Interleukin-6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC)

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Original

research

article

Interleukin-6

(IL-6)

and

C-reactive

protein

(CRP)

concentration

prior

to

total

nephrectomy

are

prognostic

factors

in

localized

renal

cell

carcinoma

(RCC)

Michał

Hrab

_,

_Karolina

_Olek-Hrab

_,

_Andrzej

_Antczak

_,

_Zbigniew

_Kwias

_,

Tomasz

Milecki

a_{DepartmentandClinicofUrologyandUrologicOncology,UniversityofMedicalSciences,3SzwajcarskaSt,}

61-285Poznan,Poland

b_{DepartmentandClinicofDermatology,UniversityofMedicalSciences,49PrzybyszewskiegoSt,61-355Poznan,}

Poland

c_{ScientificSocietyofUrology,UniversityofMedicalSciences,Poznan,Poland}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received18February2013 Accepted13June2013

Keywords:

Renalcellcarcinoma Interleukin-6 C-reactiveprotein Prognosticfactors Nephrectomy

a

b

s

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Background:Radicalnephrectomyisthegoldstandardfortreatmentofrenalcellcarcinoma (RCC),butevenforlocalizeddiseasethesurvivalratesarestillunsatisfactory.Identification ofprognosticfactorslisthebasisforfuturetreatmentstrategiesforanindividualpatient.

Aim:TheaimofourstudywastoassesstheusefulnessoftheconcentrationofIL-6andCRP asprognosticfactorsinpatientsafternephrectomyduetolocalizedRCC.

Materialsandmethods:Ourprospectivestudyincluded89patients(55menand34women) whohadbeensurgicallytreatedforRCC.Theexaminedgroupincludedpatientswith local-izedadvanceddisease(fromT1toT3)withnometastasesinlymphnodes(N0),andwith nodistantmetastases(M0).Allpatientshadbloodsamplesdrawnthreetimesduringthe study(onedaybeforesurgery,sixdaysaftersurgeryand6monthsaftersurgery)toevaluate theconcentrationofCRPandIL-6.IneachpatientRCCofthekidneywasremovedduring radicalnephrectomy.Statisticalanalysiswasconductedusingstatisticav.7.0.

Results:StatisticallysignificantrelationshipswerefoundbetweentheconcentrationofCRP beforetheoperationandOS(p=0.0001).CRPconcentrationatbaselinewasstatistically sig-nificantlycorrelatedwithCSS(p=0.0004).ThelevelofIL-6assessedbeforethesurgerywas significantlycorrelatedwithsurvivaltimessuchasOS(p=0.0096)andCSS(p=0.0002).The concentrationofIL-6andCRPmeasured6daysaftersurgeryand6monthsaftersurgery werenotstatisticallysignificantlycorrelatedwithsurvivaltimes.

Conclusions:ResultsofourstudyshowedthatelevatedlevelsofIL-6andCRPinperipheral bloodbeforesurgeryofRCCwerecorrelatedwithworseOSandCSS.

©2013GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.All rightsreserved.

∗ _{Correspondingauthorat:3SzwajcarskaSt,61-285Poznan,Poland.Tel.:+48601316763.}

E-mailaddress:tmilecki@wp.pl(T.Milecki).

1507-1367/$–seefrontmatter©2013GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.

Table1–Bloodtestsresultsbeforesurgery,after6daysandafter6monthsfor89patientswithRCCafterradical nephrectomy.

Variables Baseline(priorsurgery) After6days After6months Significancelevel

N 89 89 69 WBC 7.48(3.15–18.43) 8.38(3.2–15.4) 7.48(3.55–30.8) 0.00294 RBC 4.57(3.13–5.78) 3.94(2.77–4.91) 4.70(2.56–7.62) <0.0001 HGB 8.29(7.1–10.7) 7.20(7.5–12.4) 8.65(7.6–12.4) <0.0001 PLT 259.60±103.78(78.0–651.0) 313.39±103.48(121.0–583.0) 242.16(119.0–562.0) <0.0001 LDH 346.36(169.0–846.0) 435.42(208.0–895.0) 34,280(228.0–597.0) <0.0001 FE 17.48(3.5–39.0) 7.66(2.0–21.4) 17.64(3.1–44.5) <0.0001 CHOL 5.24(3.2–8.8) 4.88(3.0–9.4) 5.84(3.7–8.9) <0.0001 Cre 84.58(48.2–216.5) 110.72(55.3–331.7) 105.71(3.2–242.1) <0.0001 CRP 19.13(0.5–178.1) 61.40(11.4–301.6) 6.53(0.2–50.3) <0.0001 IL-6 11.63(0.0–291.8) 17.47(0.0–135.8) 3.59(0.0–63.68) <0.0001

1.

Background

Renalcellcarcinoma(RCC)accountsforabout3–4%of malig-nant neoplasms in adults. In Poland, in 2008, RCC was diagnosed in 2469 men and 1695 women. The number of deathscausedbythediseaseamountedto1574inmenand 989inwomen.1_{Radicalnephrectomyisthegoldstandardfor}

treatmentofRCC,butevenforlocalizeddiseasethesurvival rates are still unsatisfactory. Identification ofgood predic-torsofsurvival isthe basisforfuture treatment strategies foranindividual patient.Prognostic factors are universally utilized inthe management ofmany cancers and take an importantrole intheir treatment.2,3 _{Prognosticfactors can}

allowinthefuturetoestablishmoreefficientsupplementary methodsoftherapyforRCC.Generally,prognosticfactorsin RCCaredividedintoanatomical,histologicalandmolecular. Manymolecularfactorshavebeenexaminedintermsoftheir clinicalusefulnessinthecourseofRCC.Amongthemwere carbonicanhydrase9(CA9),vascularendothelialgrowthfactor (VEGF),hypoxia-induciblefactor(HIF),p53protein,E-cadherin andmanyothers.Unfortunately,noneofthemhasbeen con-firmedtobeareliableprognosticfactorandtheyhavenotbeen usedindailyclinicalpractice.4–6_{Theusefulnessofother}

pro-gnosticfactorsinRCCwithpotentialclinicalusability,suchas IL-6andCRP,isyettobeconfirmed.

2.

Aim

Theaimofourstudywastoassesstheusefulnessofthe con-centrationofIL-6andCRPasprognosticfactors inpatients afternephrectomyduetolocalizedRCC.

3.

Materials

and

methods

89patients(55menand34women)agedfrom30to81years (meanage60.08±9.99years)wereincludedintothis prospec-tivestudy.AllpatientshadbeensurgicallytreatedforRCCin theClinicofUrologyandUrologicOncologyofthePoznan Uni-versityofMedicalSciencesfrom2004to2005year.Allpatients with primary renal tumor were diagnosed by ultrasono-graphic(US)examinationandcomputertomography(CT).The examinedgroup includedpatients withlocalizedadvanced disease (from cT1 to cT3) without metastases in lymph

Table2–Clinicalandpathologicalcharacteristicof89 patientswithRCCafterradicalnephrectomy.

Parameters Value Numberofpatients N=89(100%) Gender Male 55(62) Female 34(38) Tumorstage pT1 47(53) pT2 23(26) pT3 19(21) Tumorgrade G1 27(30) G2 47(53) G3 15(17) Meanage 60.8 Survival Alived 74(83) Deceased 15(17) Cancerrelated 11(12) Non-cancerrelated 4(5)

nodes(cN0)andnodistantmetastases(M0).Allpatientshad bloodsamplesdrawnthreetimesduringthestudy:oneday before surgery as baseline, six daysafter surgery, and the last one six, months after surgery (Table 1). The patients’ performance status according to the Eastern Cooperative Oncology Group(ECOG) was 0or 1and noneofthem suf-feredfromchronicinflammatorydiseasenorhadundergone priorsurgeryhemodialysis, bloodtransfusion,radiotherapy, chemotherapy,andimmunotherapy.Ineachcase,thekidney removedduringnephrectomywashistopathologically exam-ined in the Department of Histopathology of the General MunicipalHospitalinPoznan.Toassesspathologicaltumor stage,theTNMclassificationfrom2002wasused.Allpatients with histologically confirmed metastases to lymph nodes and/orpT4stagewereexcludedfromthestudy.Patient’s clin-icalandpathologicalcharacteristicsarepresentedinTable2. Allpatientswerefollowedaftertheoperationatthe Urol-ogyClinicinPoznanaccordingtothefollowingschema:first visitaftersurgerywasat1month,thenat3-monthintervals uptooneyear,andthereafter,at6-monthintervalsuptothe endoffollow-up.Duringeach visit,thefollowing examina-tionswereconducted:generalexamination,USofabdomen

and/orCT,chestX-ray(onceperyear)andadditional exami-nationsinanycaseofsuspecteddiseaseprogression.CRPwas measuredusing therocket immunoelectrophoresis method withtheestablishedreferencevalueofupto5mg/l. Quan-titativeanalysisofhumanIL-6wasconductedwiththeuseof thesandwichELISAtechnique(Enzyme-Linked Immunosor-bent Assay) witha complete analysis set byR&D Systems withthemethodsensitivityof0.70pg/ml.Thetestprocedure wasconductedaccordingtothemanufacturer’s recommenda-tions,andtheresultswereanalyzedusingKCJuniorsoftware byBio-Tek.

StatisticalanalysiswasconductedusingStatisticaversion 7.0wherethefollowingtestswereapplied:Wilcoxon, Fried-manandANOVAtests.Additionallyforsurvivaltimessurvival, curvesweregeneratedusingtheKaplan–Meiermethod.The studywasapprovedbytheBioethicsCommissionatthe Uni-versityofMedicalSciences,Pozna ´n.

4.

Results

Duringthe follow-up,4patientsdiedforreasons unrelated tocancer:myocardialinfarction(n=3),cerebralstroke(n=1). On the other hand, death caused bydevelopment ofRCC wasobservedfor11patients.Statisticallysignificant relation-shipswere foundbetweenthe higherconcentrationofCRP atbaseline(beforetheoperation)andshortersurvivaltime (p=0.0001).ThehigherlevelofIL-6measuredbeforethe oper-ationcorrelatedwithworstsurvivaltimes(p=0.0096),too.An analysisofIL-6showedhighermeanvaluesinthegroupof patientswithdeathrelatedtoRCC (23.8units)in compari-sonwiththegroupoflivingpatients(9.2units).Inthegroup ofpatientswhodiedduetoRCC,meanCRPconcentrationat baselinewas49.7units.Ontheotherhand,meanCRPlevelin thegroupoflivingpatientswas12.9units.However,3patients inthe groupof52 patients withinitiallynormal resultsof CRPtestdied.TheexaminationofIL-6concentrationbefore theoperationshowedthat9(38%)patientsofthegroupof24 patientswithanelevatedlevelofIL-6died,whileinthegroup of74patientswithnormalresultsonly6(9%)patientsdied. LongerOStimewasdemonstrated inthegroupofpatients withRCC,inwhomtheCRPconcentrationbeforethe begin-ningoftherapywasnormal,incomparisontothegroupof patientswithanincreasedCRPconcentration(log-ranktest

p=0.001).Longersurvivaltimewasnotedinthepatientsin whomtheinterleukin-6levelbeforethesurgerywasnormal whencomparedtothegroupwithinitiallyelevatedIL-6level (log-ranktest,p=0.001)(Figs.1and2).

WeanalyzedalsoCSSdependingonCRPandIL-6. Statis-ticallysignificantcorrelationswerefoundforboth.Alonger survivaltimewasobservedinthepatientsinwhomCRP lev-elsbeforetheoperationwerenormalwhencomparedtothe patientswithaninitiallyincreasedlevelsoftheprotein (log-ranktest,p=0.0004)(Fig.3).AlongerCSStimewasfoundalso inthepatientswithanormalinitialIL-6concentrationas com-paredtothepatientswithIL-6concentrationabovenormal (Fig.4).

Inouranalysis,therewerenocorrelationbetween concen-trationofIL6andCRPaftersurgery(6daysaftersurgeryand6 monthsaftersurgery)intermsofCSSandOS.

Overall Survival (OS)

Complate Censored IL-6 - AB IL-6 - NL 0 10 20 30 40 50 60 70 Time (months) 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Probability Test log-rank p = 0,00133

Fig.1–Kaplan–Meiersurvivalprobabilityanalysisin

relationtotheconcentrationofinterleukin-6.

Overall Survival (OS) Complate Censored CRP -NL CRP - AB 0 10 20 30 40 50 60 70 Time (months) 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Probability Test log-rank p = 0,00101

Fig.2–Kaplan–Meiersurvivalprobabilityanalysisin

relationtotheconcentrationofC-reactiveprotein.

Cancer specific survival (CSS)

Complate Consored CRP - NL CRP - AB 0 10 20 30 40 50 60 70 Time (months) 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Probability Test log-rank p = 0,0004

Fig.3–Probabilitiesofcarcinoma-specificsurvivalfor

patientswithlocalizedRCCaccordingtoconcentrationof

CRP(normallevelversushigherlevel)priortoradical

Cancer specific survival (CSS) Complate Censored IL-6 - AB IL-6 - NL 0 10 20 30 40 50 60 70 Time (months) 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Probability Test log-rank p = 0,0002

Fig.4–Probabilityofcarcinomaspecificsurvivalfor

patientswithlocalizedRCC(normallevelvs.abnormal

level)accordingtoIL-6concentrationpriorradical

nephrectomy.

5.

Discussion

RCCderivedfrom epithelium ofrenal tubulesaccountsfor about90%ofprimaryrenalcarcinomasinadults.7_Itisa

het-erogeneouscancerand, inaddition, the onewithcomplex biologywhichdoesnotallowtofollowclearlythecourseof the disease;therefore, prognostication in many patients is verydifficult.Inmostlocallyadvancedtumors,recoveryafter radicalnephrectomyorpartialtumorremovalinthecaseof smalltumors,canbeexpected.Unfortunately,onehastobe awarethatstudiesdemonstratethatdistantmetastasesmay developinabout30%ofthesepatients.8,9 _{Ongoingresearch}

attemptstoidentifyfactorsthatcouldhelpinamoreprecise determinationofthecourseofRCCandenabletodistinguish thegroupsofpatientsforwhomcomplementarytreatment shouldbeoffered.Therefore, maybeinafuture,the ability torecognizetheriskgroupsforthediseaseprogressionwill allowtoadministertreatmentadequatetothedegreeof dis-easedevelopment. Atpresent, prognosticfactors inlocally advancedRCCcan bedividedinto anatomical,histological, clinicaland molecular.Clinicalprognosticfactors forOS in RCC are extensively discussed in the literature and come underreviewinmostscientificpapers.10Inmostpapers,the assessmentofacutephaseparametersinprognosticationof RCCislimitedtoCRPandproinflammatorycytokines.Inour present study,wefocused onsearchingfor prognostic fac-torsthatcanhelpinprognosisinpatientsafternephrectomy duetolocallyadvancedRCC. Thestudy includedresultsof assessmentofCRPand IL-6 concentrationsoneday before thesurgeryatbaseline.AtpresentCRPisconsidereda sensi-tiveindicatorthatsuggeststhepresenceofaninflammatory state and reflects its intensity. An increased CRP concen-trationisanundeniableevidenceofadiseaseprocess.CRP monitoringseemstobeagooddiagnostictestofadisease process.11,12 _{In the last fewyears,assessment ofCRP}

con-centrationhasbeencarriedoutinnumerousclinicalstudies onmanydiseasesofinflammatoryorigin.Thefollowing dis-easeentitiescanbenamedhere:boneandjointinflammation,

rheumatoidarthritis,psoriasisvulgaris,arthropathic psoria-sis,endocarditis,Alzheimer’sdiseaseandeyediseaseswhere increased concentration of CRP is observed in intraocular inflammation, and inpatients with cellulitis, keratitis and uveitis.13_{IncreaseCRPconcentrationhasalsobeenobserved}

inthe courseoftheneoplastic process.Theavailable liter-aturedescribes casesofanincreasedCRPconcentrationin suchcancersas:breast, lung,ovarianoresophageal.14–19 In ourstudy,weassessedprognosticfactors (CRPandIL-6),in particulartimeperiodsinRCCpatients.Distinctlyhigher lev-elsofCRPandIL-6wereobservedbeforetheoperation.Our studydemonstratedthatthelowerCRPconcentrationbefore theoperationwascorrelatedwiththelongersurvivaltimes (OS,CSS)ofRCCpatients.Inaddition,theanalysisconducted inthestudy showedthat ahigher IL-6levelbeforesurgery wasassociatedwithshortersurvivaltimes(OS,CSS),too.So far,manystudieshavebeenconductedonRCCsurvivaltime. Lambetal.showedonagroupof100patientswithRCCthe influenceofCRPconcentrationbeforetheoperationon the course ofthe disease and onCSS patients withRCC. They demonstratedthatinpatientswithaninitialCRPlevelabove 10mg/dl,CSSwas71monthsversus96monthsinthegroup ofpatientswithCRPbelow10mg/dl(p=0.001).20 _Thesame

researchteam, twoyears later,conductedanotheranalysis onagroupof60patientswithRCC.Arelationshipbetween CRP,IL-6,andexpressionofcyclooxygenase(COX-2), concen-trationofCD4+andCD8+,T-lymphocytesandprobabilityof CSSwasanalyzed.TheassociationbetweenCRP concentra-tionandCSSandprobabilityofrecurrence-freesurvivalwas demonstrated.21_{Masudaetal.intheirstudyonagroupof111}

patientsfoundthatCRPconcentrationisanegative progno-sticfactorinRCCdependentonTNMandRobsonstaging.22

Komaietal.conductedresearchonagroupof101patients sub-jectedtoradicalnephrectomyduetoRCC(pT1-3N0M0).They assessedCRPconcentrationasaprognosticfactorinRCC.An elevatedCRPlevel(>0.5mg/dl)wasobservedin26patients,of whom12(46%)and3oftheothergroupof75patientsdied duetoRCC.They demonstratedsignificantlylowersurvival inthegroupofpatientswithanincreasedCRPlevelthanin thenormalconcentrationoftheprotein(p<0.001).23_Fujikawa

etal.intheirstudysuggestedthatareductioninCRPlevelin responsetocytoreductivenephrectomyandcomplementary immunotherapypredictsbetterprognosis.24

AnothercandidateasaprognosticfactorforRCCpatients, whichdeservesmuchattention,isIL-6. IL-6isapleiotropic cytokinewithawiderangeofactivity,evidentespeciallyinthe immune,hematopoieticandnervoussystem.Mikietal.onthe basisoftheirresearchdemonstratedthatmRNAexpression ofIL-6,IL-6secretiveactivity oftumortissuesandanti-IL-6 antibodies inhibiting growth ofthetumorcan beobserved infreshlyisolatedtissuesofRCC.25_{Otherresearchby}

Take-nawaetal.showsthatbothprimaryRCCandRCCcelllines expressmRNAofIL-6andIL-6receptorandthatpatientswith increasedexpressionhavegreaterincidenceofmetastasesto lymphnodesandanincreasedlevelofCRP.26_Therearemany

reportsprovingtheroleofIL-6asanautocrinegrowthfactor inRCC. Blay etal. confirmedthe role ofIL-6 inRCC. They foundthat48%ofRCCpatientshadaconsiderablyhigherIL-6 levelthatcorrelatedwithanincreasedconcentrationofCRP.27

IL-6occurredin25%ofpatientswithRCC,whileHamaoet al. observedanincrease inIL-6in53%ofcases.28,29 _Inthe

lit-erature, thereare alsostudies on the role ofCRPassessed after nephrectomy in patients with locally advanced RCC. Johnsonetal.oftheEmoryUniversityinAtlanta(USA) moni-toredCRPconcentrationbeforenephrectomyduetoclear-cell renal cell carcinoma and one year after the surgery on a group of110 patients (T1-3N0M0).The multifactorial anal-ysisrevealed astatisticallysignificant relationshipbetween postoperativeCRPlevel,T-stageandrecurrence-freesurvival andOS(p<0.001).Theresearchersdemonstratedthat postop-erativeCRPlevelcanfacilitateidentificationofpatientswith a high risk ofprogressionmore than preoperative level of the protein,which will allowtopropose acomplementary therapy with anti-angiogenic drugs.30 _{A study by}

Kamem-oto on patients with clear-cell renal cell carcinoma (stage T1–2,N0M0) showeda normallevel ofIL-6in blood serum. TheconcentrationofserumIL-6washigherinpatientswith advancedRCC(T3N0M0)andcorrelatedwithanincreasedCRP level.31

TheproblemofidentificationofprognosticfactorsinRCC, raisedinmanystudies,seemstobeofgreatimportance.The ongoingresearchconductedinnumerousscientificcenters, allowcliniciansto determinemoreand morepreciselythe mostsignificantprognosticfactorsthatinfluencethechoice oftherapyandabilitytodeterminefurtherprognostication. Ourstudyisanattemptatemphasizingandpresentingthe role of the most important parameters that seem to play a role in prognostication in patients with clear-cell renal cell carcinoma. So, the conclusion we drew on the basis of the research conducted is that an increased preopera-tive levels ofCRP and IL-6 are negativeprognostic factors for OS and CSS in patients subjected to radical nephrec-tomy due to RCC. On the other hand, a decrease in the levelofIL-6andCRPinperipheralbloodbeforenephrectomy dueto locally advanced RCCmay be avaluable diagnostic factor in later qualification of patients forcomplementary therapy.

Conflict

of

interest

Financial

disclosure

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