with colorectal cancer according to surgical approach inpatients Correlation between preoperative CT scan and lungmetastases CIRUGI´A ESPAN˜OLA

Original article

Correlation between preoperative CT scan and lung metastases according to surgical approach in

patients with colorectal cancer

Jorge Herna´ndez

*, Laureano Molins

, Juan J. Fibla

, A´ngela Guirao

, Juan J. Rivas

, Laura Casas

, Nu´ria Pajuelo

, Rau´l Embu´n

, on behalf of the Spanish Group for Colo-Rectal Carcinoma Pulmonary Metastasis Surgery (GECMP-CCR) of the Spanish Society of

Pulmonology and Thoracic Surgery (SEPAR)

aServiceofThoracicSurgery,HospitalUniversitaridelSagratCor,Barcelona,Spain

bServiceofThoracicSurgery,HospitalClı´nic,UniversitatdeBarcelona,Barcelona,Spain

cServiceofThoracicSurgery,HospitalUniversitarioMiguelServet,IISArago´n,Zaragoza,Spain

dDepartmentofBiostatisticsandDataManagement,DynamicSolutions,Madrid,Spain

a r t i c l e i n f o

Articlehistory:

Received24August2020 Accepted15December2020 Availableonlinexxx

Keywords:

Colorectalcancer Thoracicsurgery VATS

Thoracotomy Lungmetastases Pulmonarymetastases

abstract

Introduction:Thenumberoflungmetastases(M1)ofcolorectalcarcinoma(CRC)inrelationto thefindingsofcomputedtomography(CT)istheobjectofstudy.

Methods:ProspectiveandmulticenterstudyoftheSpanishGroupforSurgeryofCRClung metastases(GECMP-CCR).TheroleofCTinthedetectionofpulmonaryM1isevaluatedin 522patientswhounderwentapulmonarymetastasectomyforCRC.WedefineM1/CTasthe ratiobetweenmetastaticnodulesandthosefoundon preoperativeCT.Disease-specific survival(DSS),disease-freesurvival(DFS),andsurgicalapproachwereanalyzedusingthe Kaplan–Meiermethod.

Results:93patientswereperformedbyvideo-assistedsurgery(VATS)and429bythoracot- omy.In90%,theM1/CTratiowas1,withnodifferencesbetweenVATSandthoracotomy (94.1%vs89.7%,p=0.874).Intheremaining10%thereweremoreM1sthanthosepredicted byCT(M1/CT>1),withnodifferencesbetweenapproaches (8.6%vs10%,p=0.874).51 patientswithM1/CT>1,showedalowermedianDSS(35.4monthsvs55.8;p=0.002)and DFS(14.2monthsvs29.3;p=0.025)comparedto470withM1/CT1.Nodifferenceswere observedinDSSandDFSaccordingtoVATSorthoracotomy.

* Correspondingauthor.

E-mailaddress:[email protected](J.Herna´ndez).

^ ThenameofthemembersoftheSpanishGroupforColo-RectalCarcinomaPulmonaryMetastasisSurgery(GECMP-CCR)oftheSpanish SocietyofPulmonologyandThoracicSurgery(SEPAR)arelistedinAppendixA.

Abbreviations: CEA,carcinoembryonicantigen;CRC,colorectalcancer;CT,computedtomography;DFS,disease-freesurvival;DSS, disease-specificsurvival;ESTS,EuropeanSocietyofThoracicSurgeons;GECMP-CCR,GrupoEspan˜oldeCirugı´adeMeta´stasisPulmonares deCarcinomaColo-Rectal;SEPAR,SociedadEspan˜oladeNeumologı´ayCirugı´aTora´cica;SPSS,StatisticalPackagefortheSocialSciences;

VATS,video-assistedthoracicsurgery.

CIRUGI´A ESPAN ˜ OLA

www.elsevier.es/cirugia

https://doi.org/10.1016/j.ciresp.2020.12.012

0009-739X/#2020AEC.PublishedbyElsevierEspan˜a,S.L.U.Allrightsreserved.

Introduction

Distantmetastasis,especiallylocatedinliverandlung, are nearly the mostimportant prognostic factor forcolorectal cancer(CRC). Itisestimatedthat between10% and20% of patients with CRC will develop pulmonary metastasis.

Pulmonarymetastasectomycanonlybeperformedinasmall groupofpatients,duetothehighincidenceofextrathoracic disease at the moment of the diagnosis,or the significant pulmonary involvement.^1,2 Whenever feasible, surgery is consideredaneffectivetherapeuticoption,withreported5- yearoverallsurvivalratesafterradicallungresection,ranging from41%to68%.^3,4Inproperlyselectedpatients,pulmonary metastasectomyhasbecomewidelyacceptedasapotential curativeoptionforlungmetastasisfromCRC.^5,6

Open thoracotomy and video-assisted thoracic surgery (VATS)arebothacceptedtechniquestoperformpulmonary metastasectomy,but,sincefewyearsago,VATShasgained popularity,andrightnow,numeroussurgeonschoseVATSas thefirstsurgicalapproach.^7–9Asurveydonetomembersofthe EuropeanSocietyofThoracicSurgeons(ESTS)reported;60%of surgeonsconsideredVATS anacceptable surgicalapproach forselectedcases.40%ofthemconsideredthisapproachthe firstchoiceforunilateraldisease.¹⁰AlthoughVATSapproach seemstobeacceptedbymostthoracicsurgeons,therearenot

prospective randomized studies comparing VATS with the standardthoracotomyforCRClungmetastasesresection.The crux lies on the undetected M1 by preoperative chest CT, whichcouldbelostduringVATSprocedures,comparedwith pulmonarynodulesthatmightbefoundbycarefulmanual palpation.¹¹

Aprospectivemulticenterstudywasdesignedtoassessthe prognostic value of preoperative CT imaging compared to histologicalfindings,regardingsurgicalapproachcomparing VATSversusconventionalthoracotomy.

Material and methods

Studydesign

TheprospectivemulticenterregistryoftheSpanishGroupfor ColorectalCarcinomaLungMetastasesSurgery(GECMP-CCR) wasestablishedbyTheSpanishSocietyofPneumologyand Thoracic Surgery(SEPAR)inJanuary2008.All patientswith oneormorehistologicallyprovenandsurgeryremovedofCRC lungmetastasisbetweenMarch2008andFebruary2010bythe ThoracicServicesof32publichospitalswereincludedinthe database.ThepurposeoftheGECMP-CCR-SEPARregistrywas toobtainnationwidehigh-qualitydatainashortanddefined periodoftime,inordertodocumentthecurrentpracticeofthe Conclusions: OurstudyshowsequivalentoncologicalresultsintheresectionofM1ofCRCusing VATSorthoracotomyapproach.ThegroupofpatientswithanM1/CTratio>1haveaworseDSS andDFS,whichmaymeanamoreadvanceddiseasethanpredictedpreoperatively.

#2020AEC.PublishedbyElsevierEspan˜a,S.L.U.Allrightsreserved.

Correlacio´nentreTCpreoperatoriaymeta´stasispulmonaressegu´n abordajequiru´rgicoenpacientesconca´ncercolorrectal

Palabrasclave:

Ca´ncercolorrectal Cirugı´atora´cica

Cirugı´avideotoracosco´pica Toracotomı´a

Meta´stasispulmonar Meta´stasispulmonar

resumen

Introduccio´n:Elnu´merodemeta´stasispulmonares(M1)decarcinomacolorrectal(CCR)en relacio´nconloshallazgosdelatomografı´acomputarizada(TC),esobjetodeestudio.

Me´todos:Estudioprospectivoymultice´ntricodelGrupoEspan˜oldeCirugı´adelasmeta´stasis pulmonares delCCR (GCMP-CCR). Seevalu´a elpapel de la TC en ladeteccio´n de M1 pulmonaresen522pacientes intervenidosdeunametastasectomı´a pulmonarporCCR.

DefinimoscomoM1/CTalcocienteentrelosno´dulosmetasta´sicosyloshalladosenlaTC preoperatoria.Seanalizo´ lasupervivenciaespecı´ficadeenfermedad(SEE),lasupervivencia libredeenfermedad(SLE)yelabordajequiru´rgicomedianteelme´tododeKaplan-Meier.

Resultados:En93pacientesseutilizo´ lacirugı´avideoasistida(VATS)y429toracotomı´as.En un90%elcocienteM1/TCfue1,sindiferenciasentreVATSytoracotomı´a(94,1vs.89,7%;

p=0,874).Enel10%restanteexistı´anma´sM1quelaspredichasporlaTC(M1/CT>1),sin diferenciasentreabordajes(8,6vs.10%;p=0,874).CincuentayunpacientesconM1/CT>1, mostraronunamenormedianadeSEE(35,4vs.55,8meses;p=0,002)ySLE(14,2vs.29,3 meses;p=0,025)encomparacio´ncon470conM1/CT1.Noseobservarondiferenciasenla SEEylaSLEsegu´nVATSotoracotomı´a.

Conclusiones:Nuestro estudio muestra unos resultados oncolo´gicos equivalentes en la reseccio´ndeM1de CCRmediante abordajeVATS otoracotomı´a.Elgrupode pacientes conuncocienteM1/CT>1presentanunapeorSEEySLE,pudiendosignificarunaenfer- medadma´savanzadadelapredichapreoperatoriamente.

#2020AEC.PublicadoporElsevierEspan˜a,S.L.U.Todoslosderechosreservados.

Spanishhealthcaresystem,regardingatleastthe60%ofall patientswiththispathologycontrolledinSpain.Detailsofthe GECMP-CCR-SEPARdatabasewerepreviouslydescribed.¹² Patients

Availabledatacorrespondedto543patientsundergoingtheir firstCRCpulmonarymetastasectomyduringtwoconsecutive years (March 2008–March 2010) with a follow-up period completedinMarch 2013,ensuring aminimum threeyear follow-up.Lung resectionmust be carriedout with radical intention, that is, without leaving apparent macroscopic disease,and atleastoneexcisedlesionmustbeconsistent withhistologicallyconfirmedCRCmetastasis.Thestudywas approved by the Ethics Committee of each participating hospitals as well as the regional Ethics Committee for ScientificandMedicalResearchofthedifferentAutonomous Communitieswhennecessary.Writteninformedconsentwas obtainedfromallpatients.

Becauseofthestudypurpose,patientsweredividedintwo groupsaccordingtothesurgicalapproach;VATS surgeryor conventional open thoracotomy.VATS was definedby the non-use ofrib separation by using a rib retractor, making manualpulmonarypalpationimpossiblebyintroducingone ortwohandsinfull.Theselectionoftheapproachwasdecided by the primary surgeon based on his own criteria and experience.

Datacollection

Thefollowing variables weretaken into account; age, sex, disease-freeinterval(DFI)(definedas;timeelapsedfromthe lastdiseaseepisode,regardlessoflocation,untilthedateof pulmonarymetastasisdiagnosis);preoperativedataincluding serum carcinoembryonic antigen (CEA) level, CT findings (numberandnodulessizeaswellasbilaterallesions),lymph node status according to CT, and when done, positron emission tomography (PET) and PET/CT findings were also recorded,surgicalapproach(VATS,open surgery),typeand extend of surgical resection, postoperative data including;

numberoflungremovednodules,sizeofmetastaticnodules, histologiclymphnodeinvolvement,otherstructuresinvolve- ment,postoperativemorbidity,postoperativemortality,adju- vant treatment, local lung recurrence and recurrent metastaticdiseaseafterthefirstpulmonarymetastasectomy.

M1/CT ratio corresponded to the quotient between the actual number of metastatic lung nodes identified by histopathologicreportaftersurgeryandthenumberofnodes identified by preoperative CT scan. The M1/CT ratio was definedas1or>1.

Statisticalanalysis

Survivalanalysiswas carried out fromthefirst pulmonary metastasectomy date. In bilateral disease cases requiring bilateral procedures, the date of the second surgery was considered. Such survival analysiswas specific fordisease [disease-specificsurvival(DSS)],excludingpatientswhodied in early postoperative period (first 30 days or during hospitalization), and considered censored those who died

fromothercausesdifferentthantheircancerdisease.Disease- freesurvival(DFS)wasdefinedasthetimeelapsedfromthe first pulmonary metastasectomy until the first metastatic lesionregistrationdate.Patientswhowerelosttofollow-up werealsocensored,recordingthetimeuntilthelastdateof knownfollow-upperiod.

The relationship between the clinical and oncological variablesoftheCRCepisodeandthetypeofsurgicalapproach wasanalyzedbybivariateanalysis,usingthechi-squaretest or the Fisher’sexact testforthe comparison ofcategorical variables,andtheStudent’sTtestortheMann–WhitneyUtest forthecomparisonofcontinuousvariables.DSSandDFSwere assessed with the Kaplan–Meier method and differences betweencurveswereanalyzedwiththelog-ranktest.Factors independently associatedwithDSS and DFSwereassessed usingaCoxregressionmodelinwhichallvariableswithap value of <0.2 in the bivariate analysis were included. All hypothesistestswerebilateralandstatisticalsignificancewas setatp<0.05.AnalyseswerecarriedoutusingtheStatistical Package for the Social Sciences (SPSS) version 18.0 for Windows.

Results

Fromthe543initiallyincludedpatients,21wereexcludeddue todifferentreasons,includingduplicatepatient’sinformation in1patient,lackofdataonpulmonarymetastasectomyin7, and metastasectomy performedbefore March 1,2008 in8.

Therefore,thestudypopulationconsistedof522patients,335 men(64.2%),withamean(standarddeviation,SD)ageof64.7 (10.2)yearsold.SurgeryprocedureswerecarriedoutbyVATS in93(17.8%)patientsandbyopenthoracotomyin429(82.2%).

VATS procedure wasnotperformedin11 (34.4%)ofthe 32 participatinghospitals.Resectionsclassificationaccordingto the surgicalapproachisshown inTable 1. Majorresection frequency was significantly different, being much more

Table1–Typeofresectionandsurgicalapproach.

Pulmonarymetastasectomy VATS No.(%)

Opensurgery No.(%)

Total No.(%)

Numberofpatients 93 429 522

Typeofresection(p<0.001)

Pneumonectomy 0 4(0.9) 4(0.8)

Lobectomy 6(6.5) 94(22.1) 100(19.3)

Anatomicalsegmentectomy 1(1.1) 18(4.2) 19(3.7)

Wedge 85(92.4)309(72.7) 394(76.2)

Total 92 425 517^a

Extendedresection(p>0.99)

No 92(98.9)123(98.6) 394(76.2)

Yes 1(1.1) 6(1.4) 7(1.3)

Total 93 429 522

Majorresection(p<0.001)

No 87(93.5)331(77.2) 418(80.1)

Yes 6(6.5) 98(22.8) 104(19.9)

Total 93 429 522

a Incompleteinformationin5patients.

frequentinthethoracotomygroupthanintheVATS group (22.8%vs.6.5%;p<0.001).

Resultsofbivariateanalysisofpreoperativevariablesare shown inTable2.There werestatistically significantdiffe- rences between VATS and open surgery groups, when >1 nodulewasfoundontheCTscan(p=0.048)andwhenthesize ofthelargestnoduleonCTscanwas>30mm(p<0.001),with higherpercentages inopen surgerygroup. Regarding post- operative variables (Table 3), significant differences were found; percentage of nodules >10mm (p=0.015), mean numberoflymphnodesremoved(p=0.022)andlymphnode involvement(N0,N1,N2,andNX)(p<0.001).Alltheprevious differenceswerefoundwithahigherpercentageintheopen surgery group when compared with VATS. Although the postoperativemorbiditywassignificantlylowerintheVATS group(5.4%)thanintheopensurgerygroup(17.9%)(p=0.002), the percentage ofpatientswithpulmonary recurrenceand metastatic disease was similar inboth groups (pulmonary recurrence32.7%vs.34.2%,p=0.810;metastaticdisease71.4%

vs. 67.5%, p=0.730). The postoperative mortality rate was 0.4%, corresponding to two metastasectomies by open

approach because of ventricular fibrillation in one patient andsepsisintheotherpatient.

The different values of the M1/CT ratio were similar (Table 4) regardless the surgical approach, either VATS or thoracotomy. CTand histologicalfindings (M1/CTratio1) agreedin90%ofcases,withoutdifferencesbetweenVATSand open thoracotomy(94.1%vs.89.7%).Fortheremaining10%

disagreement cases (M1/CT ratio> 1), differences between VATSandopenthoracotomywereeithernotfound(8.6%vs.

10%)(Table4).

Fromtheoverallstudypopulation(522patients),2patients diedaftersurgeryand64werelosttofollow-up;therefore,a totalof456patientswereincludedforthesurvivalanalysis.

The median follow-up was 38.7 months (range 0.7–60.3 months). Themedianoverallsurvival was55 months. The surgical approach(VAT vs. opensurgery) didnoeffect the outcome.ThemedianDSSwas47.1months(95%confidence interval[CI]38.2–56.0)forVATSand55.8months(95%CI18.0–

39.4)foropensurgery(p=0.159)(Fig.1).ThemedianDFSwas 28.7months(95%CI18.0–39.4)forVATSand28.1months(95%

CI 22.2–34.0) for open surgery (p=0.955) (Fig. 2). However, Table2–Bivariateanalysisofpreoperativevariables.

Variables Total

No.(%)

VATS No.(%)

Opensurgery No.(%)

pvalue

Totalpatients 522 93 429

Male 335(64.2) 53(57) 282(65.7) 0.12

Disease-freeinterval,months

>12 338(65.1) 65(69.9) 273(64.1) 0.33

>24 182(35.1) 31(33.3) 151(35.4) 0.72

>36 97(18.6) 16(17.2) 81(18.9) 0.77

SerumCAElevel,IU/mL

>5 123(23.6) 26(27.9) 97(22.6) 0.89

>10 67(12.8) 13(14.0) 54(12.6) 0.86

NodulesonCTscan

>1nodule 211(40.4) 29(31.2) 182(42.4) 0.048

>2nodules 105(20.1) 15(16.1) 90(21.0) 0.32

>3nodules 59(11.3) 6(6.4) 53(12.3) 0.14

CTsizelargernodule>30mm 65(12.4) 2(2.1) 63(14.7) <0.001

BilaterallesionsonCTscan 116(22.2) 22(23.6) 94(21.9) 0.78

Clinicallymphnodeinvolvement 381 66 315

N0 351(92.1) 58(87.9) 293(93.0) 0.30

N1 7 2(3.0) 5(1.6)

N2 14 3(4.5) 11(3.5)

N3 9 3(4.5) 6(1.9)

Previoushepaticmetastasis 59(11.3) 9(9.7) 50(11.7) 0.71

Previoushepaticmetastasectomy 55(93.2) 7(77.8) 48(96.0) 0.10

Colorectalcancer 519 93 426

Colon 252(48.6) 49(52.7) 203(47.7) 0.48

Rectum 234(45.1) 37(39.8) 197(42.6)

Colon-rectum 33(6.4) 7(7.5) 26(6.1)

NeoadjuvantchemotherapyforCRC 130(24.9) 22(23.7) 108(25.2) 0.79

CRCstage 514 93 421

StageI,II,III 379(73.7) 74(79.6) 305(72.4) 0.19

StageIV 135(26.3) 19(20.4) 116(27.6)

AdjuvantchemotherapyforCRC 396(75.9) 67(72.0) 329(76.7) 0.35

CAE:carcinoembryonicantigen;CRC:colorectalcancer.

differencesinsurvivalaccordingtotheM1/CTratiovaluefor bothapproacheswereobserved,withamedianDSSof55.8 months (95% CI unknown) for patients with M1/CT1 comparedto35.4 months(95%CI 24.1–46.6)forthose with M1/CT>1(p=0.002)(Fig.3).ThemedianDFSwas29.3months (95%CI22.9–35.7) forthegroup ofpatientswithM1/CT1 comparedto14.2months(95%CI11.7–16.8)forthegroupof patientswithM1/CT>1(p=0.025)(Fig.4).

Inthemultivariateanalysis,majorresectionappearedtobe aprotectivefactorinDSS(hazardratio[HR]0.6,95%CI0.3–09,

p=0.002)andDFS(HR0.5,95%CI0.3–0.8,p=0.001),whereas ageof70yearsoldormore,bilateralhistologicalinvolvement, andhistologicallymphnodeinvolvementwereindependent predictors of DSS. More than 1 nodule reported by the preoperativeCTwasasignificantpredictorofDFS(Table5).

Discussion

Thepresentstudyshowstwomainfindings.Ononehand,it demonstratesthatCRCpulmonarymetastasesresectioncan beeffectivelyand safely performedusingeitherVATS ora conventional thoracotomyapproach. On the other hand,it provesthatopenapproachisnotsuperiortoVATSdetecting Table3–Bivariateanalysisofpostoperativevariables.

Variables Total

No.(%)

VATS No.(%)

Opensurgery No.(%)

pvalue

Totalpatients 522 93 429

Bilateralsurgicalapproach 81(15.5) 19(20.4) 62(14.5) 0.15

Extendedresections 7(1.3) 1(1.1) 6(1.4) 0.99

Numberofmetastasis

>1 179(34.3) 29(31.2) 150(35.0) 0.54

>2 83(15.9) 14(15.1) 69(16.1) 0.87

>3 42(8.0) 5(5.4) 37(8.6) 0.4

Largersizehistologicalnodules

>10mm 359(70.9) 54(58.0) 305(73.3) 0.015

>30mm 70(13.8) 7(7.8) 63(15.1) 0.09

Histologicallymphnodeinvolvement

N0 119(22.8) 3(3.2) 116(27.0) <0.001

N1 8(1.5) 0 8(1.9)

N2 18(3.4) 2(2.1) 16(3.7)

Nx 374(71.6) 87(93.5) 287(66.9)

N1–2–3 26(5.0) 2(2.1) 24(5.6)

Lymphnodesremoved,mean 5.5 2.9 5.6 0.022

Involvementofotherstructures 27(5.2) 6(6.4) 21(4.9) 0.6

Postoperativemorbidity 82(15.7) 5(5.4) 77(17.9) 0.002

Postoperativemortality 2(0.4) 0 2(0.5) >0.9

Adjuvantchemotherapyafterpulmonarymetastasectomy 321(61.5) 56(60.2) 265(61.8) 0.81

Dataexpressedasfrequenciesandpercentagesinparenthesisunlessotherwisestated.

Table4–Percentagesofpatientsundergoingpulmonary metastasectomywithVATSoropensurgeryaccordingto resultsoftheM1/CTratio.

Total No.(%)

VATS No.(%)

Opensurgery No.(%)

pvalue

Totalpatients 522 93 429

M1/CTratio

0.25 6(1.2) 0 6(1.4) 0.161

0.5 32(6.1) 2(2.1) 3(7.0)

0.75 6(1.2) 0 6(1.4)

1 386(73.9) 77(82.8) 309(72.0) 1.5 15(2.9) 2(2.1) 13(3.0)

2 17(3.2) 3(3.2) 14(3.3)

3 5(0.9) 2(2.1) 3(0.7)

5 1(0.2) 0 1(0.2)

1 470(90.0) 85(91.4) 385(89.7) 0.874

>1 51(9.8) 8(8.6) 43(10.0) 0.874

M1/CTratio:quotientbetweentheactualnumberofmetastatic lymph nodes identified by histopathologic examination of the surgicalspecimenandthenumberidentifiedbypreoperativeCT scan.

Fig.1–Disease-specificsurvival(DSS)accordingtosurgical approach:VATSoropenthoracotomy.

hiddenlungmetastasesduringthepreoperativeradioimaging studies.

Afteratleast3years’follow-up,wedidnotobservesurvival differencesbetweenpatientsundergoingmetastasectomyby VATSoropensurgery.However,VATSwasassociatedwitha significantlylowerpostoperativemorbidityand,inaddition, no patient from the VATS group, died. These results are consistentwithapreviousanalysisofmorbidityandmortality of data collected from the GECMP-CCR-SEPAR registry, in which VATS vs. thoracotomy showedan independent pro- tectiveeffect(OR0.3,95%CI0.1–0.8,p=0.01).¹³Theadvantages of the minimally invasive route (including smaller and esthetic wounds,less bloodloss, minorpostoperativepain, lower immunosuppression consequences,fewer postopera- tive complicationsand shortedhospital stay),as compared with more invasive approaches, have been highlighted in differentstudies.^14–16Allthesefactorscontributetoafaster recoveryandpromptuseofadjuvantchemotherapy.

Therateofrecurrenceaftercompletemetastasectomywith bimanual palpationexceeds50%,asexactlyexpectedfora systemicdisease.Thatiswhy,someauthorssuggestthatopen surgicalresectionofallpalpablepulmonarynodulesisnota complete biological resection of all metastatic deposits.¹⁷ However, similar long-term survival outcome for patients undergoingVATSpulmonaryresectionCRClungmetastases andthoseundergoingconventionalopenthoracotomyhave been reportedinnumerousstudies.2,7,15,18,19,8Inagreement withtheseresults,wedidnotfinddifferencesinDSSandDFS, neither in the rate of recurrence of pulmonary disease betweenpatientsundergoingVATSorconventionalthoraco- tomy.Although VATSisanacceptablealternativetothora- cotomy for anatomic lung resection, there is still a large variabilityinitsclinicalapplicationroutine.^20,21

CTisconsideredthegoldstandardtoassessintrathoracic extension before performing metastasectomy, but despite technicalimprovementsinthediagnosticaccuracyofCT,the rateofnon-imagedmalignantpulmonarymetastasisremains around 15–25%.²² Although the sensitivity ofhelical CT to correctly identify histologicallyproven metastases exceeds high-resolution CT (82% vs. 75%), preoperative radiological assessmentoflunglesionssmallerthan6mmisstilllimited.²³ Somestudiesonthedetectionoflungmetastaseshaveshown correlationbetweenradiologicalfindingsandresectedlesions inthesurgicalspecimen.Kangetal.²⁴reportedadiagnostic accuracyof97%forthe1-mmthin-section16-channelmulti- detector rowCT(TSMDCT).Also,inhighlyselectedgroups, thistechniqueallowedtodetectthesamemetastaticnodules asmanualpalpation.²⁴Inpatientswithaunilateralsolitary lesion, the sensitivity of helical CT on the detection of pulmonary metastasis in patients with CRC can reach 95.5%.²⁵ However, discrepancies grow as the nodule count increases.²⁶ Therefore, open procedures theoretically may provide better identification and removal of occulted lung nodulescomparedtoVATS.^11,19Completeremovalofmetas- taticlesionsshouldimprovelong-termsurvivalsinceR0lung resection is the major prognostic factor of survival after metastasectomy. Incomplete resectionis apoorprognostic factor. Nonetheless, persistency of occult residual disease provides abetter prognosis than incomplete excision with evidence of macroscopic disease.²⁷ A review by Patel and Fig.2–Disease-freesurvival(DFS)accordingtosurgical

approach:VATSoropenthoracotomy.

Fig.3–Disease-specificsurvival(DSS)accordingtoM1/CT ratioforbothtypesofapproach(VATSandopensurgery).

Fig.4–Disease-freesurvival(DFS)accordingtoM1/CTratio forbothtypesofapproach(VATSandopensurgery).

DeCamp²⁸justifiedtheunilateralapproachsincetherewasno evidenceofimprovedsurvivalafterabilateralapproach.

Interestingly, disagreement in the detection of lung metastases by CT scan and histological examination (M1/

CT>1)wasfoundinonly10%ofcases.Differencesaccording tothesurgicalapproachwerenotobserved,butpatientsinthe M1/CT>1group,independentofundergoingVATSoropen surgery, had a significantly worse DSS and DFS when comparedwithpatientswithconsistentCTandhistological findings.Therefore,thedecisionofthesurgicalapproachused shouldbemadebythesurgeon responsibleforthe surgery basedonhissurgicalexperienceinbothproceduresandwith thepremiseofbeingabletoresectthetumour‘‘visible’’inthe preoperativeimagingtests.

Regarding lymphadenectomy, a high percentage of patientslackedexaminationoflymphnodes(Nx72%),being evensignificantlyhigheronVATSgroupcomparedtotheopen surgery group. In a previous analysis of the GECMP-CCR- SEPARdatabase,²⁹lymphnodemetastasiswasdetectedin10%

of patients who had undergone lymphadenectomy. 5-year DSS,accordingtolymphnodestatus,was58.3%withoutof lymph nodes involvement vs. 24.8% when positive lymph node was confirmed, and 44% for uncertain lymph node status. Lymphnode involvement increases the riskof late deathandadequatelymphnoderesectionismandatoryinall metastasectomies. The multivariate analysis of our study, shows that histological lymph node involvement and >1 nodule on preoperative CT scan are poor DSS and DFS predictors,respectively,constitutingagroupofpatientswith morediseasethanthatdetectedinthepreoperativestudy,so theyshouldbeevaluatedmorecautiously foralater, more strictmonitoringoradjuvanttreatment.

Thisstudyhasseverallimitationstoconsider. First,the subjectivityoftheradiologistinthenumberandcharacteri- zationofsuspiciousnodulesobservedinthepreoperativeCT.

Ontheotherhand,thisstudybegantocollectpatientsin2008.

During these 12 years the use of the videothoracoscopic approachhasbeenincreasinganditseemssafetoaffirmthat thenumber of pulmonarymetastasectomiescurrently per- formedusingVATSwillexceed17.8%ofourstudy.

Conclusions

Accordingtotheresultsofourstudy,wecanconcludethatthe surgicalapproachusedisnot relatedtoanincreaseinthe

radiopathological discrepancy between the resected and expectedpulmonaryM1s,accordingtothepreoperativestudy bythoracicCT,norisitrelatedwithavariationinsurvival(DSS orDFS).Onlyinasmallpercentageofpatients(10%)willwe findadiscrepancywithmorepulmonaryM1sthanexpected.

However, in this group ofpatients, it is worth noting the worseninginbothsurvivals.Thisworseningcouldsuggestthe existenceofmoretumordiseasethaninitiallyexpected,soit would seem reasonable to assess the possibility of closer postoperative monitoring or to assess its candidacy for adjuvanttreatment.Itwouldbeadvisabletocarryoutfuture studiesaimedatclarifyingthemanagementofthisspecific groupofpatients.

Funding

The GECMP-CCR-SEPAR database was founded by Ethicon Endosurgery.Thisresearchhasnotreceivedspecificaidfrom agenciesofthepublicsector,commercialsectorornon-profit entities.

Conflicts of interest

None.

Acknowledgements

TheauthorsthankMarı´aJose´ Sa´nchezforhelpintheretrieval ofreferencesandMartaPulido,MD,foreditingthemanuscript andeditorialassistance.

Appendix A. Members of the Spanish Group for Surgery of Lung Metastases from Colorectal Carcinoma (GECMP-CCR-SEPAR)

Coordinators: Juan J. Rivas (Hospital Universitario Miguel Servet,Zaragoza)andLaureanoMolins(HospitalUniversitari del Sagrat Cor, Barcelona); Secretary: Rau´l Embu´n (Hospital Universitario Miguel Servet, Zaragoza); Local Heads and Departments: FranciscoRivas (HospitalUniversitari del Bell- vitge, L’Hospitalet de Llobregat, Barcelona); Rau´l Embu´n (Hospital Universitario Miguel Servet, Zaragoza); Jorge Her- Table5–Coxregressionanalysisofdisease-specificsurvival(DSS)anddisease-freesurvival(DFS).

Variables Hazardratio 95%confidenceinterval pvalue

DSSregressionmodel

Age70years 1.6 1.2–2.2 0.002

Histologicallaterality(unilateralvs.bilateral) 2.1 1.5–3.0 <0.001

Histologicallymphnodeinvolvement 0.001

Nx 1.2 0.8–1.9 0.2

N1–2 3.2 1.7–6.2 <0.001

Majorresection(lobectomyorpneumonectomy) 0.6 0.3–0.9 0.002

DFSregressionmodel

>1noduleonpreoperativeCTscan 1.5 1.2–1.9 0.001

Majorresection(lobectomyopneumonectomy) 0.5 0.3–0.7 0.001

na´ndezandJose´ ManuelMier(HospitalUniversitaridelSagrat Cort,Barcelona);Fe´lixHeras(HospitalGeneralUniversitariode Valladolid,Valladolid);JavierdelaCruz(HospitalUniversitario VirgendelRocı´o,Sevilla);MatildeRubio(HospitalUniversitari JosepTrueta,Girona);EstherFerna´ndez(HospitalUniversitari GermansTriasiPujol, Badalona,Barcelona);MiguelCarbajo (Hospital Universitario Marque´s de Valdecilla, Santander);

Rafael Pen˜alver (Hospital Universitario Gregorio Maran˜o´n, Madrid); Jose´ Ramo´n Jarabo (Hospital Clı´nico San Carlos, Madrid); Diego Gonza´lez-Rivas (Complejo Hospitalario Uni- versitario A Corun˜a, A Corun˜a);Sergio Bolufer (Hospital General Universitario de Alicante, Alicante); Carlos Page´s (Hospital General Universitario Carlos Haya, Ma´laga); Sergi Call(Hospital UniversitariMu´tuaTerrassa, Terrassa,Barce- lona); David Smith (Hospital Italiano, Buenos Aires, Argentina); Richard Wins (HospitalClı´nicoUniversitario de Valencia, Valencia); Antonio Arnau (Hospital General Uni- versitario de Valencia, Valencia); Andre´s Arroyo (Hospital Universitario Virgen de la Arrixaca, Murcia); M. Carmen Marro´n(HospitalUniversitario12deOctubre,Madrid);Akiko Tamura(Clı´nicaUniversitariadeNavarra,Pamplona);Montse Blanco(ComplejoHospitalarioUniversitariodeVigo,Ponteve- dra);BeatrizdeOlaiz(HospitalUniversitariodeGetafe,Getafe, Madrid); Gemma Mun˜oz (Hospital Universitario Ramo´n y Cajal, Madrid); Jose´ M. Garcı´a Prim(Complejo Hospitalario Universitario de Santiago, Santiago de Compostela); Carlos Rombola´ (HospitalGeneral Universitario de Albacete,Alba- cete);SantiagoGarcı´aBarajas(HospitalUniversitarioInfanta Cristina,Badajoz);AlbertoRodrı´guez(HospitalUniversitaridel Mar, Barcelona); Jorge Freixinet (Hospital Universitario Dr.

Negrı´n, Las Palmas de Gran Canaria); Javier Ruiz(Hospital Universitario Virgen de las Nieves, Granada); Guillermo Carriquiry (Hospital Maciel, Universidad de la Repu´blica, Montevideo,Uruguay);Moise´sRosenberg(InstitutoOncolo´gico Alexander Fleming, Buenos Aires, Argentina); and Emilio Canalı´s(HospitalUniversitari.U.JuanXXIII,Tarragona).

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