Measurement of primary tumor volume by PET–CT to evaluate risk of mediastinal nodal involvement in NSCLC patients with clinically negative N2 lymph nodes

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Original

research

article

Measurement

of

primary

tumor

volume

by

PET–CT

to

evaluate

risk

of

mediastinal

nodal

involvement

in

NSCLC

patients

with

clinically

negative

N2

lymph

nodes

Andrzej

Lebioda

a,∗

_{, Roman}

_Makarewicz

a

_,

_Bogdan

_Małkowski

b,c

_,

_Maciej

_Dancewicz

d,e

_,

Janusz

Kowalewski

d,e

_,

_Wieslawa

_Windorbska

f

a_Clinic_of_Oncology_and_{Brachytherapy,}_Collegium_Medicum_of_Bydgoszcz,_Nicolaus_Copernicus_University_in_Torun,_Poland b_Department_of_Nuclear_Medicine,_Center_of_Oncology_in_Bydgoszcz,_Poland

c_Department_of_Positron_Emission_Tomography_and_Molecular_Imagining,_Collegium_Medicum_of_Bydgoszcz,_Nicolaus_Copernicus

UniversityinTorun,Poland

d_Department_of_Thoracic_Surgery_and_Tumors,_Collegium_Medicum_of_Bydgoszcz,_Nicolaus_Copernicus_University_in_Torun,_Poland e_Department_of_Thoracic_Surgery_and_Tumors,_Center_of_Oncology_in_Bydgoszcz,_Poland

f_Department_of_{Radiotherapy,}_Center_of_Oncology_in_Bydgoszcz,_Poland

a

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t

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o

Articlehistory:

Received8September2011 Receivedinrevisedform 31July2012

Accepted27November2012

Keywords: Tumorvolume Nodalmetastases

Mediastinallymphnodestatus PET–CT

Non-smallcelllungcancer

a

b

s

t

r

a

c

t

Aim:Thestudy aimedtodetermine aprognosticvalueofprimarytumorvolume mea-suredonthebasisofintegratedpositronemissiontomography–computerizedtomography (PET–CT)intermsofmediastinalnodalmetastases(N2)predictioninnon-small-celllung cancer(NSCLC)patientswithPET–CTN2negativelymphnodes.

Methods:Therecordsof70potentiallyoperableNSCLCpatientstreatedwithsurgical resec-tionwereanalyzed.Allpatientsunderwentdiagnostic,preoperativePET–CT,whichwasthe basisfortumorvolumecalculationsaswellastheevaluationofN2nodesstatus.The logis-ticregressionanalysiswasemployedtodeterminecorrelationbetweenmediastinalnodal involvementandvolumeofprimarytumor(izoSUV2.5volume),thatisthevolumeof pri-marytumorinsideSUV2.5line,tumorhistology,location(peripheralvs.central),hilarnode status.

Results:Astatisticallysigniﬁcantcorrelationbetweenmediastinalnodeinvolvementand izoSUV2.5volume,tumorhistology,locationsperipheralvs.centralandhilarnodestatus wasfound.Theriskofmediastinal lymphnodemetastasisis24%fortumorvolumeof 100cm3_and_increases_up_to_40%_for_tumor_volume_of₃₆₀_cm3_._An_increase_of_tumor_volume

by1cm3_increases_the_risk_of_lymph_node_disease_by_0.3%._Tumor_histology_{adenocarcinoma}

vs.squamouscellcarcinomaincreasestheriskofmediastinallymphnodeinvolvementby 195%,locationcentralvs.peripheralby68%andhilarnodeinvolvementby166%.

∗ _{Corresponding}_author_at:_Clinic_of_Oncology_and_{Brachytherapy,}_Collegium_Medicum_of_Bydgoszcz,_Nicolaus_Copernicus_University_in

Torun,Romanowskiej2St.,85-796Bydgoszcz,Poland.Tel.:+48523743320;fax:+48523743432. E-mailaddress:lebiodaa@co.bydgoszcz.pl(A.Lebioda).

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Conclusions:ThestudydemonstratesthatizoSUV2.5volumeofprimarytumormaybe con-sideredasaprognosticfactorinNSCLCpatients,sinceitstronglycorrelateswithmediastinal lymphnodepathologicalstatus.Thiscorrelationismodiﬁedbyprimarytumorlocation, histologyandhilarnodeinvolvement.

1. Background

Themostabsorbingissueinmodernoncologyof non-small-celllungcancer(NSCLC)istheimplementationofintegrated positron emission tomography–computerized tomography (PET–CT) to the diagnostic process. PET–CT offerssuperior sensitivityandspecificitycomparedtoCTorPETaloneand may improve staging accuracy. Mediastinal lymph nodes status in NSCLC patients has important therapeutic and prognosticimplications.Thecurrentconsensusisthata posi-tivemediastinalnodaluptakeonPET–CTshouldbeverified histologically by mediastinoscopyor transbronchial needle aspirationwhilenegativeuptakeinthemediastinumshould proceedtoresection.AsignificantproportionofPET–CT medi-astinumnegativecaseswillturnouttobepositivefollowing resection.Thereisahighprobabilitythattumorvolumehas greatvalueinpredictinglymphnodeinvolvement,afeature, whichdecreases5-yearsurvivalby30–40%.

1.1. Aim

Thestudyaimedtodetermineaprognosticvalueofprimary tumorvolumemeasuredonthebasisofPET–CT(izoSUV2.5 volume)intermsofmediastinalnodalmetastasesprediction inNSCLCpatients.

2. Material

and

methods

2.1. Selectionofpatients

BetweenSeptember2008andDecember 2009,atotal num-ber of 70 consecutive potentially operable NSCLC patients weretreatedwithacurativeintent.From thetotalnumber of425evaluatedbyPET–CTnewlydiagnosedNSCLCpatients, 355 (83%) presented a more advanced disease. Diagnostic PET–CTperformedinall70didnotdepictmediastinallymph node involvement(PET–CTN2 negativepatients). Allthese patientsweretreatedradically,62ofthemunderwent anatom-icalresectionsand8ofthemwedge resections.Asregards anatomicalresections, 8pneumonectomies – allleft-sided, 6inferiorbilobectomiesand 48 lobectomies(22 right-sided and26left-sided)wereperformed.Allpatientsunderwenta systematiclymphnodedissectionandwerethenexamined pathologically.Thepatientsweregivenantibioticsand anti-thromboticprophylaxisperioperatively.

Themeanageofpatientswas63years,rangingfrom22 to78;44 ofthem weremale(62.9%)and 26female(37.1%). Theclinicalstagingwasbasedonthefollowingcriteria: gen-eralclinical examination,biopsy,routineblood cellcounts, bloodchemistryproﬁle,chestX-rayandchestCT,abdominal

ultrasonography,bronchoscopyandpulmonaryfunctiontest. Thepathologicaldiagnosis ofmostpatientswassquamous cell carcinoma in 35 patients (50%),adenocarcinoma in 26 (37%), largecellcarcinomain8(12%)and mucoepidermoid carcinomain1(2%)case.Thegradingwas:G1in1,G2in28, G3in17andunknownin24cases.Primarytumorstagewas T1in23,T2in35,T3in12 patients.Therewere33PETN1 positivecasesand37negativeones.Peripherallocationwas determinedin55patientswhilecentralin15.

2.2. Imageanalysis

AllpatientsunderwentPET–CTexaminationasaroutine pro-cedurebeforethedecisionofsurgery.Thewholebodyscan (Biograph 6and Biograph 16,Siemens, Erlangen, Germany) wasperformedfortheevaluationofprimarytumor,lymph node involvement, distant metastases and tumor volume computations.Allpatientswerefastedforatleast6hbefore theexamination.Bloodglucoselevelsweredeterminedbefore injection of 5–7MBq/kg [18_{F]ﬂuorodeoxyglucose} _(FDG). _FDG was produced in our own laboratory. Sixty minutes after administrationofFDG,PET–CTscanswereobtainedfromthe skullbasetothe¼upperlevelofthehips.DiagnosticCTwas done in6–7 beds,2mineach, ofPETimagining performed according tothe heightofthe patient. Imageswere recon-structedusing3Diterativereconstruction.1,2

WholebodyimagesinDICOMformatsweresentonlinevia PACSsystem (Siemens,Erlangen, Germany) totheexternal beamradiotherapytreatmentplanning system.Tumor area was identiﬁedand delineatedon each PET–CTscan bythe oncologistwiththeassistanceofanuclearmedicine special-ist,who wasunaware ofclinical and pathologicalﬁndings. IzoSUV2.5volumes,thatisthevolumeofprimarytumorinside SUV2.5line,werecalculatedautomaticallyusingtheTrueD radiotherapytreatmentplanningsystem(Siemens,Erlangen, Germany;Fig.1).

Lymph nodes greaterthan 10mminthe shortaxis and SUV>2.5wereinterpretedasmetastatic.

2.3. Statisticalanalysis

Pathologically confirmed mediastinal lymph node involve-mentwastheendpointofthestudy.Thecorrelationbetween mediastinal nodal metastasis occurrence (pathologically confirmed)andsuchparametersas:izoSUV2.5volume,SUV max,tumorpathologicaltypeandgrade,primarytumorstage, diameterandlocation(peripheralvs.central),hilarnode sta-tus(PETN1)aswellaspatient’sageandsexweredetermined usingtheunivariatelogisticregression.Correlationbetween statistically significant variables and lymph node involve-mentwereassessedusingthemultivariatelogisticregression

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Fig.1–PET–CTscan–delineatedtumor(whiteline)is

visibleasahigh-signalmasscomprisingtheperipheral

partofthelung.ThecalculatedizoSUV2.5volumeof

primarytumor,withoutN1mass,isshown.

analysis.Oddsratio(OR)andits95%confidentialinterval(CI) wereestimated.Additionally,asigmoidriskcurvewasdrawn and its coefficient was obtained. Themaximum likelihood method enabled drawing the best adjusted risk curve and assessingastatisticalsignificanceoftheadjustment.Avalue of p=0.05 was accepted as statistically significant. Tumor volumes were computed for both distinguished patient groups,withand withoutmediastinallymphnode disease, and compared with the t-Student test. All the calculations weremadeusingtheStatistica’99software.3

3. Results

Mediastinalnodalmetastases(pN2+)werefoundin16(23%) outof70operatedpatients.Thus,54(77%)outof70patients representedanegativemediastinallymphnodestatus(pN2−). Inthewholegroupofpatients,approximately9.1lymphnodes (standard deviation(SD) 5.3;range 1–27) were removed.In groups(pN2+) and(pN2−), approximately10 (SD5.8;range 1–23)and8.8(SD5.1;range1–27)lymphnodeswereremoved, respectively. In the mediastinal lymph node involvement groupavesselembolismofneoplasmcellsin5patientsand anextracapsularinﬁltrationin4otherswereobserved.

Themean izoSUV2.5 volumewas 45cm3_, _SD ₉₉_cm3_. _In patientswithnodalmetastasesizoSUV2.5volumeswere sig-niﬁcantlyhighercomparedtothoseinpatientswithnonodal involvement:65.9cm3_,_SD_113.5_cm3_vs._40.9_cm3_,_SD_91.3_cm3_;

ttestp=0.003(Fig.2).

In the univariate logistic regression analysis the statis-tical signiﬁcance was found forsix parameters: SUV max, izoSUV2.5volume,tumorhistologytype,stageandlocation peripheralvs.centralandhilarnodestatus(Table1).

Fig.2–Tumorvolumeparameterscategorizedintotwo

groupsaccordingtothestatusofmediastinallymphnodes,

pN2positive(metastatic)lymphnodes,pN2negative(free)

lymphnodes.

Inthemultivariatelogisticregressionanalysisthe statisti-calsigniﬁcancewasfoundforfourparametersonly,including izoSUV2.5volume,tumorhistologytype,locationperipheral vs.central,hilarnodestatus(Table2).

Fig. 3 represents the risk of mediastinal lymph node involvementasa functionofizoSUV2.5volumedeﬁnedon the basisofPET–CTimages.Theprobability ofmediastinal lymphnodemetastasisis24%fortumorvolumeof100cm3 and increasesupto40%fortumorvolumeof360cm3_._The logisticregressionanalysisshowedthateach1cm3_of_tumor volumeincreasestheriskofmediastinallymphnode involve-mentby0.3%,withoddsratioof1.0034.Themodelpredictsa 23%riskforthe“0”cm3_izoSUV2.5_volume_(invisible_tumor). Tumor histology adenocarcinoma vs. squamous cell carci-nomaincreasedtheriskofmediastinallymphinvolvement by195%.Tumorlocationcentralvs.peripheralincreasedthe risk ofmediastinallymphinvolvementby68%. PET–CTN1 metastatic featureincreasedthe riskofmediastinallymph involvementby166%.

Fig.3–Relationshipbetweentheriskofmediastinalnodal

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Table1–Theriskofmediastinallymphnodeinvolvement,theunivariatelogisticregressionanalysis.

Oddsratio Conﬁdenceinterval p-Value

−95% +95%

izoSUV2.5volume 1.0022 1.0006 1004 <0.001

Locationperipheralvs.central 1.45 1.02 2.22 0.04

HPadenovs.squamous 2.1 1.6 2.9 <0.001

N1PETvs.N0PET 2.38 1.6 3.4 <0.001

Tstage 1.31 1.00 1.73 0.04

SUVmax 1.05 1.00 1.12 0.02

Table2–Themultivariatelogisticregressionanalysis,theriskofmediastinallymphnodeinvolvementasafunctionof independentvariable.

Oddsratio Conﬁdenceinterval p-Value

−95% +95%

izoSUV2.5volume 1.0034 1.0015 1.0053 0.0004

Locationperipheralvs.central 1.68 1.02 2.77 0.04

HPadenovs.squamous 2.95 2.02 4.30 <0.001

N1PETvs.N0PET 2.66 1.76 4.02 <0.001

Tstage 0.5

SUVmax 0.2

Fig.4presentstheriskofmediastinallymphnode involve-mentasafunctionofizoSUV2.5volumeandtumorhistology.

4. Discussion

According to expectations, a statistical signiﬁcance was demonstratedbetweentheizoSUV2.5volumeandmediastinal lymphnodeinvolvementrisks,assessedpathologically.

Asamura4_found_that_among_patients_with_resected

periph-eral NSCLC, the prevalence of lymph node metastases increasedfrom19.5%intumors2.0cmorsmallerto32.5%in tumors2to3.0cmindiameter.LikeStiles,5_he_highlights_that

inthegroupofprimarytumors0–2cmvs.>2cmtheriskrises 2.4times.

Lee6_discovered_a_growing_risk_of_{micrometastasis:}_4.8%,

6.5%,6.3%,57%forprimarytumors0–2,2.1–4,4.1–6and>6cm indiameter,respectively.

Fig.4–Relationshipbetweentheriskofmediastinalnodal

involvementandtumorvolumeaccordingtopathological

type,adenocarcinoma–dashed,squamous–dottedline.

In ourresult, the23% incidenceofoccultpN2 metasta-sisapproachedthatgivenbyMelek20.3%,7_Periguad8_19.6%,

Al-Sarraf9 _16%, _Tournoy10 _16%, _Gomez-Caro11 _14.4%, _who

recruitedfromasimilargroupofpatients.Atthesametime, however, there is much concern about our cutting point (SUV2.5and1cminshortaxis)whichcouldbesuggestedas beingtooliberal.

Current evidence conﬁrms that there is a connection between adenocarcinoma and an increased risk of under-staging:our resultssupportthisthesis. Suchoutcomesare alsopresentedbyGomez-Caro,11_Melek,7_Lee,6_Carnochan,12

Bille,13_Stiles.5

WeagreewithGomez-Caro11_and_Cardia14_that_such

vari-ablesassideandagearenotinﬂuential.Butincontrasttous, theydonotindicatethesigniﬁcanceoftumorsize,butgender role.

Thefeatureofprimarytumor,whichisconverselyassessed astheriskfactorofincidenceofoccultN2disease,isSUVmax. Lee6_concluded_that_tumors_with_occult_N2_metastases_had_a

signiﬁcantlyhighermedianSUVmaxcomparedwiththose withoutN2disease:6.0g/mLvs.3.6g/mL.Andtheprevalence ofoccultN2diseaseincreasedsigniﬁcantlyfrom1.9%to10.5% whenSUVmaxoftheprimarytumorexceeded4.0g/mL.

Downey15_also_noted_that_uptake_in_patients_with

patho-logicalnodalinvolvementwashigherthaninthosewhowere N0too.ThemeanSUVinN0patientswas8.9±6.3andthe mean SUVinN1–2patientswas 13.6±6.9. Inthis observa-tion,tumorvolumecompoundisneededtoassessthemean SUVofprimarytumor.Inourgroupofpatientswedidnot found statistically significant differences between the SUV maxofprimarytumorinbothsubgroups,pN2negativevs. pN2positive,inthemultivariatelogisticregressionanalysis. ThestatisticalsignificanceoftheSUVmaxisdisappearingfor thebenefitofizoSUV2.5volume,whichbetterexplainstherisk ofmediastinalnodalmetastases.

Thecoexistenceoftwoindependentvariables,i.e.thesize ofprimarytumorandhistology,issuggestedbyCasali16 _in

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and,asaresult,prognosis.Thesetwofactorsarerelevantin ourmaterialaswell.

Kanzaki17 _demonstrated _that _{adenocarcinoma,} _tumors

locatedinthe upperormiddle lobe,tumorsize>3cm,and SUVmaxofprimarytumor>4.0g/mLareriskfactorsforoccult MLNmetastasis.

ThelimitofresolutionforthePET–CTsystemcanexplain themajorityoffalsenegativecases.8Theothercausecouldbe acentraltumorlocation,whichobscuresadjacentlymphnode invasion.9_On_the_other_hand,_the_presence_of_air_in

surround-ingstructures(lungs)makesultrasoundvisualizationofthe lymphnodesimpossibleinoppositiontoe.g.headandneck cancerpatients.18,19

Ourprincipalfindingisthecorrelationbetweentumor vol-umeandlymphnodestatus.Thefrequencyoflymphnode metastases wassignificantly higherin patientswithlarger tumorvolumescomparedwith thosewith smallerones. A changeoftumorvolumeby1cm3_highly_alter_the_risk_of medi-astinalnodalinvolvementby0.3%.Thisrelationismodified aswellbyhistology,tumorlocationsandhilarnodes involve-ment.

It is a well known fact, however, that, apart from dis-tantmetastases,positive mediastinallymph nodesare the mostsigniﬁcantprognosticfactorsforrecurrenceanddeath inNSCLCpatients.

Werealizethata relativelysmall groupofpatientsthat mighthaveinﬂuencedthestatisticalpoweroftheanalysisis ameaningfullimitationofourresults.However,the impor-tantfactisthatourmodelallowedustodistinguishagroupof patientswhoseriskoflymphnodediseaseislow,forexample lessthan25%or33%(predictedforthevolumeof48cm3_and 210cm3_,_{respectively).}_A_more_pronounced_risk,_for_example greaterthan50%(predictedinourmodelfor540cm3₎_could suggestanalterationintreatmentstrategy,forexample an exclusionofsurgery.Unquestionably,furtherstudies,witha highernumberofpatients,arerequiredtoconﬁrmthe pre-sentedpreliminaryresults.Sofar,ourretrospectiveresearch, restrictedtoonehospital,doesnotallowustosuggestany strongrecommendationsonchangingthetreatmentprotocol, dependingontumorvolumeandthustheriskof mediasti-nalnodemetastasis.Thisisonlyamonographtodiscussthat topicaswellasthecost-effectivenessaspect.20

Conﬂict

of

interest

Theauthorsdeclarethattheyhavenoconﬂictofinterest.

Financial

disclosure

Nonedeclared.

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