Refers to article:
The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer
Accepted 9 May 2011
September 2011 (Vol. 60, Issue 3, pages 448 - 454)
Refers to article:
Sunitinib Prior to Planned Cytoreductive Nephrectomy: Is This the New Litmus Test for Metastatic Renal Cell Carcinoma?
September 2011 (Vol. 60, Issue 3, pages 455 - 456)
We would like to thank Kim and Thompson for their incisive and detailed editorial. We are pleased they acknowledge the importance of our data by asking whether presurgical targeted therapy with sunitinib is the new litmus test in previously untreated clear cell metastatic renal cell carcinoma (RCC) and the primary tumour in place .
The concept of presurgical therapy for patient selection in metastatic RCC is not new and has been recognized by others previously, based on retrospective data involving various targeted agents  and . The overall survival data available from our study suggest that this may be the case in that a period of upfront sunitinib prior to planned nephrectomy may select out patients with primary refractory disease . This approach results in a subpopulation with a favourable outcome, which is particularly apparent in the Memorial Sloan-Kettering Cancer Centre (MSKCC) intermediate-risk population. However, because we observed frequent temporary progression during the treatment break, these intriguing findings require robust evaluation before they become incorporated into treatment algorithms.
A randomized trial of immediate versus delayed nephrectomy following presurgical sunitinib is under way (European Organisation for Research and Treatment of Cancer 30073 SURTIME study [ClinicalTrials.gov identifier NCT01099423]) and is currently recruiting patients in the Netherlands, Belgium, Italy, the United Kingdom, and Canada . The principal objective of this trial is to investigate whether the sequence of nephrectomy in patients who receive sunitinib has an effect on outcome. The primary end point is progression-free survival; secondary end points include overall survival, safety, overall response to treatment in the deferred nephrectomy arm (including the proportion of patients who become unresectable), and the effect of nephrectomy on early progression in both arms. However, as with the meta-analysis of the single-arm phase 2 studies described above, patients with rapid disease progression may be identified prior to planned surgery and be spared a procedure from which they may not derive any benefit. Results of this randomised study are expected in 2015.
Kim and Thompson  point out that proper patient selection for surgery is paramount. Culp and coworkers identified a number of prognostic factors for inferior overall survival in surgical patients that further refine the MSKCC risk score, including raised lactate dehydrogenase level, low albumin, symptoms caused by a metastatic site, sites of disease (liver metastasis and specific lymphadenopathy), and clinical ≥T3 for the primary tumour category . However, the data from the two studies suggest that primary progression of disease in the metastatic sites, as published in this issue of the Platinum Journal, is perhaps a better discriminating factor .
Recent retrospective studies have consistently shown that patients with good performance and low metastatic burden have improved overall survival following cytoreductive nephrectomy in the era of targeted therapy. In addition to the data of Choueiri and coworkers , already mentioned in Kim and Thompson's editorial, a very recent Dutch population-based study concluded that even after accounting for prognostic profile, patients with metastatic RCC still benefited from cytoreductive nephrectomy with a 50% reduction in mortality . Consequently, it is likely, despite the known biases of retrospective data collection, that nephrectomy has a role for some patients, and we speculate that it is in those with disease that is responsive to targeted therapy.
This conclusion makes sense in that simply removing the primary renal cancer while the lethal metastatic sites progress seems counterintuitive. The paradigm of presurgical therapy is based on a clinical problem: Despite selecting along the best prognostic factors currently available, approximately 20% of patients with metastatic RCC are refractory to sunitinib and progress rapidly . If those patients undergo upfront nephrectomy progression will only become evident after surgery. In our publication in this issue of the Platinum Journal, we observed a 26% progression rate at metastatic sites with presurgical sunitinib prior to planned nephrectomy in the intermediate-risk group . As with drug therapy, we believe that nephrectomy should not be a “one size fits all” approach, and patients should be carefully selected instead. In the absence of predictive biomarkers, presurgical sunitinib seems like a promising step in this direction. The SURTIME trial described above will collect sequential tissue from these patients, and we hope that will provide a biomarker profile that will unlock the answer to this and other questions.
Conflicts of interest
Axel Bex and Thomas Powles have received honoraria for taking part in advisory board meetings of Pfizer and GlaxoSmithKline.
-  S.P. Kim, R.H. Thompson. Sunitinib prior to planned cytoreductive nephrectomy: is this the new litmus test for metastatic renal cell carcinoma?. Eur Urol. 2011;60:455-456
-  C.G. Wood, V. Margulis. Neoadjuvant (presurgical) therapy for renal cell carcinoma: a new treatment paradigm for locally advanced and metastatic disease. Cancer. 2009;115:2355-2360 Crossref.
-  C.G. Wood. 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;13:697s-702s Crossref.
-  T. Powles, C. Blank, S. Chowdhury, et al. The outcome of patients treated with sunitinib prior to planned nephrectomy in metastatic clear cell renal cancer. Eur Urol. 2011;60:448-454 Abstract, Full-text, PDF, Crossref.
-  US National Institutes of Health. Immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer. ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01099423. Accessed May 5, 2010.
-  S.H. Culp, N.M. Tannir, E.J. Abel, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy?. Cancer. 2010;116:3378-3388 Crossref.
-  T.K. Choueiri, W. Xie, C. Kollmannsberger, 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;185:60-66 Crossref.
-  Aben KK, Heskamp S, Janssen-Heijnen ML, et al. Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands. Eur J Cancer. In press.
-  R.J. Motzer, T.E. Hutson, P. Tomczak, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124 Crossref.
a The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Amsterdam, The Netherlands
b Department of Medical Oncology. St Bartholomew's Hospital London, United Kingdom
Corresponding author. The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 512 2553; Fax: +31 20 512 2554.
© 2011 European Association of Urology, Published by Elsevier B.V.