Kyle Richards MD.

	Dr. Richards is a urologic oncology fellow and Dr. Eggener is associate professor of surgery/urologic oncology at the University of Chicago Medical Center. Series Editor Christopher M. Gonzalez, MD, MBA, is professor of urology at Northwestern University’s ­Feinberg School of Medicine, Chicago.

	An estimated 35% of patients newly diagnosed with renal cell carcinoma (RCC) present with metastases or regionally advanced disease. Additionally, after surgical treatment of localized RCC, 10% to 28% of patients develop recurrence or metastases (SEER cancer statistics review, 1975-2008). To optimize outcomes for patients with advanced RCC, multimodal therapy is often required, which may include surgery, systemic therapy, and occasionally radiation therapy. Herein, we discuss the various treatment options and a systematic approach to the patient newly diagnosed with metastatic RCC (mRCC).

	RCC is unique in that the primary tumor has the ability to withstand systemic immunotherapy, inhibit immune responsiveness, and provide a source for additional metastatic progression. These observations led the Southwest Oncology Group (SWOG) and European Organization for the Research and Treatment of Cancer (EORTC) to conduct two separate randomized prospective clinical trials evaluating cytoreductive nephrectomy followed by interferon-α (IFN-α) versus IFN-α alone, with the primary endpoint being overall ­survival.

	Both trials were published in 2001, with the SWOG trial showing a 3-month improvement in median overall survival in the cytoreductive nephrectomy arm (

 2001; 345:1655-9) and the EORTC trial showing a 10-month survival advantage (

 2001; 358:966-70) (table 1). Thereafter, cytoreductive nephrectomy prior to systemic therapy became a reference standard for patients considered candidates for surgery; however, it is unknown whether this treatment strategy is beneficial in the contemporary era of targeted therapy and, if so, whether all patients with mRCC benefit from cytoreductive ­nephrectomy.

	Patient selection remains critical for optimizing outcomes, as not all patients are appropriate for cytoreduction. For instance, the SWOG and EORTC trials excluded patients with poor performance status (ECOG ≥2), prior systemic therapy, tumor thrombus beyond the renal vein, an unresectable primary tumor, and brain metastases (EORTC trial only). In a large multivariable analysis, lactate dehydrogenase (LDH) level >618 IU/L, albumin <3.5 g/dL, symptomatic metastases at presentation, liver metastases, retroperitoneal or supradiaphragmatic adenopathy, and clinical T3/T4 disease were independent preoperative predictors of inferior survival. Of these seven variables, patients with four or more risk factors did not appear to benefit from cytoreductive nephrectomy (

 2010; 116:3378-88). In contrast, favorable prognostic factors included lung-only metastases and good performance status (ECOG ≤1).

	Cytoreductive nephrectomy has not been formally evaluated in the setting of targeted therapy (table 2). However, in the phase III clinical trials of the tyrosine kinase inhibitors sunitinib (Sutent) and sorafenib tosylate (Nexavar), the rates of nephrectomy (performed at time of localized disease or cytoreductive) in the treatment arms were 91% and 94%, respectively (

	Despite the routine use of cytoreductive nephrectomy in these trials, the benefit remains largely theoretical and is extrapolated from evidence obtained in the immunotherapy trials. A potential downside to cytoreductive nephrectomy is operative morbidity and prolonged convalescence resulting in a delay in the delivery of systemic therapy. A multicenter retrospective study of 201 patients revealed the median time from cytoreductive nephrectomy to the start of targeted therapy was 5 months, highlighting the potential delay in administration of systemic targeted therapy (

	An ongoing phase III clinical trial, CARMENA (Clinical Trial to Assess the Importance of Nephrectomy), is accruing in France and randomizing 576 patients to cytoreductive nephrectomy followed by sunitinib versus sunitinib alone (

; NCT00930033). The primary endpoint is overall survival, with anticipated completion of enrollment in May 2013. Until the results of this trial are known, cytoreductive nephrectomy remains a standard care option in appropriately selected patients.

	While there are no randomized clinical trial data to support the routine administration of targeted therapy prior to nephrectomy, several observations support the rationale of a neoadjuvant approach.

	First, several case series and phase II clinical trials have shown pre-surgical targeted therapy can lead to meaningful primary tumor responses in a subset of patients, thereby rendering surgical resection feasible for tumors previously deemed unresectable (

 2011; 22:1041-7). A retrospective analysis of 10 patients with mRCC receiving presurgical sunitinib due to uncertainty regarding resectability showed a partial response in two patients, a median change of –10% (range, –20% to +11%) in the primary tumor, and allowing for nephrectomy in three of the patients (

	Second, initiation of systemic targeted therapy at diagnosis of mRCC might decrease cancer-related morbidity prior to surgery.

	Finally, neoadjuvant targeted therapy can serve as a potential “litmus” test, as patients not responding to treatment with development of progressive disease can be spared the potential morbidity of surgery.

There are also several theoretical disadvantages of pre-surgical targeted therapy, including an alteration in tumor biology, progression of primary tumor or metastasis, more difficult surgery, and increased postoperative wound complications. However, the operative morbidity does not seem to be increased in patients who have received targeted therapy prior to nephrectomy (table 3) (

 2011; 60:964-71). Ongoing clinical trials will answer these questions and better define the optimal patient and time to initiate systemic targeted therapy (EORTC phase III clinical trial SURTIME, 

	Patients with RCC can present with synchronous metastases or subsequently develop metachronous metastases in a variety of sites, including lung, bone, brain, liver, pancreas, lymph nodes, adrenal, and locally in the nephrectomy bed. Metastasectomy involves the surgical removal of these metastatic foci with the goal of improving survival or palliating local symptoms. The rationale of metastasectomy is largely supported by multiple retrospective series showing 30% to 50% 5-year survival, although they must be interpreted by acknowledging inherent selection bias. Metastasectomy is nearly always performed for solitary metastases, although some centers will perform multiple resections (

 2011; 117:2373-82). Patients with mRCC can be risk stratified into favorable (0 points), intermediate (1-2 points), and poor risk (3-5 points) categories based on five readily available clinical parameters:

	• time from nephrectomy to recurrence <12 months

	• serum hemoglobin <gender-specific lower limit of normal

	Risk stratification is useful to guide potential treatment and counsel patients, as favorable-, intermediate-, and poor-risk patients have been shown to have median survival following metastasectomy of 78, 28, and 4 months, respectively (

2008; 180:873-8). Furthermore, metastasectomy may improve survival in patients with recurrent RCC following nephrectomy, albeit the benefit appears to be limited to patients with favorable- and intermediate-risk disease (

	Generally speaking, all patients with recurrent resectable metastatic disease who are in reasonable medical condition should be considered for metastasectomy. Furthermore, a recent phase II clinical trial has been initiated evaluating the efficacy of sorafenib after metastasectomy (

; NCT01444807), intending to randomize 132 patients to sorafenib versus observation with a primary endpoint of recurrence-free survival.

	There are currently 10 phase II trials enrolling patients with mRCC evaluating the efficacy of sorafenib, sunitinib, bevacizumab (Avastin), pazopanib (Votrient), and everolimus (Afinitor) prior to nephrectomy (

). Additionally, as noted, the EORTC is enrolling patients in the randomized phase III SURTIME trial. Patients are randomized to immediate nephrectomy followed by oral sunitinib beginning 4 weeks post surgery (four cycles) versus sunitinib for three courses (in the absence of disease progression or unacceptable toxicity) followed by cytoreductive nephrectomy 1 day after completion of the third course of sunitinib followed by an additional two courses of sunitinib starting 4 weeks after nephrectomy. The study commenced in April 2010, with plans to enroll 458 patients and an estimated completion date of October 2014 (

; NCT01099423). SURTIME and CARMENA (as mentioned above) will help answer several key questions regarding the timing and integration of targeted systemic therapy in the multimodal management of mRCC.

	The treatment of mRCC involves a multimodal approach to optimize survival and patient quality of life. Surgical removal of the primary tumor and resectable metastatic deposits, usually solitary, should be considered for appropriately selected patients. Targeted systemic therapy has improved the survival of patients with mRCC and plays a crucial role in the management of these patients. Ongoing clinical trials will help elucidate the proper timing of surgery and targeted therapy with a potential paradigm shift toward pre-surgical targeted ­therapy followed by consolidative cytoreductive nephrectomy if there is a favorable response.

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To optimize outcomes for patients with advanced renal cell carcinoma, multimodal therapy is often required.

Kyle Richards MD.

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