKIs? 2. If nephrectomy is essential, which intervention (surgical versus TKI therapy) should be performed first? The proposed CARMINA phase III study will hopefully address the first question by recruiting 700 mcc- RCC patients with the primary tumor in situ and randomize them to either nephrectomy plus sunitinib or sunitinib alone (Fig. 1). Second, if primary tumor cytoreduction is found to have a role in mcc-rcc treatment, then the scheduling of TKI therapy needs to be determined. If the CARMINA trial is positive, a proposed subsequent phase III trial by the European Organization for Research and Treatment of Cancer (EORTC) will hopefully address this question, by recruiting 440 patients to compare the effect of sunitinib prenephrectomy with that postoperatively (Fig. 2). The overall benefit of performing up-front surgery, particularly in poor-prognosis patients or in those with rapidly progressive disease, should be called into question. Such patients, indeed all patients, may benefit from initial targeted therapy with a wait and see approach depending on the clinical response. Proponents of such a neoadjuvant strategy purport that such a delayed nephrectomy approach could facilitate better patient selection for nephrectomy, and prevent patients who demonstrate no response to targeted therapies from undergoing unnecessary nephrectomy, with all the attendant morbidity and mortality risks. Also, if the primary tumor responds to TKI therapy, the potential downstaging/downsizing may facilitate surgical debulking. Other centers outside Europe are currently recruiting patients to individual phase II trials using sunitinib and sorafenib, as well as novel synergistic biological therapies (such as bevacizumab and erlotinib), to assess their roles in the perinephrectomy setting [22].

5 56 Cytoreductive Nephrectomy in mcc-rcc RCC can reduce local tumor complications, significantly reduce overall tumor burden, and possibly improve responses to systemic immunotherapy with a longer overall survival time. However, critics of cytoreductive surgery suggest that it is associated with significant morbidity and the potential for serious complications, particularly given that the presence of metastasis per se is an independent predictor of perioperative mortality following open nephrectomy. Similarly, it is also important to appreciate that patients with an ECOG performance status score of 1 clinically benefit from nephrectomy for only a few weeks. Although nonrandomized trials have not been useful in affirming the clinical benefit of cytoreductive nephrectomy, it is, however, possible to draw on such trials to describe nephrectomy-related morbidity and mortality. These issues are particularly important because the aging demographic in many Western countries means that cytoreductive surgery will be more frequently clinically indicated in older patients, particularly in those 75 years old, in whom the incidence of CC-RCC is the highest. A retrospective study from Kader et al. [23], involving mainly patients with a performance status score of 0 or 1, evaluated the role of surgery in the older population. That series consisted of 24 patients 75 years old and 380 patients 75 years old. Five of the 24 patients (21%) 75 years old died in the perioperative setting, whereas only four of the 380 (1.3%) died in the younger age group. In patients 75 years old, those who died had longer operating times, greater blood loss, and more requirements for blood transfusions than those who did not die (p.05). One possible explanation for these findings is that medical comorbidities such as cardiovascular disease have a higher incidence within such older age groups, but this was not specifically stated within this study. The data of Kader et al. [23] suggest that elderly patients with mcc-rcc may be suitable candidates for cytoreductive nephrectomy mainly when they have a good performance status score, stage T3b disease or lower, and N1 nodal disease or lower. However, conclusions from those data should be judged very cautiously, because the patient cohort sizes were not balanced and, more importantly, there are no prospective surgical studies addressing the role of cytoreductive nephrectomy in the elderly. The mitigation of surgical complications and better disease outcomes have already been demonstrated for patients undergoing cancer surgery for renal and other primary solid tumors by ensuring that the operations are performed by specialist teams within high-volume cancer centers. Whether minimal access techniques, such as laparoscopic surgery, can mitigate some of these perioperative morbidities seen for open cytoreductive nephrectomy is not definitively known. The lack of studies in this area is probably a reflection of the complexity of primary tumor surgery in mcc-rcc, because patients are more likely to have local nodal disease involvement, which in turn would favor an open-nephrectomy approach. This is distinct from the established use of minimal access approaches for radical nephrectomy in primary CC-RCC, where the natural history of the disease is different. However, data from Rabets et al. [24] suggest that patients treated with laparoscopic nephrectomy have an equivalent 1-year survival rate to those treated with open nephrectomy (61% versus 65%), but notably, a shorter time to initiation of immunotherapy (36 versus 61 days; p.01). The laparoscopic approach was also associated with significantly less blood loss (288 ml versus 1,228 ml; p.001), but there were no differences in the duration of surgery or the nonhemostatic complication rates. However, the nonrandomized nature of that study and the fact that tumor size was slightly smaller in the laparoscopic group, by 1.6 cm on average (7.9 cm versus 9.5 cm; p.04), are two important mitigating factors to the validity of the study. Similarly, it is not known whether nephron-sparing surgery (NSS) for small peripheral primary renal tumors ( 4cm in diameter) in mcc-rcc is better in terms of operative morbidity and at least equivalent in prognostic outcome to open nephrectomy. However, one small retrospective study has found that it is not detrimental to disease-specific survival [25]. However, the actual clinical utility of NSS is likely to remain unknown given that there are too few patients within this setting to conduct a clinical trial. Therefore, NSS is likely to remain a procedure applied selectively in mcc-rcc patients. The role of cytoreductive nephrectomy in patients with large primary tumors (T4) has also been investigated. This issue is of particular importance because surgery could be of greater morbidity and therefore potentially compromise the initiation of postoperative systemic therapy. Kassouf et al. [26] investigated this in 23 patients with T4NxM1 disease, of whom 21 underwent nephrectomy. Although 79% of the 21 patients who underwent nephrectomy were well enough postoperatively to receive immunotherapy, the 21% who did not only had a median disease-specific survival duration of 2.5 months, versus 7.1 months for patients who received postoperative immunotherapy. The main perioperative issue in patients who did not receive immunotherapy was a median blood loss of 2.5 liters. However, T4 tumors have a high preponderance for invading extrarenal organs, which means that multidisciplinary surgical management is required. This is manifest in the Kassouf et al. [26] study, in which 15 of the 21 patients required major adjacent organ resection (e.g., colectomy and partial hepatectomy) and 3 of the 21 patients had positive surgical margins on pathological analysis. However, there was no demonstrable operative mortality. Because this was a retrospective analysis of data over 11 years, this may just be a consequence of a study involving very small numbers of selected patients.

6 Biswas, Kelly, Eisen 57 Overall, the data of Kassouf et al. [26] suggest that trying to attenuate intraoperative blood loss and possibly identifying patients preoperatively who are at a high risk for blood loss could be important strategies. However, the increasing use of stored allogenic packed red cells or cell-saver techniques may offset many of these issues. Although the overall outcome for these patients is poor, cytoreductive nephrectomy can still offer significant palliation from primary tumor-induced symptoms (such as pain and hematuria), although importantly, it remains to be determined whether surgical debulking of T4 tumors improves the overall disease-specific survival. TKI DRUG TOXICITIES AND THEIR POTENTIAL IMPLICATIONS IN PROPOSED CYTOREDUCTIVE NEPHRECTOMY TRIALS Antiangiogenic TKIs and mtor kinase TKIs can have notable toxicities. Common side effects between these two classes of TKIs are lethargy, nausea, diarrhea, hepatic toxicity, cytochrome P450 (CYP)3A4-induced drug interactions, and myelosuppression. Specifically, hand foot syndrome with sorafenib and sunitinib may interfere with preoperative mobility and function if toxicity is grade 2. Although most of these toxicities are manageable and reversible with an adequate washout period, it is important that the time to surgery is not delayed in the neoadjuvant setting, and that the introduction of therapy is not delayed in the adjuvant setting. However, certain specific issues are worth discussing. Surgical and Anesthetic Considerations CYP3A4 induction and marked hepatic toxicity are notable issues concerning TKIs [27, 28]. These factors may compromise the efficacy of opiate or nonsteroidal analgesics used for the palliation of primary tumor symptoms perioperatively, when such analgesics are commonly required. Similarly, the efficacy of antibiotics may be compromised. This may have implications particularly in the immediate postoperative setting, where wound or respiratory infections are frequently encountered. Because temosirolimus also has immunosuppressive effects [27], it is possible that perioperative treatment may make patients more susceptible to systemic infections. This could possibly be of particular importance in the postoperative period when patients are at a higher risk for iatrogenic infections. Another peculiar complication of temsirolimus is pulmonary toxicity [28]. This is usually a mild, reversible complication, forwhich treatment can be reintroduced after complete resolution. Therefore, if neoadjuvant protocols involving temsirolimus are conceived for MSKCC poor-risk mcc-rcc patients, it would be interesting to investigate, using serial pulmonary function test monitoring, whether this translates into overall reductions in lung function. This could potentially compromise nephrectomy because of an increased anesthetic risk. If an appropriate prenephrectomy washout period for TKIs is not present within neoadjuvant trials protocols, it is conceivable that potential drug interactions may arise with certain general anesthetics. This could potentially interfere with both the efficacy and toxicity of anesthesia during nephrectomy. Venous Thromboembolic Effects Antiangiogenic TKIs are known to increase the risk of developing venous thromboembolic events. Given that patients with advanced renal cancer are at a high baseline risk for venous thromboembolism anyway, patients treated with neoadjuvant and/or adjuvant TKIs need to be carefully monitored. Given this, it could be suggested that the prophylactic use of low-molecular-weight heparins within this setting requires prospective validation, rather than empirical-based practice translated from standard postoperative care procedures. POSTOPERATIVE WOUND HEALING AND BOWEL PERFORATION This mainly involves the necessary physiological requirement for angiogenesis and growth factor signaling in surgical wound healing. There is a potential risk that perinephrectomy TKI strategies could increase the time to wound healing, and in turn possibly increase the risk for wound dehiscence and infection. Because adjuvant TKI trials, such as the SORCE trial in resected primary CC-RCC, are currently open to recruitment, there are no specific postnephrectomy safety data on this issue at present. Also, bowel perforation is a known complication of treatment with antiangiogenic TKIs and temsirolimus [27 29]. In any proposed neoadjuvant trial using such drugs, particularly in patients who have extensive abdominal/ pelvic tumor burden, this would be important to monitor. This could also be a particular problem within trials where antiangiogenic or anti-mtor therapy would be started or continued postnephrectomy, such that postoperative adhesions, scarring, and intra-abdominal sepsis could potentially be exacerbating factors for bowel perforation. CARDIOVASCULAR TOXICITIES WITH ANTIANGIOGENIC TKIS Both sunitinib and sorafenib can cause hypertension and cardiotoxicity. Comparatively, sunitinib has the greater potential for inducing cardiac toxicity, whereas sorafenib has the most significant risk of inducing hypertension [30]. Transthoracic echocardiography, to assess left ventricular (LV) function, is one convenient method of monitoring cardiac function. However, at what point a TKI-induced dete-

7 58 Cytoreductive Nephrectomy in mcc-rcc rioration in LV function becomes clinically relevant and whether or not impairment of LV function is reversible over time have not currently been evaluated. Phase III data in treatment-naïve mcc-rcc patients showed that 21% of sunitinib-treated patients demonstrated a decline in LV ejection fraction below the lower limit of normal, with 4% of patients experiencing a 20% decline in LV function from baseline and to 50%. However, only 1% of patients had clinical signs of LV dysfunction, with 1% actually developing congestive heart failure [6, 27]. To date, it is not known what role, if any, potentially cardioprotective agents, such as angiotensin-converting enzyme inhibitors or cardioselective -blockers, have in TKI-treated patients with a clinically occult deterioration in LV function. However, the development of symptomatic cardiac failure in this setting would almost certainly preclude immediate nephrectomy because of the risk of a general anesthetic. Future clinical translational trials could be designed to incorporate the use of serial cardiac troponin or brain natriuretic peptide measurements as putative biomarkers of cardiotoxicity. Similarly, cardiac magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) techniques [31, 32] could also be useful to investigate within such trials, because metabolic cardiac changes would be expected to occur before kinetic changes in LV function. Because sunitinib is also known to prolong the QT interval [27], sunitinib-based neoadjuvant trial protocols are contraindicated in patients with known paroxysmal ventricular tachyarrhythmias, or with known prolongation of the QT interval. Similarly, the use of clarithromycin for perioperative infections is contraindicated, because concomitant prescription of sunitinib and clarithromycin could potentiate the QT interval, leading to the development of torsade de pointes. For analogous reasons, it is important that perioperative electrolyte deficiencies, such as hypokalemia and hypomagnesemia, particularly postnephrectomy, are corrected before treatment with sunitinib is initiated. FUTURE POSSIBILITIES FOR CLINICAL RESEARCH INVOLVING CYTOREDUCTIVE NEPHRECTOMY IN THE TKI ERA Cytoreductive nephrectomy may also potentially contribute to the investigation of mcc-rcc tumor biology, because cytoreductive nephrectomy permits the collection of the whole primary tumor in metastatic disease. If such patients also have synchronous metastatic lesions that are amenable to image-guided biopsy, this would also facilitate translational research investigating the potential differences in biology between the primary tumor and its metastases. If the CARMINA trial and the subsequent EORTC trial demonstrate a clinical benefit for sunitinib prenephrectomy, then subsequent neoadjuvant trials in mcc-rcc should be designed to facilitate better translational research in this disease. Such future studies could be designed to incorporate the following. 1. Collection of tissue and serum samples at various stages of drug therapy and in the pre- and postnephrectomy setting could potentially improve our understanding of the pharmacogenomics of TKIs and other biologically targeted therapies. Potentially, this could be useful in the development of clinical/molecular prognostic nomograms to assist in patient selection for cytoreductive nephrectomy. 2. Dynamic contrast-enhanced (DCE) MRI could be used to monitor in vivo blood flow into the primary tumor, and therefore potentially assess the effect of antiangiogenic therapies prenephrectomy. 3. In vivo functional imaging of the primary tumor using MRS could be used to assess whether any one particular candidate neoadjuvant therapy has a novel metabolic signature. This could potentially lead to the development of functional bioimaging being used to predict drug efficacy and disease response. DCE MRI and MRS could also allow crosscorrelation with ex vivo primary tumor tissue data, such as histopathology and cdna microarray, as well as with putative serum markers of antiangiogenic efficacy, such as soluble vascular endothelial growth factor receptor 2, placenta growth factor, and circulating endothelial cells. This could also provide important information in phase I/II trials, in which mcc-rcc patients are being treated with experimental agents that have known preclinical antiangiogenic effects. CONCLUSIONS Cytoreductive nephrectomy was demonstrated to be beneficial for patients receiving immunotherapy for mrcc. Given the revolutionary therapeutic shift in the management of mcc-rcc, there is an urgent need to assess whether cytoreductive nephrectomy is clinically beneficial for patients receiving antiangiogenic therapy. It is important that the morbidity of multimodality treatment regimens, consisting of cytoreductive nephrectomy and TKI therapy, is carefully assessed. Although it has been difficult to accrue patients to such surgical trials in the past, it is hoped that the phase

8 Biswas, Kelly, Eisen 59 III CARMINA trial will address this question. If the CARMINA trial is positive, then the issue of whether the sequencing of TKIs in the surgical setting alters overall treatment efficacy, which is to be addressed in the proposed phase III EORTC trial, will be even more important. AUTHOR CONTRIBUTIONS Conception/design: Tim Eisen, John Kelly, Swethajit Biswas Administrative support: Tim Eisen Collection/assembly of data: Tim Eisen, John Kelly, Swethajit Biswas Data analysis: Tim Eisen, John Kelly, Swethajit Biswas Manuscript writing: Tim Eisen, John Kelly, Swethajit Biswas Final approval of manuscript: Tim Eisen REFERENCES 1 Cancer Research UK. UK Kidney Statistics. Available at cancerresearchuk.org/cancerstats/types/kidney, accessed October 27, Murai M. and Oya M. Renal cell carcinoma: Etiology, incidence and epidemiology. Curr Opin Urol 2004;14: Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci Signal 2007;407:cm8 cm8. 4 Fyfe G, Fisher RI, Rosenberg SA et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13: Jonasch E, Haluska FG. Interferon in oncological practice: Review of interferon biology, clinical applications, and toxicities. The Oncologist 2001; 6: Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356: Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356: Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: Motzer RJ, Escudier B, Oudard S et al. RAD001 versus placebo in patients with metastatic renal cell carcinoma (RCC) after progression on VEGFr- TKI therapy: Results from a randomized, double-blind, multicenter phase III study. J Clin Oncol 2008;26:1009s. 10 Mekhail TM, Abou-Jawde RM, Boumerhi G et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2005;23: Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2008;370: Negrier S, Perol D, Ravaud A et al. Medroxyprogesterone, interferon alfa- 2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: Results of a randomized controlled trial. Cancer 2007;110: Zisman A, Pantuck AJ, Wieder J et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002;20: Pierorazio PM, McKiernan JM, McCann TR et al. Outcome after cytoreductive nephrectomy for metastatic renal cell carcinoma is predicted by fractional percentage of tumour volume removed. BJU Int 2007;100: Fallick ML, McDermott DF, LaRock D et al. Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997; 158: Amato RJ, Harris L, Dalton M et al. A phase II trial of intra-patient doseescalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 2007;25(18 suppl): Rini B, Rixe O, Bukowski R et al. AG , a multi-targeted tyrosine kinase receptor inhibitor, demonstrates anti-tumour activity in a phase 2 study of cytokine-refractory, metastatic renal cancer (RCC). J Clin Oncol 2005;23(suppl 16): Hutson TE, Davis ID, Machiels JP et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT). Presented at the 2007 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 1 5, A phase III randomised controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse. Available at StudyDetail.aspx?StudyID 1753, accessed January 9, Haas N. Update on targeted therapy adjuvant trials (ECOG/MRC). Presented at the Fifth International Symposium of the Kidney Cancer Association, Chicago, IL, October 14 15, van der Veldt AAM, Meijerink MR, van den Eertwegh AJM et al. Sunitinib for treatment of advanced renal cell cancer: Primary tumor response. Clinical Cancer Research 2008;14: Wood CG. Multimodal approaches in the management of locally advanced and metastatic renal cell carcinoma: Combining surgery and systemic therapies to improve patient outcome. Clin Cancer Res 2007;13(2 suppl):697s 702s. 23 Kader AK, Tamboli P, Luongo T et al. Cytoreductive nephrectomy in the elderly patient: The M.D. Anderson Cancer Center experience. J Urol 2007; 177: Rabets JC, Kaouk J, Fergany A et al. Laparoscopic versus open cytoreductive nephrectomy for metastatic renal cell carcinoma. Urology 2005;64: Hutterer GC, Patard JJ, Colombel M et al. Cytoreductive nephron-sparing surgery does not appear to undermine disease-specific survival in patients with metastatic renal cell carcinoma. Cancer 2007;110: Kassouf W, Sanchez-Ortiz R, Tamboli P et al. Cytoreductive nephrectomy for T4NxM1 renal cell carcinoma: The M.D. Anderson Cancer Center experience. Urology 2007;69: Highlights of Prescribing Information. New York: Pfizer, Available at accessed October 27, Temsirolimus [prescribing information]. Madison, NJ: Wyeth Pharmaceuticals, Inc., Available accessed October 27, George DJ, Moore C. Angiogenesis inhibitors in clinical oncology. Update Cancer Ther 2006;1:429D 434D. 30 Wu S, Chen JJ, Kudelka A et al. Incidence and risk of hypertension with sorafenib in patients with cancer: A systemic review and meta-analysis. Lancet Oncol 2008;9: Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007;7: Neubauer S. The failing heart an engine out of fuel. N Engl J Med 2007; 356: