The Evolving Role of Cytoreductive Surgery for Metastatic Renal Cell Carcinoma

May 1, 2003

Drs. Uzair Chaudhary and GeraldHull provide a comprehensivereview of the role ofcytoreductive surgery in metastaticrenal cell carcinoma. This controversialtopic has been debated for manyyears. Metastatic renal cell carcinomacontinues to be a chemotherapyresistanttumor with a poor prognosis.About 30% of newly diagnosedpatients present with metastatic disease.In the metastatic setting, themost recognized treatment modalitiesinvolve the biologic agents interferon-alpha and interleukin-2 (IL-2,Proleukin). They produce an objectiveresponse rate of about 10% to15%, with approximately 5% of patientsachieving a durable completeresponse.

Drs. Uzair Chaudhary and GeraldHull provide a comprehensivereview of the role ofcytoreductive surgery in metastaticrenal cell carcinoma. This controversialtopic has been debated for manyyears. Metastatic renal cell carcinomacontinues to be a chemotherapyresistanttumor with a poor prognosis.About 30% of newly diagnosedpatients present with metastatic disease.In the metastatic setting, themost recognized treatment modalitiesinvolve the biologic agents interferon-alpha and interleukin-2 (IL-2,Proleukin). They produce an objectiveresponse rate of about 10% to15%, with approximately 5% of patientsachieving a durable completeresponse.Cytoreduction Followedby Immunotherapy
Cytoreduction in the metastaticsetting has been discussed since theearly 1970s. Initially, proponents usedreports of immune-mediated regressionof metastatic deposits followingangioinfarction of the primary tumoras the proof with which to advocatecytoreduction.[1] Unfortunately, themorbidity and/or mortality of thisprocedure far exceeded the rate ofregression.In the late 1980s, the surgicalbranch of the National Cancer Institute(NCI) required that all patientsentering their high-dose IL-2 clinicaltrial for metastatic renal cell carcinomaundergo a prior nephrectomy.[2]The result was that nephrectomy followedby immunotherapy becamecommon practice in the setting ofmetastatic disease. The evidence forthis approach was not based onprospective, randomized trials, andthe rate of postoperative complications,mortality, and rapidly progressivedisease prior to the initiation ofhigh-dose IL-2 therapy was notinsignificant.Flanigan et al reported on theSouthwest Oncology Group (SWOG)study of nephrectomy followed byinterferon alfa-2b (Intron A) comparedwith interferon alfa-2b alonefor metastatic renal cell carcinoma.[3]This was a randomized, prospectivetrial in 246 patients accrued over 7years from 80 institutions. Patientswere stratified according to SWOGperformance status, the presence orabsence of lung metastases, and thepresence or absence of at least onemeasurable metastatic lesion.The analysis showed a significantimprovement in overall survival(P = .05) favoring the patients assignedto surgery followed by interferon(11.1 vs 8.1 months). Themedian survival for patients with aperformance status of 0 was 17.4 vs11.7 months, and for those with aperformance status of 1, 6.9 vs4.8 months. The difference in survivalwas not dependent on performancestatus, metastatic site, or thepresence or absence of measurabledisease. One confounding factor inthe analysis of the data was the highernumber of patients with a performancestatus of 1 in the arm thatreceived interferon alone (58.1% vs45%, P = .04).Mickisch et al reported on an identicaltrial conducted by the EuropeanOrganization for Research and Treatmentof Cancer (EORTC).[4] Thistrial enrolled 85 patients, and thefindings confirmed the results of theSWOG trial. A significant advantagein median survival (17 vs 7 months)and time to progression (5 vs 3months) favored patients in the surgery-plus-interferon arm.Management Considerations
These pivotal studies have recentlyled to a shift in the management ofmetastatic renal cell carcinoma. Manyclinicians are calling for cytoreductionfollowed by immunotherapy tobe the standard arm in future studies,but such a sweeping change needs tobe approached with caution.Both the SWOG and EORTC studieslimited enrollment to patients witha performance status of 0 or 1. Patientswith a performance status of 2were correctly excluded secondaryto their poor survival and higher probabilityof postoperative complicationsand mortality. The 2-month improvementin survival noted in the groupwith a performance status of 1 in theSWOG trial argues against the routineuse of nephrectomy for all suchpatients. Patients with a performancestatus of 0 should be strongly consideredfor surgery, but if their primarytumor burden is smaller than theiroverall tumor burden, a nephrectomywould not be advisable despite theirperformance status.Another major consideration thatlimits the generalizability of this approachis the operability of the primarylesion. In the SWOG study, anattending surgeon determined operability.As the result of surgery, mortalityand morbidity were much lowerin the SWOG trial than noted in previousreports. This does not meanthat all centers will achieve similarresults. The slow rate of accrual forthis trial (less than one patient peryear from each participating institution)may be explained by the requirementof an operable patient witha high performance status.Conclusions
We would recommend nephrectomyin the setting of metastatic diseaseonly in a few situations. In ouropinion, all patients with a performancestatus of 0 and a low volumeof disease should be considered forcytoreduction. Selected patients witha performance status of 1 should beoffered the option of cytoreduction.Patients with a performance status of2 should not undergo cytoreductionprior to systemic therapy.Although the SWOG and EORTCtrials were well designed and demonstrateda significant improvementin survival among patients who receivecytoreduction plus interferonalfa-2b, the lack of generalizabilityto the majority of patients with metastaticrenal cell carcinoma limits thisapproach. At present, the mechanismthat mediates the improvement in survivalis unknown. Referral to a majorcenter that handles a large volume ofcases should strongly be consideredto lower surgical complication rates.An unanticipated benefit of this approachis that tumor specimens canbe retrieved and analyzed for the geneticand protein patterns that predictoutcome.[5]

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Garfield DH, Kennedy BJ: Regression ofmetastatic renal cell carcinoma following nephrectomy.Cancer 30:190-196, 1972.

2.

Walther MM, Yang JC, Pass HI, et al:Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastaticrenal cell carcinoma. J Urol158:1675-1678, 1997.

3.

Flanigan RC, Salmon SE, BlumensteinBA, et al: Nephrectomy followed by interferonalfa-2b compared with interferon alfa-2b alonefor metastatic renal-cell cancer. N Engl J Med345:1655-1659, 2001.

4.

Mickisch GH, Garin A, van Poppel H, etal: Radical nephrectomy plus interferon-alfabasedimmunotherapy compared with interferonalfa alone in metastatic renal-cell carcinoma:A randomised trial. Lancet 358:966-970, 2001.

5.

Takahashi M, Yang XJ, Lavery TT, et al:Gene expression profiling of favorable histologyWilms tumors and its correlation with clinicalfeatures. Cancer Res 62:6598-6605, 2002.