The Case for Cytoreductive Nephrectomy for the Management of Metastatic Renal Cell Carcinoma
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Group) performance status of 0 to 1; no central ner- vous system, bone or liver metastases; adequate pul- monary and cardiac function; clear cell histology; and expectation that surgical excision will remove greater than 75% of the tumor burden. 3 It is impor- tant to note that level 1 evidence supporting CN exists only for patients who received adjuvant im- munotherapy, and similar data do not exist for tar- geted therapies. Other patients with mRCC un- likely to benefit from CN include those with nonclear cell RCC, sarcomatoid differentiation, high nuclear grade, recent weight loss and locally advanced tumor. 4 In 1 study only 21% of patients with mRCC were candidates for CN. 5 Recently the role of cytoreductive nephron spar- ing surgery has been explored. 6,7 Data on a small number of patients indicate that it can be oncologi- cally as effective as total nephrectomy, while confer- ring better preservation of renal function in select patients with mRCC. This result may be of rele- vance for patients with a solitary kidney, bilateral tumors and preexisting chronic kidney disease. Concerns regarding the timing and potential for complications of CN have led to exploration of neo- adjuvant approaches with the premise that upfront therapy would eliminate delay in treating systemic disease, while reserving surgery for only the re- sponders, who may be more likely to derive clinical benefit. Even with meticulous patient selection as in the SWOG and EORTC trials, nearly a quarter of patients in each arm had rapid disease progression and died within 6 months. The development of newer targeted therapies has renewed interest in the neodjuvant therapy para- digm due to the substantial responses seen with these agents. Recent data indicate that sunitinib can shrink primary tumors enough to make even an unresectable primary tumor resectable in 21% of patients. 8 These are promising findings that portend well for the future and could potentially obviate the need for surgical cytoreduction as better and more powerful agents are developed. To conclude, there is a role for CN in the manage- ment of mRCC, albeit as part of a multimodality comprehensive treatment strategy. Indiscriminate use of CN could render this a mere surgical exercise with potential to cause harm. Given the rapid devel- opments in systemic therapy with newer targeted agents, CN should ideally be offered to carefully selected patients only in the setting of clinical trials. Monish Aron Section of Laparoscopic and Robotic Surgery Glickman Urological and Kidney Institute Cleveland Clinic Cleveland, Ohio and Inderbir S. Gill Department of Urology University of Southern California Los Angeles, California REFERENCES 1. Rendon RA: New surgical horizons: the role of cytoreductive nephrectomy for metastatic kidney cancer. Can Urol Assoc J, suppl., 2007; 1: S62. 2. Flanigan RC, Mickisch G, Sylvester R et al: Cytore- ductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004; 171: 1071. 3. Fallick ML, McDermott DF, LaRock D et al: Ne- phrectomy prior to interleukin-2 therapy for pa- tients with metastatic renal cell carcinoma. J Urol 1997; 158: 1691. 4. Kassouf W, Sanchez-Ortiz R, Tamboli P et al: Cytoreductive nephrectomy for T4NxM1 renal cell carcinoma: the M.D. Anderson Cancer Center ex- perience. Urology 2007; 69: 835. 5. Bromwich E, Hendry D and Aitchison M: Cytore- ductive nephrectomy: is it a realistic option in patients with renal cancer? BJU Int 2002; 89: 523. 6. Krambeck AE, Leibovich BC, Lohse CM et al: The role of nephron sparing surgery for metastatic (pM1) renal cell carcinoma. J Urol 2006; 176: 1990. 7. Hutterer GC, Patard JJ, Colombel M et al: Cytore- ductive nephron-sparing surgery does not appear to undermine disease-specific survival in patients with metastatic renal cell carcinoma. Cancer 2007; 110: 2428. 8. Thomas AA, Rini BI, Lane BR et al: Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J Urol 2009; 181: 518. The Case for Cytoreductive Nephrectomy for the Management of Metastatic Renal Cell Carcinoma THE American Cancer Society estimates that in 2009 approximately 57,760 cases of kidney cancer will be diagnosed and 12,980 patients will die of the disease. Despite the stage migration of renal cell carcinoma attributed to incidental detection of localized disease, as many as 30% of patients will have metastatic disease at initial presentation. Traditionally, patients with metastatic RCC have been treated with cytokine based immunotherapy with response rates of approximately 15%. Previ- ous randomized trials have demonstrated a signif- icant benefit to cytoreductive nephrectomy for patients with metastatic disease undergoing cyto- kine based therapy. 1,2 Recently, tyrosine kinase inhibitors (sunitinib and sorafenib) have demon- strated a significant benefit in progression-free OPPOSING VIEWS 833
Transcript of The Case for Cytoreductive Nephrectomy for the Management of Metastatic Renal Cell Carcinoma
OPPOSING VIEWS 833
Group) performance status of 0 to 1; no central ner-vous system, bone or liver metastases; adequate pul-monary and cardiac function; clear cell histology;and expectation that surgical excision will removegreater than 75% of the tumor burden.3 It is impor-tant to note that level 1 evidence supporting CNexists only for patients who received adjuvant im-munotherapy, and similar data do not exist for tar-geted therapies. Other patients with mRCC un-likely to benefit from CN include those withnonclear cell RCC, sarcomatoid differentiation,high nuclear grade, recent weight loss and locallyadvanced tumor.4 In 1 study only 21% of patientswith mRCC were candidates for CN.5
Recently the role of cytoreductive nephron spar-ing surgery has been explored.6,7 Data on a smallnumber of patients indicate that it can be oncologi-cally as effective as total nephrectomy, while confer-ring better preservation of renal function in selectpatients with mRCC. This result may be of rele-vance for patients with a solitary kidney, bilateraltumors and preexisting chronic kidney disease.
Concerns regarding the timing and potential forcomplications of CN have led to exploration of neo-adjuvant approaches with the premise that upfronttherapy would eliminate delay in treating systemicdisease, while reserving surgery for only the re-sponders, who may be more likely to derive clinicalbenefit. Even with meticulous patient selection as in
the SWOG and EORTC trials, nearly a quarter ofREFERENCES
Metastatic Renal Cell Carcinoma
Traditionally, patients with metastatic RCC have
patients in each arm had rapid disease progressionand died within 6 months.
The development of newer targeted therapies hasrenewed interest in the neodjuvant therapy para-digm due to the substantial responses seen withthese agents. Recent data indicate that sunitinibcan shrink primary tumors enough to make even anunresectable primary tumor resectable in 21% ofpatients.8 These are promising findings that portendwell for the future and could potentially obviate theneed for surgical cytoreduction as better and morepowerful agents are developed.
To conclude, there is a role for CN in the manage-ment of mRCC, albeit as part of a multimodalitycomprehensive treatment strategy. Indiscriminateuse of CN could render this a mere surgical exercisewith potential to cause harm. Given the rapid devel-opments in systemic therapy with newer targetedagents, CN should ideally be offered to carefullyselected patients only in the setting of clinical trials.
Monish Aron
Section of Laparoscopic and Robotic SurgeryGlickman Urological and Kidney Institute
Cleveland ClinicCleveland, Ohio
and
Inderbir S. Gill
Department of UrologyUniversity of Southern California
Los Angeles, California
1. Rendon RA: New surgical horizons: the role ofcytoreductive nephrectomy for metastatic kidneycancer. Can Urol Assoc J, suppl., 2007; 1: S62.
2. Flanigan RC, Mickisch G, Sylvester R et al: Cytore-ductive nephrectomy in patients with metastaticrenal cancer: a combined analysis. J Urol 2004;171: 1071.
3. Fallick ML, McDermott DF, LaRock D et al: Ne-phrectomy prior to interleukin-2 therapy for pa-tients with metastatic renal cell carcinoma. J Urol
4. Kassouf W, Sanchez-Ortiz R, Tamboli P et al:Cytoreductive nephrectomy for T4NxM1 renal cellcarcinoma: the M.D. Anderson Cancer Center ex-perience. Urology 2007; 69: 835.
5. Bromwich E, Hendry D and Aitchison M: Cytore-ductive nephrectomy: is it a realistic option inpatients with renal cancer? BJU Int 2002; 89:523.
6. Krambeck AE, Leibovich BC, Lohse CM et al: The
strated a signific
(pM1) renal cell carcinoma. J Urol 2006; 176:1990.
7. Hutterer GC, Patard JJ, Colombel M et al: Cytore-ductive nephron-sparing surgery does not appearto undermine disease-specific survival in patientswith metastatic renal cell carcinoma. Cancer 2007;110: 2428.
8. Thomas AA, Rini BI, Lane BR et al: Response of theprimary tumor to neoadjuvant sunitinib in patientswith advanced renal cell carcinoma. J Urol 2009;
1997; 158: 1691. role of nephron sparing surgery for metastatic 181: 518.
The Case for Cytoreductive Nephrectomy for the Management of
THE American Cancer Society estimates that in2009 approximately 57,760 cases of kidney cancerwill be diagnosed and 12,980 patients will die ofthe disease. Despite the stage migration of renalcell carcinoma attributed to incidental detection oflocalized disease, as many as 30% of patients willhave metastatic disease at initial presentation.
been treated with cytokine based immunotherapywith response rates of approximately 15%. Previ-ous randomized trials have demonstrated a signif-icant benefit to cytoreductive nephrectomy forpatients with metastatic disease undergoing cyto-kine based therapy.1,2 Recently, tyrosine kinaseinhibitors (sunitinib and sorafenib) have demon-
ant benefit in progression-free
OPPOSING VIEWS834
survival for patients with cytokine refractory andnaïve metastatic RCC, and have replaced cytokinebased immunotherapy as first line treatment,leaving us to question the beneficial role of cytore-ductive nephrectomy in this setting.3,4
There are several theoretical advantages to cy-toreductive nephrectomy before initiation of sys-temic therapy, including palliation of symptomsrelated to the primary tumor such as pain, hema-turia and paraneoplastic syndromes. Additionally,some patients may experience an improvement inperformance and the likelihood of receiving andtolerating systemic therapy. However, the mostcompelling reason focuses on the primary goal ofsystemic treatment, which is prolongation of pro-gression-free survival.
The volume of disease has been demonstrated toimpact response to systemic therapy in a varietyof malignancies, such as ovarian cancer for whichdebulking surgical procedures are routinely per-formed before systemic therapy. This finding isalso postulated for RCC as demonstrated by 2randomized trials in which a significant benefit insurvival was noted for patients treated with cy-toreductive nephrectomy before cytokine basedsystemic therapy compared to systemic therapyalone.1,2 This benefit is likely secondary to theeradication of a potentially sheltered site of pri-mary disease with limited access to the systemictherapy. It is well recognized in fact that in pa-tients with metastatic RCC the primary tumorrarely responds to cytokine based immunother-apy. Additionally, surgical resection of the pri-mary tumor may prevent continued metastaticseeding from occurring. Lastly, cytoreductive ne-phrectomy may reduce the global volume of dis-ease on which the systemic therapy is targetingand reduce systemic signaling (angiogenic, immu-nosuppressive, growth/survival pathways) fromthe primary tumor influencing distant sites.
While we do not know the benefit of cytoreduc-tive nephrectomy in patients with metastatic dis-ease treated with first line tyrosine kinase inhib-
REFERENCES
(EORTC) Genitourinary Group. Radical nephrectomy cinoma. N Engl J Med 2007
derived from the cytoreductive nephrectomy trialscombined with cytokine based immunotherapy.The SWOG 8949 and EORTC 30957 clinical trialsevaluated the role of cytoreductive nephrectomyplus interferon-� compared to interferon-� alonefor metastatic RCC.1,2 In both trials perioperativemortality was low, confirming the safety of cytore-ductive nephrectomy in patients with metastaticdisease, and a significant benefit in overall sur-vival was noted for patients undergoing cytoreduc-tive nephrectomy before systemic therapy com-pared to systemic therapy alone (improvement inmedian survival was 3 months in SWOG 8949 and10 months in EORTC 30957).
An issue that has been raised regarding the useof cytoreductive nephrectomy in combination withtyrosine kinase inhibitors is the potential for in-creased perioperative morbidity. However, thiscriticism has not been confirmed in the literature,with several series demonstrating no differencesin wound complications or perioperative morbidityin either the neoadjuvant or adjuvant setting.Furthermore, there are currently a number of clin-ical trials under way evaluating the role of adju-vant tyrosine kinase inhibitors in patients at highrisk for metastatic disease following nephrectomyfor RCC.
Ultimately, the role of cytoreductive nephrec-tomy before tyrosine kinase inhibitor systemictherapy for the treatment of metastatic diseasemust be evaluated in an appropriately designedclinical trial. Until the results of this trial areavailable we should continue to use our currentcriteria for recommending cytoreductive nephrec-tomy before systemic therapy based on the datafrom the randomized clinical trials to date, whichdemonstrate a survival benefit in favor of cytore-ductive nephrectomy.
Brett S. Carver
Department of Surgery, Division of UrologyMemorial Sloan-Kettering Cancer Center
itors, it is reasonable to extrapolate the data New York, New York
1. Flanigan RC, Salmon SE, Blumenstein BA et al:Nephrectomy followed by interferon alpha-2b com-pared with interferon alpha-2b alone for metastaticrenal cell cancer. N Engl J Med 2001; 345: 1655.
2. Mickisch GH, Garin A, van Poppel H et al: EuropeanOrganisation for Research and Treatment of Cancer
plus interferon-alfa-based immunotherapy comparedwith interferon alfa alone in metastatic renal-cellcarcinoma: a randomized trial. Lancet 2001; 358: 966.
3. Motzer RJ, Hutson TE, Tomczak P et al: Sunitinibversus interferon alfa in metastatic renal cell car-
; 356: 115.
4. Motzer RJ, Rini BI, Bukowski RM et al: Sunitinib inpatients with metastatic renal cell carcinoma.JAMA 2006; 295: 2516.
