Study of risk factors and causes of death after analyzing morbidity and mortality reviews (UroCCR-33 study)

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ORIGINAL ARTICLE

Who is dying after nephrectomy for cancer?

Study of risk factors and causes of death after analyzing morbidity and mortality reviews (UroCCR-33 study)

Qui meurt après une néphrectomie pour cancer ? Étude des facteurs de risque de décès, des causes de décès et des réunions de morbi-mortalité (étude UroCCR-33)

A. Fontenil

^a^,∗

, P. Bigot

^a

, J.-C. Bernhard

^c

,

J.-B. Beauval

^d

, M. Soulié

^d

, T. Charles

^e

, S. Larre

^f

, L. Salomon

^g

, R. Azzouzi

^a

, A. Méjean

^h

, K. Bensalah

^b

, Cancerology Committee of the French Association of Urology (CCAFU)

aDepartmentofurology,Angersuniversityhospital,4,rueLarrey,49933Angers,France

bDepartmentofurology,Rennesuniversityhospital,35000Rennes,France

cDepartmentofurology,Bordeauxuniversityhospital,33000Bordeaux,France

dDepartmentofurology,Toulouseuniversityhospital,31400Toulouse,France

eDepartmentofurology,Poitiersuniversityhospital,86021Poitiers,France

fDepartmentofurology,Reimsuniversityhospital,51100Reims,France

gDepartmentofurology,Henri-Mondoruniversityhospital,94010Créteil,France

hDepartmentofurology,HEGP,75015Paris,France

Received4September2018;accepted1stFebruary2019 Availableonline5April2019

KEYWORDS

Renalcellcarcinoma;

Nephrectomy;

Surgery;

Thirty-daymortality;

Summary

Backgroundand methods.—Nephrectomy isthe treatment for renal cell cancer fromT1-4 tumorsbutremainsatrisk.Todeterminethethirty-daymortalityrateafternephrectomyfor cancerandtoidentifycausesandriskfactorsofdeathinordertoﬁndclinicalapplications.From 2014to2017,we performedaretrospectivemulticentricanalysisofprospectivelycollected datastudyinvolvingtheFrenchnetworkforresearchonkidneycancer(UroCCR).Allpatients

∗Correspondingauthor.

E-mailaddress:alexisfontenil@gmail.com(A.Fontenil).

https://doi.org/10.1016/j.purol.2019.02.009

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Morbidityand mortalityreviews;

Riskfactorsofdeath;

Causesofdeath

whodiedafternephrectomyfor cancerduringtheﬁrst thirtydayswereidentiﬁed.Patients’

characteristics,causesofdeathandmorbidityandmortalityreviewsreportswereanalyzedfor eachdeath.

Results and limitations.—In total, 2578 patients underwent nephrectomy and 35 deaths occurred.Thethirty-daymortalityratewas1.4%.Inunivariateanalysis,symptomsatdiagnosis (P=0.006,OR=2.56IC(1.3—5.03)),cstagesuperiortocT1(P<0.0001,OR=6.13IC(2.8—13.2)), cTstagesuperiortocT2(P<0.0001,OR=8.8IC(4.39—17.8)),nodalinvasion(P<0.0001,OR=4.6 IC(1.9—10.7)),distantmetastasis(P=0.001,OR=4.01IC(1.7—8.9)),opensurgery(P<0.0001, OR=0.272IC(0.13—0.54))andradicalnephrectomy(P=0.007,OR=2.737IC(1.3—5.7))were risk factorsof thirty-day mortality. In a multivariablemodel, only cTstage superior to T2 (P=0.015,OR=3.55IC(1.27—10.01))wasariskfactorofthirty-daymortality.Themaincauseof postoperativedeathwaspulmonary(n=15;43%).Thesecondcausewaspostoperativedigestive sepsisfor7patients(20%).Only2morbidityandmortalityreviewshadbeendoneforthe35 deaths.Limitationsarerelatedtothethirty-daymortalitycriteriaanddescriptivestudydesign.

Conclusions.—Symptomaticpatients,stagecTNMandtypeandtechniquesofsurgeryaredeter- minantsofthirty-daymortalityafternephrectomyforcancer.Theﬁrstcauseofpostoperative deathispulmonary.Morbidityandmortalityreviewsshouldbeconsideredtobetterunderstand causesofdeathandtoreduceearlymortalityafternephrectomyforcancer.

Levelofevidence.—4.

MOTSCLÉS Carcinomerénalà cellulesclaires; Néphrectomie; Chirurgie; Mortalitédansles trentepremiers jours;

Réunionsde morbi-mortalité; Facteursderisquede décès;

Causesdedécès

Résumé

Introduction.—Lanéphrectomieestletraitementderéférenceducarcinomerénalàcellules clairespourlestumeursT1àT4.Elleresteunetechniquenondénuéederisques.L’objectifde cetteétudeétaitdedéterminerletauxdemortalitédanslestrentepremiersjoursaprèsune néphrectomiepourcanceretd’identiﬁerlescauses,lesfacteursderisqueetlesconclusionsdes réunionsdemorbi-mortalitépouraméliorerlapriseenchargepériopératoiredecettechirurgie.

Méthode.—Nousavonsréaliséuneétuderétrospectivemulticentriqueàpartird’unebasede donnéescollectéesprospectivementde2014à2017incluantleréseaufrançaisderecherche surlecancerdurein(uroCCR).Touslespatientsopérésd’unenéphrectomiepourcancerdans septcentresuniversitairesfrançaisontétéinclusettouslespatientsdécédésdanslestrente premiersjoursontétéidentifiés.Leurscaractéristiques,lescausesdedécès etlescomptes rendus des réunions de morbi-mortalité ontété analysés pour chaque patient décédé. Les statistiquesontétéréaliséesàl’aidedulogicielSPSS^®version20.0.Lestestsstatistiquesréalisés étaientdesChi²etdestestsdeStudent.

Résultats.—Au total,2578 patients onteu unenéphrectomie et 35 sontdécédés. Le taux demortalitéétaitde1,4%.Enanalyseunivariée,lecaractèresymptomatiqueaudiagnostic (p=0,006,OR=2,56IC(1,3—5,03)),unstadecliniquesupérieuràcT1(p<0,0001,OR=6,13IC (2,8—13,2))etcT2(p<0,0001,OR=8,8IC(4,39—17,8)),l’invasionganglionnaireN+(p<0,0001, OR=4,6 IC (1,9—10,7)), le caractère métastatique (p=0,001, OR=4,01 IC (1,7—8,9)), la chirurgieouverte(p<0,0001,OR=0,272IC(0,13—0,54))etlanéphrectomieradicale(p=0,007, OR=2,737 IC (1,3—5,7)) étaient des facteursde risquede décès dans les trente premiers jours. Enanalyse multivariée, seulle stadeclinique supérieur à T2(p=0,015, OR=3,55IC (1,27—10,01))étaitunfacteurderisquededécès.Laprincipalecausededécèspostopéra- toireétaituneoriginepulmonaire(n=15;43%).Lasecondecauseétaituneoriginedigestive (péritonite)pour7patients(20%).Seulementdeuxpatientsparmiles35décédésonteuune réuniondemorbi-mortalité.Les limitesdecetteétudeétaientliéesaucritèredejugement principalainsiqu’àcellesdetoutesétudesrétrospectives.

Conclusions.—Lecaractèresymptomatique,lestadeTNMetletypedechirurgieétaientdes facteursderisqueindépendantsdedécès.Laprincipalecausededécèsétaituneoriginepul- monaire.Lesréunionsdemorbi-mortalitédevraientêtreconsidéréespourmieuxcomprendre lescausesdedécèsetréduirelamortalitépostopératoiredanslestrentepremiersjoursaprès néphrectomiepourcancer.

Niveaudepreuve.— 3.

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Introduction

Renal cell carcinoma (RCC) represents 3% of all cancers [1]. The incidence of RCC has increased worldwide and in Europe [2] due to the use of abdominal imaging [3].

Surgical treatment such as radical and partial nephrectomy is recommendedfor T1-4 tumors.The improvement ofsurgicaltechniques andperioperativecareshavedimin- ished perioperative morbidity [4]. However, nephrectomy remains at risk: studies suggest that the thirty-day mortality (TDM) after nephrectomy ranges between 0.6% and 3.6% [5—7]. It has been suggested that the TDM rate is related to age, disease stage and type of surgery [7].

To our knowledge, there is no data in the literature reporting outcomes and measurements of morbidity and mortalityreviews(MMR)afternephrectomy.Ourobjective wastodeterminetheTDMrateafternephrectomyforcan- cerin alarge multicentricdatabaseaswell asidentifying causesofandriskfactorsofdeath.

Methods

After approval from each institutional review board, we performedaretrospectivestudyonaprospectivedatabase involving seven centers (Toulouse, Bordeaux, Poitiers, Rennes,HenriMondor,ReimsandAngersuniversityhospitals) partof theFrenchnetwork forresearchonkidney cancer UroCCR(ClinicalTrials.gov:NCT03293563).

The data of patients who had been treated by surgery for a renal tumor between 2014 and 2017 were prospectively collected in the national registered institutional review board approved multicenter database UroCCR (CNIL agreement DR-2013-206). Upper-tract tran- sitional cell carcinomas and non-cortical renal tumors (melanomas,sarcomas,andlymphomas)werenotincluded.

Pre-andpostoperative parameterssuch asage, sex,local symptoms (hematuria, lower back pain, abdominal mass) and general (fever, general status, paraneoplastic syn- droms),cTNMstage,typeofprocedure(open,laparoscopic, robot-assisted surgery), type of surgery (partial, radical nephrectomy), time to death and death cause were recorded.

Weidentiﬁedallpatientswhodiedafternephrectomyfor cancerduringtheﬁrstthirtydaysandweanalyzedcausesof death.WeusedTDMthatisoftenusedtodescribemortality aftersurgicalinterventions[8,9].

Forevery deceasedpatient,we looked atmedicaland MMRreportsinordertoﬁndoutabout theanalysisofthe caseandclinicalconclusions.

The SPSS^®, version 20.0 software package was used forallstatistical analysis.Independent-samplet-testsand chi-square tests were used for comparisons of quanti- tative and qualitative variables, respectively. Univariate and multivariate regression models were used to assess the inﬂuence of different variables on postoperative death.

Table1 Causesofpostoperativedeaths.

Causes n=35(%)

Pulmonary 15(43)

PneumoniaorInhalation 10(29)

Pulmonaryembolism 5(14)

Digestivesepsis 7(20)

Hemorrhage 4(11)

Relatedtocancer 3(9)

Liverfailure 2(6)

Heartfailure 2(6)

Neurological 1(3)

Multipleorgandysfunctionsyndrome 1(3)

Results

Causes of TDM

The main cause of postoperative death was pulmonary (n=15,43%): 11patients diedof pneumonia orinhalation (29%)and5patientsofpulmonaryembolism(14%).Among thoseﬁvepatients, threehadacaval thrombus(9%).The secondleadingcausewaspostoperativedigestivesepsisin 7 (20%) patients. Hemorrhage was the third causewith 4 (11%)patients.Threepatientsdiedfromtheircancer(9%).

Liverfailureandheartfailurewerefoundin2patients(6%).

NeurologicalandMultipleorgandysfunctionsyndromewere foundinone(3%)patienteach.CausesofTDMarereported inTable1.

Thirty-day mortality rate

From2014to2017,2578patientsunderwentnephrectomy and35 deathsoccurred duringthe initialthirtydays.The TDMratewas1.4%.Themediantimetodeathwas10.5days (range:0—30).

Characteristics of patients who died in the thirty days after nephrectomy

Amongthe35deceasedpatients,medianagewas71years (extremes:40—86), 27(77%) weremaleand8(23%) were female. Local and systemic symptoms at diagnosis were presentinrespectively12(34%)and8(23%)patients.Rad- icaland partial nephrectomywere performed in 25 (71%) and10(29%)patients,respectively.Open,laparoscopicand roboticsurgerieswereperformedin20(57%),13(37%)and2 (6%)patients,respectively.Therewere9(27%)pT1,5(15%) pT2,17(49%)pT3and2(6%)pT4tumors.Sevenpatientshad lymphnodeinvolvement(20%) andeighthadametastatic disease(23%).ASAscores,ECOGscoresandotherspatients’

characteristicswerereportedinTable2.

Risk factors of TDM

In univariate analysis symptoms at diagnosis (P=0.006, OR=2.56IC(1.3—5.03)),cstagesuperiortocT1(P<0.0001,

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Table2 Dead patient demographics and tumor characteristics.

Characteristics n=35

Sex,n(%)

Male 27(77)

Age,year 64(40—86)

BMI,kg/m² 27

Symptomsatdiagnosis,n(%)

Asymptomatic 15(43)

Localsymptoms 12(34)

Systemicsymptoms 8(23)

ASAscore,n(%)

ASA2 17(48)

ASA3 15(44)

ASA4 3(8)

ECOGstatus,n(%)

ECOG0 12(34)

ECOG≥1 23(66)

Medicalhistory,n(%) 34(97)

Highbloodpressure 19(54)

Diabetes 10(29)

Dyslipidemia 10(29)

Smoking 7(20)

Antiplateletoranticoagulant drugs

11(31) Deepveinthrombosisor

pulmonaryembolism

4(11)

Renalfailure 4(11)

Treatmenttype,n(%)

Radicalnephrectomy 25(71)

Partialnephrectomy 10(29)

Opensurgery 20(57)

Laparoscopic 13(37)

Robotic 2(6)

Histologicalsubtype,n(%)

ClearcellRCC 28(80)

PapillaryRCCtype1 4(11)

PapillaryRCCtype2 2(6)

Angiomyolipoma 1(3)

Clinicaltumorstage,n(%)

T1 9(27)

T2 5(15)

T3 17(49)

T4 2(6)

N1 7(20)

M1 8(23)

OR=6.13 IC (2.8—13.2)), cT stage superior to cT2 (P<0.0001, OR=8.8 IC (4.39—17.8)), nodal invasion (P<0.0001, OR=4.6 IC (1.9—10.7)), distant metastasis (P=0.001,OR=4.01IC(1.7—8.9)),opensurgery(P<0.0001, OR=0.272 IC (0.13—0.54)) and radical nephrectomy (P=0.007,OR=2.737IC(1.3—5.7))weresigniﬁcantlyasso- ciatedtoTDM.InthemultivariablemodelonlycTstage>T2 (P=0.015,OR=3.55 IC(1.27—10.01)) wasan independent predictorofTDM(Table3).

Discussion

Inourstudy,wefoundathirty-daymortalityrateof1.4%and identiﬁedseveral risk factors of TDM includingsymptoms atdiagnosis,cTNMandoperativetechniques.Symptomatic patientswithalarge advancedtumorarethemost atrisk especiallyafterradicalnephrectomy.

Intheavailableliterature,theoverallTDMrateisaround 0.55% (PN 0.10%; RN 0.52%) [10,11]. Cloutier and al. [7]

reportedsimilarﬁndingswithaTDMrateof0.9%.Beisland andal. [12] reportedsimilar risk factors of TDMbut also foundhospitalvolumetobeanindependentparameterof TDM[13—16].Themortalityrateofnephrectomyseemsto decreaseovertime:itwentdownfrom3.1%between1978 to1997 [12] and 2.8% between 1970 and 2000 [17]. This decreaseinmortalityprobablyresultsfromabetterpatient selection and from the improvement of minimal-invasive surgicaltechniquesandperioperativecares.

In our cohort, pulmonary affections, namely pneumonia and embolism, were the leading causes of TDMafter nephrectomy.Thesecondcausewasdigestivesepsisinclud- ingperitonitis,intestinalperforationornecrosis.Lookingat ourresults,somedeathscouldhaveprobablybeenavoided:

3ofourpatientsdiedinthepostoperativeperiodbecauseof apoorgeneralstatusrelatedtoadvancedcancer.Itishighly probable that these three metastatic patients were not carefullyselectedandshouldnothavebeenoperated.These deaths underline the limit of cytoreductive nephrectomy thatshould be decidedona case-by-case basis according toprognosisandlifeexpectancy[18].

We analyzed every medicalreport andfound only two reports ofMMR. The ﬁrst patientdied frombilateral pulmonary embolism during surgery. He had a level 3 caval thrombuswhichprobablyspreadoutquicklyafterthecavo- tomy.Themultidisciplinarymeetingleadsurgeonstobetter evaluatepreoperativeextensionofthethrombusinorderto betterpredictperioperativeneeds(collaborationofcardio- thoracicsurgeons,resorttothisextracorporealcirculation).

Thesecondpatientdiedfrompostoperativehemorrhageon day2.Hewasafrailpatientof79yearsoldwithmanycar- diacaffectionsincludinga mechanicmitralvalve. He was takingantiplatelet, anticoagulant andantiarytmics drugs.

The MMR identiﬁed a failure in the postoperative mana- gementespecially in themanagement of anticoagulation.

The multidisciplinary meeting lead surgeons to a general evaluationin the hospitalof postoperative use of unfrac- tionatedheparin,torealizeapreciseheparinprotocoland toasystematic medicaloversightduringthetwoor three ﬁrstpostoperativedaysinasurgicalcareintensiveunitfor thistypeofpatient.

WewereverysurprisedtofindonlytwoMMRreportsfor the35 patients. The first reasonof our surprise wasthat MMRs are suggested by all surgical guidelines. The main aim is to improve patient’ care and safety witha multi- disciplinaryreviewingofalldeathcircumstances[19].MMR can beseen asa ‘‘postoperative black box’’ similar toa flightrecorderwiththeaimoffacilitatingtheinvestigation ofmedicalaccidentsandincidents.MMRsoftentakeplace

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Table3 Univariableandmultivariateanalysisofriskfactorsofpostoperativedeathafternephrectomy.

Univariateanalysis Multivariateanalysis

Variable Total OR(95%CI) Pvalue OR(95%CI) Pvalue

Sex

Male 1647 1

Female 896 0.54(0.24—1.2) 0.115 0.51(0.21—1.2) 0.131

Age,years NA 1.027(0.99—1.05) 0.058 1.024(0.99—1.05) 0.129

Symptomsatdiagnosis

No 1689 1

Yes 890 2.56(1.3—5.03) 0.006 1.09(0.48—2.46) 0.822

InitialcTstage

T1 1515 1

>T1 679 6.13(2.8—13.2) <0.0001 1.55(0.45—5.37) 0.48

>T2 306 8.8(4.39—17.8) <0.0001 3.55(1.27—10.1) 0.015

InitialcNstage

0orX 2441 1

1-2 138 4.6(1.9—10.7) <0.0001 1.26(0.48—2.46) 0.63

InitialcMstage

0orX 2396 1

1 183 4.01(1.7—8.9) 0.001 1.3(0.52—3.25) 0.57

Operativetechnique

Opensurgery 807 1

Laparoscopicorroboticsurgery 1718 0.272(0.13—0.54) <0.0001 0.65(0.29—1.47) 0.3 Operativetype

Partialnephrectomy 1326 1

Radicalnephrectomy 1227 2.737(1.3—5.7) 0.007 1.35(0.48—3.82) 0.56

insurgicalenvironmentsandprovidepracticaladvicethat participatestomedicaleducation[20].Antonaccietal.[21]

suggestedthatinsurgicaldepartments,MMRscandecrease themortalityby40%.

Webelieveourresultsareofinterest:datawasextracted fromamulticentricandprospectivelymaintaineddatabase in a modern era. However there are several limits. The TDMcriteriaisthe mostused instudies but itis notper- fect and it may be questionable to think that mortality within 30 days is always related to surgery. Also, TDM does notevaluate thesubjective dimension ofpostopera- tivequalityoflifeofpatientsafternephrectomy.Also,this retrospectivestudyisbasedondeclarativedatasubmitted bysurgeonswhoparticipatein theUroCCRproject.There werenoobligationtoincludeallnephrectomyandforthe includedpatients,someﬁlesweredeﬁcientwithalackof descriptivedata.Finally, thismulticentricstudy maypose aproblemofexternalvaliditybecauseitreliesonaFrench population that is not necessarily representative of other populations.

Conclusion

Ourresultsshowthatmortalityafternephrectomyforcan- cerisminimalandmostlydrivenbycomorbiditiesandtumor stage.Pulmonaryaffectionsaretheleadingcausesofdeath inourFrenchcohort.

Authorship form

Studyconceptanddesign:Fontenil,Bigot,Bensalah,Bern- hard.

Acquisitionofdata:Fontenil,Latxague.

Analysisandinterpretationofdata:Fontenil,Bigot.

Draftingofthemanuscript:Fontenil,Bigot,Bensalah.

Criticalrevisionofthemanuscriptforimportantintellec- tualcontent:Bigot,Bensalah,Bernhard.

Statisticalanalysis:Bigot.

Obtainingfunding:none.

Administrative,technical,ormaterialsupport:Latxague, Bernhard,Bigot.

Supervision:Fontenil,Bigot,Bensalah.

Other(specify):none.

Funding/support and role of the sponsor

None.

Author contributions

AlexisFontenil hadfullaccesstoallthedatain thestudy andtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

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Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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