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Controversies and Consensus Surrounding Initial Cytoreductive Nephrectomy vs Targeted Therapy: What Is the Optimal Approach?

Michael L. Blute, MD
Walter S. Kerr, Jr, Professor of Surgery, Urology
Harvard Medical School
Chief, Department of Urology
Massachusetts General Hospital
Boston, Massachusetts

 

Keywords: cytoreductive nephrectomy, initial, targeted therapy, CARMENA trial, SURTIME, IMDC risk criteria, NCCN guidelines, TKI.  

Corresponding Author: Michael L. Blute, Sr, MD, Chief, Department of Urology, Massachusetts General Hospital, 165 Cambridge Street, 7th Floor, Boston, MA 02114  Email: MBLUTE@mgh.harvard.edu 

 

Few topics have generated as much controversy and debate as determining the optimal approach for cytoreductive nephrectomy in the targeted therapy era. Although the paradigm has been a moving target, with many reports taking opposing viewpoints, new population-based studies are closing in on a consensus. The debate is not going away soon, but clear guidelines are emerging. 

Compared to the era of cytokine therapy, when the benefits of initial cytoreductive nephrectomy (CN) for meta-static renal cell carcinoma (mRCC) were well established, the advent of targeted therapy has not only ushered in a new treatment paradigm, it has created a conundrum surrounding the role of CN, its timing, and related survival benefits. Here is the conundrum: In the targeted therapy era, recent reports have indicated declining utilization rates of CN; and yet, the most up-to-date guidelines from the National Comprehensive Cancer Network support the role of CN with targeted therapy (TT) in the appropriate clinical setting.1

Questions and quandaries about CN have been around for a long time so this is nothing new. However, as Molina et al posted in an analysis in the Journal of Clinical Oncology,2 the current trajectory and confusion about the role of CN is alarming when one considers differences in overall survival between patients who did and did not undergo such surgery. For clinicians in the 1990s, a debate raged about the benefit of CN for patients who were subsequently treated with cytokine therapies, such as interleukin-2 or interferon-alfa (IFN-alpha-2a). But the debate was virtually laid to rest when two randomized trials comparing CN plus IFN-alpha-2a vs IFN-alpha-2a alone demonstrated a significant improvement in survival of patients with mRCC, thereby offering compelling evidence that CN should be the new standard in this setting. In the cytokine era, urologists and oncologists would evaluate every patient who presented with mRCC to determine whether they were an appropriate surgical candidate for CN before systemic therapy. 

Why is that not true today, despite the evidence? For example, consider survival data for 13,000 patients from the National Cancer Data Base (NCDB)3 that showed a median survival of 17.1 months for patients who underwent CN compared with 7.7 months for patients who did not. These results are markedly similar to what was found in the pivotal study by Flanigan et al4 at the tail end of the cytokine era when median survival differences were compared for patients randomly assigned to receive CN.

CN Questioned in Era of Targeted Therapy
As phase 2 and phase 3 studies of targeted therapies (such as sunitinib and pazopanib, and sorafenib) suggested translational impact and radically changed the treatment paradigm, the success of these efforts began to undermine the rationale for upfront CN. Questions about the conventional wisdom of going to CN initially arose, namely: 

  • Does CN extend survival in the era of VEGF-targeted therapies? 
  • Should CN be performed before or after targeted therapy? 

The era of targeted therapies has brought with it a wide range of other questions as well, and although these are beyond the scope of this paper, they reflect a more nuanced approach to the management of mRCC, including strategies that evaluate far more closely than was the case in the cytokine era various risk factors and a basis for stratification (favorable to intermediate to poor risk) that influences clinical decision making. As is the case with the rationale for using different approaches of targeted therapy, a somewhat similar line of thinking can be applied to the use of CN. And many recent reports highlight the extent to which these risk factors should be considered in delineating the role of CN. 

There are hopeful signs, however, that new studies will more definitively address all of these issues. Two prospective randomized trials, the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA)5 and the European Organisation for Research and Treatment of Cancer’s Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients with Metastatic Kidney Cancer (SURTIME)6 were designed to examine these issues. Still, the conundrum endures: there has been a decline observed in the number of CNs over the last 10 years, (Figure 1) a decline coinciding with the use of effective systemic medical therapy.7-9 This is a decline that has occurred despite retrospective reports showing that CN improves outcomes, including a meta-analysis concluding that CN reduces the risk of death in mRCC by more than 50%.10-15 

Figure 1. Trend use of cytoreductive nephrectomies. The annual number of cyto-reductive nephrectomies (CNx) decreased between 2005 and 2010 by about 50%. This decline began when the use of targeted cancer therapies nearly tripled from 2004 to 2005.

In view of this confusing picture, and while we await results from studies like CARMENA and SURTIME, there are reports not only evaluating contemporary utilization rates of CN but examining the survival benefit of CN compared with non-CN patients treated with targeted therapy, and proposing risk stratification criteria to be followed. In their analysis of these risk factors, a new calculus has emerged to more clearly understand the benefits of CN in the targeted therapy era. Several conclusions can be made regarding use of CN in this context:

  • Guidelines suggest that upfront CN should be considered in all patients with good to intermediate prognosis. 
  • Patients with rapidly progressing mRCC  based on IMDC risk factor stratification (25% to 30%) are difficult to identify and yet, this is the group that should receive upfront targeted therapy or immunotherapy. There are ongoing efforts to identify these patients. 
  • The magnitude of benefit with CN in the targeted therapy era appears to be three times greater than what was observed in the cytokine era.
  • As more therapies become available, PFS is likely to improve, and although total cures are not achievable, controlling the primary tumor in the retroperitoneum will become more important. 

Beyond these key conclusions, the narrative on the use of CN has become more nuanced, especially with regard to a myriad of considerations related to risk factor stratification and the timing of CN. Recent reports highlight how thinking has evolved, helping to pave the way for new data hopefully to be obtained by studies like CARMENA and SURTIME. One of the important considerations in sorting through the nuances affecting clinical decision making is how various prognostic models have changed in the era of targeted therapy. Many of the existing models, such as the MSKCC and IMDC scoring systems were created for treatment of mRCC with cytokines.16 

The most widely used scoring system is from MSKCC. Adverse prognostic factors in this model are: 

  • Interval from diagnosis to treatment of <1 year.
  • Karnofsky performance status (KPS) of <80%. 
  • Serum lactate dehydrogenase levels >1.5 times the upper limit of normal. 
  • Corrected serum calcium >10 mg/dL.
  • Serum hemoglobin less than the lower limit of normal. 
  • Previous radiotherapy.
  • >1 metastatic site.

The adverse prognostic factors for OS in the IMDC model include: 

  • Anemia, thrombocytosis, neutrophilia.
  • KPS <80% 
  • <1 year from diagnosis to first-line targeted therapy
    (continued after sidebar)


Drilling Down into the CARMENA Trial:
Let’s Reassess Its Methodology and Preserve the
‘Window of Opportunity’ for Cytoreductive Nephrectomy

An analysis by Michael L. Blute, Sr., MD

The development of targeted, non-surgical cancer therapies has led some physicians to question cytoreductive nephrectomy—surgery to remove the primary tumor—as the standard of care for metastatic renal cell carcinoma patients. Since the advent of targeted cancer therapies in the mid-2000s, there has been a 50% reduction in the number of cytoreductive nephrectomies. A review of the NCCDB showed that currently only three out of ten patients with metastatic kidney cancer undergo cytoreductive nephrectomy. 

Improved systemic effectiveness and markedly increased tolerability compared to cytokine therapy has resulted in targeted therapy as front line therapy; however, it clouds the role of cytoreductive nephrectomy in patients with metastasis. The standard of care has shifted away from cytoreductive nephrectomy in the absence of level 1 evidence for its cancer survival benefit in the targeted therapy era. Abandoning cytoreductive nephrectomy as a standard of care should be viewed with concern.

Even with the advent of new agents, studies continue to suggest that a combination of surgery and targeted therapy produces the best outcome for patients. Two preliminary reports in 20111,2 suggested a benefit from cytoreductive nephrectomy before the initiation of targeted therapy. The first report showed that median survival was 21.6 months for patients undergoing cytoreductive nephrectomy and targeted therapy (sunitinib or sorafenib), vs. 13.9 months for patients undergoing targeted therapy alone. However, the differences were not statistically significant due to small sample size. The second report, with larger sample size, showed that median survival was 19.8 months for the group undergoing cytoreductive nephrectomy combined with targeted therapy and 9.4 months for patients treated with targeted therapy (sunitinib, sorafenib, or bevacizumab) alone. 

Although targeted therapies are effective (Figure 2) and usually well-tolerated by patients, they are not a cure. Another concern is that many tumors eventually develop resistance to targeted therapies. Theoretically, surgically removing the primary tumor reduces the tumor burden, diminishes the primary tumor’s suppression of the immune system and can delay disease progression by removing growth promoters and angiogenic factors. If you treat with targeted therapy alone and the disease progresses, you may put patients out of the window of opportunity where the surgery has a great impact. The major concern is to identify patients who will not benefit with cytoreductive nephrectomy as up to 17-20% of patients with metastatic disease will rapidly progress.  Improved understanding of risk factors, surgical indication and overall health of patients will improve patient selection. Ultimately, molecular signals may help personalize options for these patients.

Figure 2. Overall survival of patients who did or did not receive cytoreductive nephrectomy in patients receiving TK1 Therapy ERA. This graph depicts overall survival from initiation of VEGF (Vascular endothelial growth factor) targeted therapy for 314 patients who did or did not receive cytoreductive nephrectomy. The median survival for those who received CN was 19.8 months compared to 9.4 months for those who did not receive CN.

Sunitinib Alone or After Nephrectomy in Metastatic Renal-Cell Carcinoma?
The results of the 450-patient CARMENA Trial were reported by Méjean et al.3 This trial demonstrates that sunitinib alone was not inferior to the addition of surgery in patients who present with stage IV disease. This was an intention to treat analysis wherein not all patients received the assigned treatment and accrual was slow over an 8-year interval but nonetheless, there was statistically significant improvement in overall clinical benefit in patients who did not undergo nephrectomy. This is the second of two highly anticipated randomize controlled trials of timing of cytoreductive nephrectomy (CN) in the targeted therapy (TT) era.4  Both study trials failed to achieve original estimated enrollment. This is mainly due to patient non-compliance to randomization.5

These randomized control trials have proven to be in contrast to large data sets that seem to demonstrate an overall survival benefit to multimodal therapy.  For instance, in a recent national cancer data base study of over 15,000 patients., more patients completed multimodal therapy with initial CN and achieved significantly improved overall survival compared with patients who had initial TT.6  However, patients who underwent initial targeted therapy and subsequent cytoreductive nephrectomy appeared to have comparable overall survival outcomes. The current CARMENA trial is remarkable for inclusion of the highest risk groups, i.e. 55% Memorial Sloan Kettering (MSK) intermediate risk and 44% MSK poor risk. In addition, 70% of the nephrectomy/sunitinib group was tumor stage T-3 or T-4 vs 51% of the sunitinib alone group.  In addition, 30% of the nephrectomy/sunitinib group had cN+ designation versus only 19% of the sunitinib alone group. MSKCC poor risk grouping, clinical T3 or 4 disease and evidence of lymphadenopathy are all identified as poor selection factors for patients to undergo CN. 

According to the MD Anderson Cancer Center, low albumin, high lactate dehydrogenase, tumor stage-clinical T3 or T4, nodal stage cN+, symptoms at presentation, and liver metastasis aide in identifying patients that will profit the most from cytoreductive nephrectomy.7 Specifically, patients with three or fewer adverse prognostic factors based on each of these stratifications are likely to draw greater benefit from cytoreductive nephrectomy. The indication for surgical treatment in metastatic renal cell cancer remains a difficult decision. The potential for survival benefit must be measured against the morbidity of an aggressive surgical procedure.  It is clear that metastatic risk group stratification is important and close attention to adverse prognostic findings would seem to mean that patients with poor risk features should not receive initial cytoreductive nephrectomy.  Patients with excellent performance and low volume metastasis remain candidates for CN followed by surveillance, TT or judicious consideration for metastasectomy.

References
1. You D, Jeong IG, Ahn JH, et al. The value of cytoreductive nephrectomy for metastatic renal cell carcinoma in the era of targeted therapy. J Urol. 2011;185:54-59.
2. Choueiri TK, Xie W, Kollmansberger C, et al. The impact of cytoreductive nephrectomy on survival of patientswith metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185:60-66.
3. Méjean AR, Ravaud S, Thezenas SC, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.  N Engl J Med. 2018 Jun 3.  doi:10. 1056/NEJmoa1803675.
4. Bex A, Mulders P, Jewett MAS, et al.  Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma mRCC) receiving Sunitinib (EORTV 30073 SURTIME). Eur Urol. Suppl 2018;17L2):e1-e2. Abstract.
5. Steward GD, Aitchison J, Bex A, et al. Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered. European Urol. 2017;71:845-7. doi:10.1016/j.eururo.2016. 10.029.
6. Bhindi B, Habermann EB, Mason RJ, et al. Comparative Survival Following Initial Cytoreductive Nephrectomy Versus Initial Targeted Therapy for Metastatic Renal Cell Carcinoma. J Urol. 2018. Doi:10.1016/j. juro.2018. 03.077.
7. Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer. 2010;116:3378-88. doi:10.1002/cncr.25046
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Patients who received CN have also been reported to have better IMDC prognostic profiles for OS; patients with <4 IMDC prognostic factors were found likely to benefit from CN.17 A number have found significantly longer OS associated with previous CN.18-22  Despite these results, a countervailing trend has emerged in the literature with regard to the probability that CN will be performed in the targeted therapy era. Psutka et al filled in some gaps in the literature by analyzing trends in national practice patterns in their study regarding the uptake of targeted therapies and their impact on CN rates at a time when these associations were poorly described. One of the areas sparsely covered concerns the use of different targeted therapies in conjunction with CN among younger, pre-Medicare-aged patients. This is the group that could benefit the most from multimodal treatment .17

Characterizing trends observed between 2004 to 2010, when the annual rate of targeted therapy utilization increased markedly from 10% to 98.2%, Psutka et al found a considerable decline in the utilization of CN. Among the key findings: 

  • Lower rates of CN were observed in women.
  • Increasing age was inversely related to receipt of CN, even among the cohort of younger patients.

Intuitively, the authors suggest that physicians perceive targeted therapy as less morbid than CN and thus are less likely to recommend surgery. Despite retrospective data on the relative safety of performing CN after neoadjuvant targeted therapy, more study is needed to generate compelling data in this regard for the targeted therapy era. Nevertheless, there already are data from the clinical trials that led to the approval of the targeted agents. 

The benefit of these therapies was demonstrated in patients who, overwhelmingly, had undergone prior CN.7 Subsequently, and much further into the experience with targeted therapies, observational data from two large European studies suggest that CN is independently associated with improved survival in mRCC patients undergoing treatment with targeted therapy—and this was after an adjustment for prognostic factors.12,23 Delineating strategies to include the use of established drugs and position the role of CN within the framework of a stepwise approach, Choueiri and Motzer24 presented an algorithm in their paper on the use of systemic therapy. Published in 2017 this report touts the advantages offered by combinatorial strategies, including the use of immunotherapy combinations. Nevertheless, the algorithm favors consideration of CN as the initial step in management.

Other recent papers have more directly addressed the utilization of CN as they evaluated utilization rates and examined the survival benefit of CN compared with non-CN patients treated with targeted therapy. Using the National Cancer Data Base to identify patients with mRCC treated in the targeted therapy era, Hanna et al3 unpacked data from information gathered on 15,390 patients. Highlights from their results:

  • As might be expected, patients who were younger, privately insured, treated at an academic center, and had a lower tumor stage and cN0 disease were more likely to undergo CN.
  • CN use was stable between 2006 and 2012; performance was relatively seldom in approximately 3 of 10 patients with mRCC treated with targeted therapy.
  • Significantly, the median OS of CN vs non-CN patients was 17.1 vs 7.7 months.
  • In an adjustment analysis to consider other covariates, CN patients had a lower risk of any death (hazard ratio, 0.45, P<.001).

Lower Rate of CN Is Worrisome
In parsing their data, and observing some distinctions between their results and other papers, Hanna et al3 suggest some disturbing trends in utilization of CN. One observation was that the overall rate of CN observed in their study (approximately 30%) was lower than the overall rate reported from centers of excellence (approximately 58% to 85%). If one extrapolates the data further, there is additional reason for concern, especially because the NCDB data are based on a sample of patients treated by cancer-accredited programs with a minimum threshold of 100 cases per year. The worrisome aspect, the authors suggest, is due to the disparity in rates that may be inferred from the academic setting to what is being utilized in the general population. It may be that the underuse of CN in the community setting may be even greater than we suspect. The study also alludes to but does not directly address the issue of timing of CN in the targeted therapy era (See the report in this section on the results from CARMENA presented at the 2018 ASCO sessions). In the study by Hanna et al,3 patients who underwent CN after targeted therapy had better OS compared with those who underwent CN before targeted therapy. However, these results with regard to timing should be regarded cautiously because there were limited data on how clinicians opted to administer targeted therapy—before or after CN. 

Still another issue addressed by Hanna et al is of overriding importance—namely, the impact of risk stratification criteria. As they report, careful patient selection remains critical in determining if patients will benefit from CN:

  • Patients with poor survival outcomes or those with rapidly progressing disease are less likely to benefit from CN. This confirms a much earlier report in 2011 by Choueiri et al25 who found that patients with poor risk features (according to the IMDC criteria) did  not benefit from CN. 
  • The National Comprehensive Cancer Network (NCCN)  has formalized guidelines on the likelihood of CN benefit. Those likely to benefit include patients with lung-only metastases, good prognostic features, and good performance status.

Timing: Initial CN or Deferred? What Is the Optimal Sequence?
The debate over the optimal sequence of CN has continued unremittingly in the last few years, and results emerging in 2018, however, have begun to more clearly delineate at least some aspects of the discussion as efforts remain underway to produce a consensus. Results from the 2017 European Society of Medical Oncology26 and two reports in 201827,28 contribute substantially to an improved understanding regarding the benefits of CN.

Treating primary tumors by administering targeted therapy with sunitinib prior to cytoreductive nephrectomy (CN) did not improve the progression-free rate at 28 weeks over a sequence of immediate CN followed by sunitinib in patients with synchronous metastatic renal cell carcinoma (mRCC), according to findings presented by Axel Bex, MD, Surgical Oncology-Urology, The Netherlands Cancer Institute in Amsterdam, Netherlands and colleagues.26 They investigated whether the outcome after sequential cytoreductive nephrectomy (CN) followed by targeted therapy with sunitinib could be improved with the opposite sequence. They randomized 99 patients with mRCC to immediate CN followed by sunitinib (n=50) versus three cycles of sunitinib followed by CN plus sunitinib (n=49). The study (EORTC 30073 SURTIME NCT01099423) included patients with histologically confirmed clear-cell subtype, and a resectable asymptomatic primary tumor plus 3 or fewer surgical risk factors. Due to poor accrual (and that is a fundamental flow in this study), it was decided to report the progression-free rate (PFR) at week 28 as the primary endpoint, which required 98 patients, instead of median progression-free survival, which required 380 events to detect a 3-month increase.

At a median follow-up of 3.3 years, 46 of 50 patients underwent CN in the immediate CN arm and 40 of these patients had received post-CN sunitinib. In the deferred CN arm, 48 of 49 patients had been treated with sunitinib prior to CN; of these patients, 40 underwent CN and 26 also received post-CN sunitinib. No significant difference between the treatment sequence was observed in PFR, which was 42.0% (95% confidence interval [CI] 28.2, 56.8) versus 42.9% (95% CI 28.8, 57.8) in the immediate and deferred arms, respectively (P > 0.99) 

One of the conundrums to emerge in the targeted therapy era is our lack of level 1 evidence for CN. The evidence has been equivocal and the need for consensus has become imperative. While one study compared the sequence of CN and targeted therapy among patients who received both therapies,3 in clinical practice not all patients undergoing initial CN will receive subsequent targeted therapy; and not all patients undergoing targeted therapy will undergo subsequent CN.28 Other variations on this theme have also been observed, further suggesting how practice patterns can diverge. In retrospective studies, for example, approximately one-third of patients did not receive targeted therapy after initial CN, according to the analysis by Bindhi et al. To what extent is targeted therapy administered in a timely fashion? Several reports indicate that approximately 40% received targeted therapy in a timely manner (defined as within 60 days of CN). If this picture seems confusing as to consistency of approaches, then consider  that in single-arm trials, 30-40% of patients initially treated with a tyrosine kinase inhibitor prior to planned CN actually underwent subsequent surgery. 

For proponents of initial CN followed by targeted therapy, two current studies offer supporting if not compelling evidence. A population-based cohort in patients over age 665 from the Surveillance, Epidemiology, and End Results registries served as the starting point for an analysis by Macleod et al.27Strategies were categorized by initial treatment and linked with Medicare claims from 2006 to 2011. Results were accrued from 537 patients’ 190 had initial CN followed by targeted therapy and 347 had initial targeted therapy. Median OS in the initial CN group was 17.4 months compared with 9.2 months for initial targeted therapy.

The second study to focus on similar questions identified patients in the NCDB diagnosed from 2006-2013 with kidney cancer.28 The report by Bindhi et al had OS as its primary outcomes with secondary outcomes that included receipt of targeted therapy after initial CN, and CN after initial targeted therapy, with death prior to receipt of the second treatment as a competing risk. The data base included 15,068 patients; 6,7731 underwent initial CN and 8,337 underwent targeted therapy. The key results: 

  • At 6 months after initial CN, 48% received targeted therapy; 15.3% had died after receiving initial CN prior to receiving targeted therapy.
  • At 6 months after initial targeted therapy, 4.7% underwent CN, with 44.9% having died after initial targeted therapy prior to moving on to CN. 
  • Initial CN was associated with improved OS compared to initial targeted therapy (median 16.5 months vs 9.2 months, P<0.001).  

The finding that initial CN was associated with an improved OS can best be explained by the greater likelihood that patients will receive multimodal therapy. Regardless of which initial strategy was adopted, both were associated with delays in receipt or non-receipt of the second therapy. This finding points toward the need for a greater effort to ensure the delivery of multimodal therapy to these patients28 The paper by Bindhi et al is particularly important in view of the failure of SURTIME to deliver what was expected: a trial evaluating the sequencing of CN and targeted therapy that closed prematurely due to poor accrual. SURTIME, however, did demonstrate no difference in PFS between the two approaches at 28 weeks. Underscoring the importance of careful patient selection in deciding initial treatment for mRCC, Bindhi et al point to earlier studies which found no benefit to CN in patients with poor-risk disease or poor performance status. If initial targeted therapy is to be pursued, then its rationale needs to be closely examined. This rationale should include assessing the biological responsiveness of the cancer to systemic treatment and using treatment response to assist with patient selection for subsequent CN. The authors describe such assessment as a “litmus test”.

Conclusion
Although more level 1 evidence for the use of initial CN in the era of targeted therapy is still needed, a consensus is taking shape from large analyses of population-based data. Initial CN is underutilized, particularly in non-academic centers where this underuse contributes to inferior survival among patients who present with mRCC. It is important for medical oncologists and urologists to seriously consider CN for every patient who presents with mRCC. The choice of an appropriate option should be in accordance with guidelines established by the NCCN and should reflect careful evaluation of risk stratification. Patients with favorable to intermediate risk constitute the group with the greatest likelihood of benefiting from initial CN. 

References
1.National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.
2. Molina AM, Hu J, Nanus DM, et al. Is underutilization of cytoreducrtive nephrectomy in patients with metastatic renal cancer contributing to inferior survival. J Clin Oncol. 2016;34:3235-3236.
3. Hanna N, Sun M, Meyer CP, et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Data Base Study. J Clin Oncol. 2016;34:3267-3275.
4. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171:1071.
5. Clinical Trial to ASSESS the Importance of Nephrectomy (CARMENA). ClinicalTrials.gov Identifier: NCT0093033.
6. Immediate Surgery versus Surgery After Sunitinib Malate in Pateitns with Metastatic Kidney Cancer (SURTIME). ClinicalTrials.gov Identifier: NCT01099423
7. Psutka SP, Kim SP, Gross CP, et al. The impact of targeted therapy on management of metastatic renal cell carcinoma: Trends in systemic therapy and cytoreductive nephrectomy utilization. Urol. 2015;85:442-451.
8.Conti SL, Thomas IC, Hagedorn JC, et al. Utilization of cytoreductive nephrectomy and patient survival in the he targeted therapy era. Int J Cancer. 2014;134:22445-2252.
9. Tsao CK, Small AC, Kates M, et al. Cytoreductive nephrectomy for metastatic renal cell carcinoma in the era of targeted therapy in the United States: a SEER analysis. World J Urol. 2013;31:1535-1539.
10. Petrelli F, Coinu A, Vavassori I, et al: Cytoreductive nephrectomy in metastatic renal cell carcinoma treated with targeted therapies: A systematic review with a meta-analysis. Clin Genitourin Cancer. [epub ahead of print on April 8, 2016]
11. Choueiri TK, Xie W, Kollmannsberger C, et al: The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 185:60-66, 2011
12. Heng DY, Wells JC, Rini BI, et al: Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 66: 704-710, 2014
13. Xiao WJ, Zhu Y, Dai B, et al: Assessment of survival of patients with metastatic clear cell renal cell carcinoma after radical cytoreductive nephrectomy versus no surgery: A SEER analysis. Int Braz J Urol. 41:288-295, 2015
14. Abern MR, Scosyrev E, Tsivian M, et al: Survival of patients undergoing cytoreductive surgery for metastatic renal cell carcinoma in the targeted-therapy era. Anticancer Res. 34:2405-2411, 2014
15. Zini L, Capitanio U, Perrotte P, et al: Population-based assessment of survival after cytoreductive nephrectomy versus no surgery in patients with metastatic renal cell carcinoma. Urology. 73:342-346, 2009
16. Pal SK, SR, Li N, et al. Real-world survival outcomes and prognostic factors among patients receiving first targeted therapyfor advanced renal cell carcinoma: a SEER-Medicare Database Analysis. Clin Genitourin Cancer. 2017;144:e573-e582.
17. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database consortium. Eur Urol. 2014;666:704-710.
18. Flanigan RC, Salmon SE, Blumenstein BA, et al. For compared with interferon-alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655-1659.
19. Mikisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal cell carcinoma: a randomized trial. Lancet. 2001;358:9666-970.
20. Motzer RJ, Bukowski RM, Figlin RA, et al. Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2008;113:1552-1558.
21.Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol.1999;17:2530-2540.
22. Leibovich BC, Cheville JC, Lohse CM, et al. A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol. 2005;174:1759-1763.
23.Bamias A, Tzannis K, Papatsoris A, et al. Prognostic significance of cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma treated with first-line sunitinib: a European multiinstitutional study. Clin Genitourin Cancer. 2014;12:373-383.
24.Choureiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354-366.
25. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185:60.
26. Bex A, Mulders P, Jewett MAS, et al. Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME). Ann Oncol. 2017; 28: v605.
27. Macleod LC, Odisho AY, Tykodi SS, et al.  Comparative Effectiveness of Initial Surgyer Versus Initial Systemic Therapy for Metastatic Kidney Cancer in the Targeted Therapy Era: Analysis of a Population-Based Cohort. Urology. 2018;113:146-152.
28. Bindhi B, Habermann EB, Mason RJ, et al. Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma. J Urol. 2018; doi:10.1016/j.juro. 2018.03.077 (Epub ahead of print).  KCJ

 

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