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Page 1of24 between this versionandtheVersionrecord. Pleasecitethis articleasdoi:10.1002/hep.28895. through thecopyediting, typesetting, paginationandproofreadingprocess, whichmayleadtodifferences This istheauthormanuscript acceptedforpublicationandhasundergone full peerreviewbuthasnotbeen Conflicts of Conflicts Interest: AHRQ. or doesand authorsnot necessarily offi represent the Centered ResearchOutcomes HS022418).(R24 cont The Key Words: 753908887 Dallas TX Title:Running HinesHarry 5959Blvd, 1, Suite POB 420 DivisionDigestive Liverof and Diseases Scholar Dedman ofClinical Care Correspondence Financial SupportFinancial An AssessmentAnofBenefits and Harmsof Hepatocellul Omair Atiq Omair 1 Department of Department Internal Medicine,MeSouthwesternUT 2 Email: Fax:2146456294 2146456029 Tel: University SouthwesternTexas of Harold C. SimmonsCancer HaroldC. Center, SouthwesternUT Me 3 Department ofClinical Department UTSciences, Southwestern Me 4 Surveillance,screening, liver cirrhosis,cancer, Department ofSurgery, Southwestern Department MedicalUT Cent 1

,Jasmin Tiro

Accepted ArticleParikh Harmsof HCCSurveillance 4

Department ofMedicine, UniversityDepartment Michigan, of Ann : Amit G. Singal, M.D., Amit G. M.S. : : workThiswaswith conducted support from theAHR 4 ,Caitlin Murphy None oftheauthors haveany relevantconflicts of This article isprotected by copyright. All rights reserved. 2,3 [email protected] , Adam C.Yopp Adam , HospitalSystem,Dallas, TX Patients with CirrhosisPatients with 3 , Katharine McCallisterKatharine , Hepatology

4 ,AdamMuffler cialviewsNational of the ofInstitutesHealth entis solely the responsibility the of dical Center and dicalCenter HealthParkland harms 1 3 arCarcinoma Surveillance in

,JorgeA.Marrero , Amit G. Singal Amit G. , dical Center, Dallas, dicalTXCenter, dical Center, Dallas, dicalCenter, TX er, Dallas,er, TX Arbor, MIArbor, Q Center PatientQ for interest to discloseinterest to ,,31,2,

1 , Neehar D.,

AASLDAmericanAssociation– Study Liver the for of alphaAFP– fetoprotein ALT – alanine ALT aminotransferase – aspartateaminotransferaseAST NCCNNationalComprehensive– NetworkCancer HCChepatocellularcarcinoma– INR – international– INRnormalized ratio NASHnonalcoholic– steatohepatitis hepatitis BHBV virus hepatitisHCVvirus– C – transarterialTACE chemoembolization EMRelectronic– medical record –immunochemical FIT fecal test Abbreviations

Accepted Article

Hepatology Hepatology

Diseases 2

Page 2of24 Page 3of24 Although surveillanceAlthough and ultrasound alpha fetoprot determiningthevalue of hepatocellularcarcinoma ( harmsdownstream from befollowup must tests weigh Conclusions: 95%CI1.263.38),2.06, hepatologyand subspecialty werewith associated elevated levelALT1.87, 9 (OR harm thanrelated AFPrelated harmvs. (22.8% 11.4% werephysical observed harms (27.5%)187in patient stagebetween tumor andultrasound AFPdetected tu had apatients proportion higher ofearly HCC(70.2 31.2%ultrasound, byand AFP, by25.0% bothsurveil period.study3year Of the48 (61.5%)HCCidentifi logistic identifiedregression. 680 cirrhosispa We demographicclinicaland correlates ofsurveillance performedproceduresother forpositivein false or andtreatment, surveillancerelatedphysical harms, recordedWe surveillancerelated benefits, defined with cirrhosispatients followedsafetyneta he at undergoing patients HCC surveillance. conducted We were to characterizewere to prevalence ofcorrelates and ABSTRACT

screening programsinscreening clinical practice. Interventionsareneeded toreducesurveillancerel positiveindeterminate or surveillance – tests more

Accepted onefourthofpatients Over withexperie cirrhosis Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology althsystembetween JulyJuly and 2010 2013. tients,ofwhomdeveloped 78 HCCduring the determinate determinate surveillanceresults.Socio surveillanceand benefits oftenultrasound related to thanAFP. harms wereharms evaluated using multivariable ated harm to increaseharm to ated thevalueHCC of as early as detection tumor curativeand ed viaed surveillance, were43.8%by detected defined asor CTMRI orbiopsies,scans, % vs. 40.0%,vs. % p=0.009), withdifference no in HCC) programs.screening ein(AFP)have minimal directharm, 5%CI1.262.76), thrombocytopenia (OR care 95%CI1.63,care (OR 1.092.42). s, withhigher a s, proportion ofultrasound lance tests. Surveillancedetected lancetests. aretrospective cohort amongstudy mors (p=0.53).mors Surveillancerelated , p<0.001). , Surveillancerelated harms ed againsted surveillance benefitswhen nce physicalnce harm false for harms inharms cirrhosis Our study’saimsOur 3

complications. abnormalwithFITassociated is withofperfor risk cancer colorectal screening has directharm minimal physicalsignificant and For exampfinancial harms. short duration.followup retrospectivedesigninwith inherentlimitations i andemonstrate association with improvedearly dete cirrhosis. withoutwithultrasound,alpha or fetoprotein(AFP) Nationaland (AASLD) Comprehensive Cancer Network ( for patientsdiagnosedforat earlyan stage. patientswithfor HCCon depends tumor stageat dia undergo biopsy,which undergo associatedis withof risks b lesionliverdefinitivelycannot be characterized o INTRODUCTION

the leadingthe fifth cause inUnited the States. CT and/or MRI,CT which areassociated with radiation evaluationdiagnostic protocols. Liver lesions foun directno and physicalhowever, harms; arethere po programs. is projectedistobecome the3 commonthe most primary livertypeof is cancer, ra did not characterize didnot potential physical, financial Severalincluding societies, theAmerican Associati Primary liverPrimary leadingthecancersecondis cause of Data for both Data benefitsfor andare neededharms dete to 4, 5 8 Experience with cancerother screening programsde Several studiesevaluating HCC surveillance among

Accepted9 , 1 0 Article

Hepatology Hepatology 1 incidenceThe ofhepatocellularcarcinoma (HCC), ncludingleadtime lengthtime bias, bias, and and/or psychologicaland/or harms. n crosssectionaln imaging, patients may ation, bleeding, ation, anesthesiaand d on ultrasoundon d aretypically evaluated with ,atsixmonth intervalsin patientswith leeding, leeding, tumorseeding,injury and tonearby le, use ofuse immunochemical le, fecal test (FIT)in pidlyin increasing the States,itUnitedand exposure, contrastinjury,cost.and tential “downstream”tential harms associated with s, buts, followupcolonoscopy among those gnosis, with gnosis, curative onlyoptions available

ction and ction overall survival were but measured HCCsurveillance measured and benefits NCCN),recommend surveillance using on for the Study on the for ofLiver Diseases cancerrelated death worldwideand rminethevalue of cancerscreening monstrates thepotentialmonstrates for patientswith cirrhosis FP hasFPdiscomfort minimal 6, 7 2 The prognosis The

11, 12 If a If 4

Page 4of24 Page 5of24 approvedby the Institutional ReviewUT of So Board JulyJulyand 2010demonstrate 2011 to Parkland was werehave required atoutpatientto one least clini with signsimaging ofportalhypertension va(e.g., definedcirrhosis,stage as on4 fibrosis liver bio StudyPopulation METHODS relatedharms to diagnosticfollowup testingpain characterizewasstudy to prevalencecorrelates and 572.4) specific andcirrhosis for 456.1, (456.0, 45 456.2, residents. HCCincludingcare,surveillance tesdiagnosticand offersParklanda scalesliding whichfee program, currentlyprovidesand inpatient outpatient care fo allsharinghospital– the same comprehensiveelect aneighborhoods, hepatology clinic,outpatient a mu healthintegrated systemcomprisedof twelveprimar HospitalSystem,andHealth thesafetynet health s organs.

outcomes directlyoutcomes relatedtoHCC surveillance cl in acknowledged,no study has thequantified frequency andsurveillance potentialphysical tests harmsfor 15 We conducted We a retrospectivestudypatiencohort of Patients with Patients cirrhosiswere identified bysetof a 13, 14 . . One authoradjudicated (O.A.) cases to confirm th

Accepted Article theAlthough imperfectsensitivity and s (~6065%)

This article isprotected by copyright. All rights reserved. Hepatology Hepatology psy or a cirrhoticappearinga psy or liver abdominalon 6.21, 567.23, 571.2,567.23,6.21, 571.5, 572.2, and572.3, c visitHCCone c and betweensurveillance test rpatientsover2000 withDallas.in cirrhosis rices, ascites, splenomegaly).ascites,rices, All patients tients with cirrhosis.tients from theseprocedures from have been inicalpractice providesaccesstoprimary subspecialtyand ystemDallas County. for anisParkland ting, at ting, uninsuredlow Dallas for cost County ltidisciplinaryaand HCC clinic, tertiary ronicmedical (EMR).recordParkland ofHCC surveillance and physicalbenefits ycareprovider clinics lowincomein uthwestern Medicaluthwestern Center. or severity or oftheseharms as adverse their their home.medical study wasThis ICD9 codes, ICD9 which are highly sensitive eydiagnosticmet criteria for ts with cirrhosists at Parkland followed pecificity(~7095%) of 4, 6, 74, 6, . Therefore,aim of our. the 5

HCC (155.0) andHCCprospectively (155.0) a list maintained of diagnosed cirrhosis with HCCtheperiostudyduring stageandearly tumor 2) ofproportionHCC patients HCCSurveillance Receipt discussionthroughestablish to consensus. independentlyand verified bysecond a investigator and imagingdata resultstheEMR. from All records CollectionData

Benefits ofHCC Surveillance Benefits indeterminateand if ≥11 upper limit ng/mL, the of the AASLD the guidelines HCCsurveillanceisParkland typicallyat performed positive if positive≥20ng/mL,the most if common usedcutoff 1 orcmunclear< if present,ismasse.g. coarse e normal (no suspiciouspositivemasses), (suspicious were classifiedenzymes, nonsurveillance as cases. exams exams. Imaging performed diagnostic reasofor “surveillance”,“screening”, “ruleoutHCC”, and “c AFP(surveillanceand diagnostic) and vs. test resu imaging orders, reports, associatedand clinical no manuallyWe abstracted oninformation patientdemog Benefits ofHCC surveillance Benefits included:1)propo the

Hepatology Hepatology irrhosis”were classified surveillance as normal, but<20normal, ng/mL. chotexture). AFPchotexture). wereresults considered tes to determine intenttes to ultrasound of exams lts. Ultrasounds lts. with indicationsincluding allHCCpatients seen Parkland the in usingultrasound, with orwithoutper AFP, (A.S.). Discrepancies wereresolved werereviewed investigatorone by (O.A.) eligible curative Patientstreatment.withfor d wered identifiedusing ICD9codes for liver cm),or≥1massindeterminate (mass for HCCsurveillance for clinical in practice whetherrecordedultrasounds wereWe ns, e.g. abdominalns, elevated liverpainor rtion ofHCC patients rtion detected atan 10 and Julyand were10 2013 abstracted. raphics,clinical history,laboratory y reviewed imaging yimaging reviewed 16 , , 6

Page 6of24 Page 7of24 diagnostic criteriadiagnosticbased AASLDon guidelines. single CT scan.CT accountsingle To differentdegreesfor of livera biopsy iscomplication clinically more sign one andtest followupphysical harm. surveillance of during theperiod,studyresults so definitewere mass) classified physical as harms. W indeterminatefor surveillanceresults (e.g. mass < intervalrecommendshort ultrasoundrepeat indefor AASLD results. and EASL guidelinesboth recognize t MRI,liver (CT, biopsy,angiogram) performed fa for each definedsurveillance for test resultperperso surveillance wasthat classifiedtest as abnormal. PhysicalofHCCHarms Surveillance localablative systemic > TACE therapychemothera > a algorithmused basedtrumping on survivalbenefit resectionsurgicalorlocal ablativepa therapy. In HCCsupportivecare. was treatment considered curat ablativetransarterial therapy, chemoembolization ( States. ofTreatmentHCC was livercategorized as t usingMilandefined commonthe Criteria, most crite studiesbyinterpreted imaging byat radiologistso diameter, maximum ofandvascular presence invasion MultidisciplinaryClinic.Tumor Liver

There is variationis in There clinical significanceamong m

Accepted indicationUsing andtest wetest results, identifi Article

Allwere HCC adjudicatedcases confirm theyto met Hepatology Hepatology 4 characteristics,Tumor includingnodules, tumor ificant ificant than theoreticalradiation harm froma tients who receivedtients multiple wetreatments, it was it possiblepatientshave to for thanmore n. Physical n. includedharms any tests followup A binaryA outcome ofphysical washarm ur institution, earlyur and stageHCC was 1 orcmnodular coarsewithoutechotexture TACE),systemic orchemotherapy,best harm based exposure on andto radiation lse positivelse orindeterminate surveillance ria liverfor transplantationUnited the in e allrecorded performed tests followupfor (livertransplantationsurgical > resection > terminate terminate results; therefore, followup tests ransplantation,surgical localresection, he lowhe diagnostic yieldof and testing py). iveitconsisted if of liver transplantation, or distant or metastases, were determined edthesubsetofpatients whoa had easuredphysicalFor example, harms.

bilirubin,(ALT),albumin, internationaland normal includedcount,platelet creatinine,aspartate amin severe/uncontrolled Laboratoryper clinical notes. encephalopathywas none,orcategorizedmildcon as infection,HBVinfection, a heavyor alcohol histor aswere NASHclassified if evidencethey had ofthe ifthey cirrhosis documented a hadhistory ofheavy ofHBV presence surfaceor viralantigen load. Pati ofa positivepresence HCV antibody,viral orload, nonalcoholicdisease, steatohepatitis (NASH),and o liver disease,of including hepatitisvirus C(HCV) abstracted fromlaboratoryand clinicaldata notes. decompensation(ascites encephalopathy),orhepatic a cutoff using of30.Data regarding underlying li usingcalculatedheight and atweightindex the vis CorrelatesofSurveillance Harms indeterminate tests. thosewho as invasive undergo such procedures, l as as thosewhoharm” underwent and/orCTmultiple MRI who those havesingle a orCTdiagnosticMRI encoun MRI,anyor biopsyCT, followup positive orinfor harm, harm,mildmoderate harm, and severeharm). “ invasivewe procedures, describedalso surveillance

Age, andAge, race,gender, ethnicity were recorded for

Accepted Article

Hepatology Hepatology verdiseaseetiology, presenceof , hepatitis B, virusalcoholrelated(HBV), liver y. Degree ofascitesDegreeandy. hepatic ized(INR). ratio determinate determinate surveillance “mildtests; harm” as otransferase (AST),otransferase alanine aminotransferase dataofinterest time from ofindex visit We classified patientsaccording etiology We to HBVgenotype.infection was bydefined the it and dichotomizedand it (obesenonobese)vs. ents were determinedents tohave alcoholrelated alcoholtheinclinical use Patients notes. metabolic syndrome theinabsence ofHCV related harmrelatedan as ordinal variable (no ther.HCVinfection was bydefined the iverbiopsyangiogram, positiveor for or and receiptofhepatology carewere trolled ontrolled ormedications, No harm”No waspatients as defined without ter withouttercomplications; “moderate exams;and harm” was“severe defined eachpatient. Body indexmass was 8

Page 8of24 Page 9of24 AFP). Further, AFP). thestratified analysisinfor be can conjunctionwith ultrasound positiveindeterminate).vs. Inrecognition ofthe stratifiedwholeand cohort by surveillance ty test Statistical Analysis Statistical

most common most etiologies cirrhosiswere HCVof infect of32.5%consisting nonHispanic 22.9% Blac Whites, patientstotalof680 A cirrhosiswith inclusimet was 54.3patients years, twothirdsand (64.7%)wer CharacteristicsPatient ReceiptofandSurveillance RESULTS statisticalsoftware Stata 11.2 (StataCorp,College Statistical care). significancewas asdefined p<0. considered clinicallyconsidered important severe).Finaland models included covariates signi patientlevelofharmcorrelates when asdefined a a secondaryharm. In analysis, we performed multiva regressionmodels were constructedtoidentify pati providerdiscourageeducation nonguidelineto conc specificity,buthigher dueharms toindeterminate strategies.Forexample, due positiv harms to false rationalebecause followupwouldfor testing likel estimatedWe proportion the ofphysical byharms te atdifferentdonetimes, with testingfollowuprec

Accepted Article reportedpointWe estimatesof surveillancerelated

This article isprotected by copyright. All rights reserved. 20 , westratified report , by surveillanceestimates ty apriori etiology,(obesity, cirrhosis Childhe score,Pugh Hepatology Hepatology debateconcerning whether use AFPinto ommended ifommendedeither surveillance is positive. test mative because ultrasoundbecausemative AFPand bemay pe (ultrasound vs.(ultrasoundpe AFP),and test result(false y differ and y differ requiremay intervention 05. All statisticalanalysis05. was performedusing Station, TX). results couldpotentiallyresults minimizedbe by e results requiremayresults surveillancee with tests fourlevel outcome (none,fourleveloutcome mild, moderate, entlevelassociated withfactors physical ficant on univariableficant analysis those and e men. The cohorte men.was The racially diverse, st result(falsepositive indeterminate)vs. ordant care.ordant Multivariable logistic riable ordinal logistic riableordinallogistic regression to define ion(56.2%), alcoholinduced liver disease ks, and Hispanic42.1% ks, Caucasians. The on criteria(Tableon 1). ofmean ageThe

benefit and physicalbenefitand harms the for pe (ultrasoundpe vs. patology 9

(5.3%) a combinationa(5.3%) ofand MRICT Althoughscans. withpatients, 22 (3.2%) subjected to CTmultiple s 2 andTable in 1. Figure all patients, 680 Of physi PhysicalHarmsof HCC Surveillance surveillancemodality(p=0.43). patients (22.9%0%,vs. p=0.005),withdifferenc no surveillancewerelikelymore toundergo curative t tumorsdetected (76.2% 66.7%,vs.p=0.53) (Figure2 inproportiondifference the ofHCC within Milan cr detected40.0% those for symptomatically inciden or detected bypatients surveillance and/or ultrasound were detectedcases incidentally presented or sympt 12byand AFPalone,(25.0%)by bothultrasound and HCCtheduring these, followup. Of 21 (43.8%) were ofHCCBenefits Surveillance developed patients HCC the3yearduring peristudy surveillance≥6had ultrasoundduringexams the 3y however,only (26.3%)179 patientshad surveilla≥3 523performedin (76.9%)patients, and 640 (94.1%) followeda mean of26.711.7for ± months.Atleast having patients Childcirrhosis PughAand 57.1% Ch and(25.7%), NASH (11.6%). Child median ThePugh sc

Physicalrelated positiveto harms indeter false or Accepted ArticlewereTumorsvia detected surveillance (61.5%)48in

This article isprotected by copyright. All rights reserved. Hepatology Hepatology cal harm washarmcal observedin 187 (27.5%) iteria betweeniteria ultrasounddetectedand AFP reatmentnonsurveillance than detected cans, 8cans, multiple(1.2%) andscans,MRI 36 AFPhad early comparedHCC, toonly one surveillance ultrasoundbeenhad e in curativeine treatmentreceipt by nce ultrasound exams ultrasound onlyandnce (1.6%) 11 tally(p=0.009). significantThere awas not ear ear period.followup 78Overall, (11.5%) omatically. majorityThe (70.2%)ofHCC od. od. had ≥1 serumhad AFP≥1 measurement; detected bydetected ultrasound15 alone, (31.2%) ildcirrhosis.BPugh were Patients ). Similarly,). patients viadetected AFP (Figure1). remaining TheHCC 30 most harm most was mild to twomoderate, orewas(IQR 68),7 with of29.9% minate minate surveillanceareshown results patientsofthe78 developedwho 10 Page 10of24 Page 11of24 Among patients Among with AFP serum≥1 measurement (n=640 surveillance exams. surveillanceamong29.6% examto thosewith 29exa increasedphysical harm theofnumberwith surveill angiograman(after MRI 5 exams).As expected, the underwent patients biopsy liver lesionsof 2 (after

heterogeneous, nodularheterogeneous, liver and echotexture 21 pat evaluationdiagnostic indeterminatefor results. In positivebytriggered ultrasounds 63in false ofth withharm,44 moderate with 2 andsevere harm (both ultrasoundrelatedphysical wereharms observed in AFPrelated than harm (p<0.001)2). (Figure Of the surveillancesignificantlya withmodality, higher hepatology care,hepatologyviral and etiologyofcirrhosis. I wasresults significantly with associated elevated Correlates ofPhysicalCorrelates Harms evaluation. AFPhadand moderate withharm and/orCTmultiple M between20and11ng/mL ng/mL. six note, of Of pat 7 ng/mL,exceedingwith20 undergoing 22 diagnostic e positivesindeterminateand results. patienOnly51 (angiogram).Similarultrasound, AFPrelatedto har physical related –harms with49 withharm,mild23 There were differencesThere in theofproportionpatient

In univariable In analyses,physical from false harm p Accepted Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology nmultivariable analysis, wasphysical harm proportionofultrasoundrelated physical harm ese cases, andcases,additional ese an underwent56 and 4 MRI 4 andexams) one and patient underwent determinate determinate includedresultspatients 35 with ALT level,ALT thrombocytopenia, receiptof ts with AFPrelatedts harm had AFPlevels ance exams from 11.9% amongexamsance from thosewith 1 moderateharm, and 1 severe harmwith mwas toa due combination of false 523 patients523 surveillancewith ≥1 ultrasound, 119 (22.8%)patients 73– with harm,mild ients with ients subcentimeter liver nodules. proportion ofproportionpatients experiencing ientswith both positive false ultrasound valuationintermediate AFPelevations for liver biopsies). Diagnosticevaluation was ms to 61.0% amongto ms thosewith ≥10 RI exams performedexams diagnosticRI for s experiencing s physical byharm ), 73 ), (11.4%)experienced AFP ositive or indeterminateositive or surveillance 11

ALT 1.92,(ORALT 95%CI1.302.83), thrombocytopenia (O screening guidelinesand alteredclinical practice, aboutwhichscreeningrelatedevolving data harms c analysisharman as evaluating ordinaloutcome simi 1.26– 95%CI 3.38),ofhepatologyand receipt care( with associated elevated levelALT1.87, 95%CI(OR

Complementarydataregarding benefits and harms ar cancer of screening programs. guidelineconcordant followup subcentimeterfor le by diagnosticcompounded imaging indeterminatefor weresurveillance harms largelyrelatedto po false surveillance to among>50%thosewithtest or 10 mo increasedsurveillance harms steadily overtime, in indeterminate andresults hadnearly 10% moderate t detection rates,overonefourth ofpatientsexperi HCCAlthoughcirrhosis. surveillanceover detected thebestofour To knowledge,ourstudy ofoneis ofHCCharms surveillance against HCCearly detecti DISCUSSION 95%CIcirrhosis 1.59,(OR 1.03– and 2.44) thromboc – 5.80),1.39 whereas ultrasoundrelated harm was a cirrhosisviral etiology95%CIof 5.25,(OR 2.31– positive/indeterminate false AFPorultrasound resu carehepatology 95%CI1.172.57).1.74,(OR

Accepted Articleexploratory subgroupIn analyses,we if evaluatedt

This article isprotected by copyright. All rights reserved. 8 Experiences withprostate and breast cancerscreen Hepatology Hepatology importance highlights the ofevaluating enced surveillanceenced positive harms false orfor 11.92) and elevatedand11.92) ALT 2.84,(OR 95%CI sitiveorAFP ultrasound harms results, were creasing from among~10%thosewith 1 sions or intermediate or AFPsions elevations. lts. AFPrelatedlts.harm waswith associated 60%ofHCC and nearly doubledearly tumor OR 1.63, 95%CIOR 1.09 2.42).secondaryA– larly found an associationlarlyan found with elevated reated controversyreated published about ssociatedwith nonviralof etiologies resurveillance Although exams. on in aincohorton large of patients with o severeo harm. prevalenceThe of 1.26– 2.76), thrombocytopenia2.06,(OR ytopenia2.14(OR1.17 – 3.90).95%CI surveillancenonincluding results, R95%CI2.18, 1.343.55), and receiptof the to andfirst quantify physical weigh hese associationshese were driven by eessential tovaluedetermine the ing,in 12 Page 12of24 Page 13of24 HCCsurveillance tobe patientsin appear modest wi programs, dataprograms, HCCforsurveillance on has focused However,similarearly to the breasevaluations for screeningrelated harmsscreeningrelated advancein of guidelinerec

effectivenessofHCC surveillanceearly for tumor d with subcentimeterwithlesions despite guidelinesrecom beneficial.observedalso utilization high diWe of is ultrasound sufficient,despite liver nodularity, examination ultrasound likelyis neededhelp to rad coarsenodularwith echotexture. Furtherdata and g noted oftenradiologists recommending diagnostic im anynonguidelineandmasses liver concordant manag indeterminate includingfindings, nodular coarseec positivehowever,harms results; ofultrasound the high priority high area research. for however,cirrhosis;authors lacknotedthe a ofdat surveillanceearlycurativeand detection, treatmen metaanalysisidentified nearly studies 50characte to priorstudies to andbetween ultrasound althoughAFP, this may have ofpatients. quarter Early detectionand curative t ultrasound attributed to alone nearlyinofca half HCCsurveillancewas tumorresponsibledetecti for and increasedpatients early detection tumor rates need address this by characterizing physical harms In terms of In terms surveillanceultrasound harms, AFPand

Accepted20 Article , ourdata , suggest complementaryAFPisthat toult

This article isprotected by copyright. All rights reserved. 7 dataareTheseof importance particular the given Hepatology Hepatology and caseswhichin imagingwouldfurther be ses, AFPses,in onequarter, bothtestsand thein reatment receiptdidnotsignificantly differ agnostic CT andCT agnostic MRI inin patients patients asurveillancerelated regarding harmsa as t, colon,prostatet, and cancerscreening t, and overalland t, survivalpatients with among werecompoundedby number a ofhigh rizing thebetweenrizingassociation HCC from 40%to70%. from detectionwas Tumor iologists distinguish iologists caseswhichin etection in etection clinical practice. hotexture hotexture precludedthatexclusion definite of ommendations andommendations widespreaduse. uidance for whatuidance for constitutesinadequatean ofHCCsurveillance. mendingshortrepeat interval ultrasound th cirrhosis. th agingwith multiphase orCTMRI cases for surveillancerelated benefits todate. been relatedbeentosmall size. Similarsample ement ofement subcentimeterlesions. We on in approximatelyinon ofHCC 60% had ahadproportion similar of false 6 , 2 0 Our studyOur begins to rasoundincreasesand the benefitsof 18 19

A 13

Although viralAlthough notassociatedetiologywas with inc AFP cutoff byAFPcutoff liver diseaseetiology helpmayredu clinicalwhen judgment interpreting “lowlevel”pos Manyhavethe studies suboptimaldiscussed specific with viralwith hepatitis,hepatic inflammation,ele and diagnostic imaging.diagnostic by highermediated providerawareness ofHCC a risk thrombocytopenia. betweenassociationThe hepatolo subspecialtypatientswithcare, elevated levelALT surveillancerelated Although harms were observed wereharms particularly someinsubsets,likely inc an earlyandan stage, perceived positive predihigher aboutof knowledge the guidelines, ofmedicolfear low ofHCC.giventhe risk provider This behavior m

may increasemay further. NASHrelated, related isto it possible the proport harm exploratoryinrelated analyses. subgroup As t analysis,associationwean withnoted increased AF are particularly are needed givenlower both sensitivit imaging. cautiouslyshouldbe in interpreted these patients, potentially of anHCC earlymissingat stage. onimportance any up followingliver inclulesions, discussing data positive false related results to u recommendations crosssectionalfor imaging. thrombocytopeniacan impair radiologists’abilityt 23, 29

AcceptedliverIncreased nodularity patientsin advancwith Article

30 Alternativesurveillance toolsthesepatients for ltrasoundimagingso providers placemaymore vatedliver enzymes. ionofphysical attributedharmultrasound to odefinitively lesions, leadingexcludeliver to yspecificityand related topoor visualization. ding areding those subcentimeter,that given fear although AFPadjustedalthough algorithmsortailoring itiveAFPvalues. luding patientsluding receiving hepatology reased physical reased harms multivariablein s, and thosewiths, portal hypertension and ctiveultrasoundvaluethan AFP. for ce rates ofrates ce unnecessary diagnostic egal liability, egal hypervigilance HCCto findat ay stem from includingseveral causes lack heepidemiology ofHCC HCVshifts from Prelated harm andPrelated lower ultrasound ityofAFP, resulting providersinusing nd and lower threshold orderingfor gy careand gy surveillanceharms bemay in nearlyin onefourthof patients, ed Childedand classPugh 23, 2423, 28 However, there arethereless However, Elevated AFPlevelsElevated positiveAFPpatientsin 21, 22

14 Page 14of24 Page 15of24 because manypatientsdidhave insurancenot and th receivedHCCsurveillance diagnosticand/or a tests harmsdownstream contrastinducedsuch as renal fai weretoreceiptlargelylimitedofdiagnostic testi electronic recordmedical and thereforeon focused psychosocialandfinancial, butourharmsstudy was be not othergeneralizable systems.healthto Secon removed from beingremoved from validatedfully readyand rofor havebut most yettoundergo phase IIIorphase IV thisalthoughwas ourinnot measured Severa study. patients havemay experiencedalso psychological ha minimal,issomepatients experienced severeharm w specificity.surveillance Althoughtest somearmay physical potential for frombothharms ultrasound a surveillancelacka ofdespitesupportin modalities stagepresentationlate tumor academicin centers, symptomatically.surveillanceSuboptimal sensitool tests.diagnostic onethird Over ofHCC cases in ou improvedsensitivityearly detectionand for tumor

results. results. may be a bemayintervention simple reducesurveillancere guidelineconcordant managementofindeterminate su surveillanceourstudy tools, over suggests 40% of anyrelatedtoharm thesebiomarkers largelalso is Our study addsstudyOur totheliterature highlighting nee a Our study hadstudyOur limitations that be must takeninto c

AcceptedFirst,thestudy conductedwasain single safetyn Article

This article isprotected by copyright. All rights reserved. Hepatology Hepatology ng,with datalessavailable toassess g data.g improvedspecificity toavoid unnecessary gue the physicalgue the orCTMRIharms imagingof yawaitingunknown. newer While nd AFP, inAFP, nd part related tosuboptimal surveillanceis relatedtonon harms utine clinicalutine use. promptingsome toadoptandCT MRI as tivity is one oftheonetivityis common most reasons for study incidentallyr presented or biomarkerand studies yearsbemay physicalFurther, harms. physical harms lated harmslated ininterim. the toutside institutions, thisalthoughunlikelyis d, surveillance d, resultphysical,incan limited to retrospectivedataavailable the in l biomarkersl arecurrently evaluated, being rms while rms evaluation,diagnostic awaiting uswould payhave outof pocketto to get lure.patients Third, havemay potentially ith biopsy and/or angiogram.biopsy ith Further,and/or rveillanceso providerresults, education 21, 31 d for bettersurveillance d for with tools, onsideration whenonsideration interpreting the ethealth system its andresults may Our study alsostudyOur highlightsthe 32 Further, dataevaluating 15

consistent withconsistent prior studies. surveillancehigher rates.However, the low surveil thelikely,that magnitudeofsurveillance benefits 3hadstudysurveillance ormore the3 duringexams outside ofsafetynetcare the health systemDalin

eae am nptet ihcrhss harms patientsinrelated with cirrhosis. of strengths thestudy, particularly giventhisis harms. harms. curativetreatmentreceipt; however,benefits these value of HCC value surveillancepatientsinof with cirrhosi providereducationdetection, helpmay reducesurve surveillancerelatedharm.awaiting more While accu ofindeterminate management ultrasound results acco positiveand ultrasound AFPwereresultsc the most surveillanceindeterminate andresults nearly 10%h In summary, HCCIn surveillance associatedis with ear

Accepted ArticleNearlyonefourthofnonHCCpatients underwentdia

This article isprotected by copyright. All rights reserved. 27, 33, 3427, 33, Overall, we feel these limitationswe Overall,arethese outweighed feel Hepatology Hepatology the tostudy characterize first HCCsurveillance and harms would harms and bewithsettingsin greater s. s. las. Finally, las. onlyofpatientsourin onefourth lance rates observedlancerates instudy our are mustweighed be against surveillance ad diagnosticmultiple Althoughtests. false ommoncauses, nonguideline concordant rate surveillancerate early tumor tools for illancerelatedharmsimprove and the year studyyear period,andis it ifpossible, not unted nearlyunted for ofonethirdcaseswith lydetection tumor and increased gnostic gnostic testingpositive false orfor by the 16 Page 16of24 Page 17of24 Figure 1: Figure

Figure 2: Figure ofPatients Cohort with Cirrhosis than AFPrelated than physical (22.8%harm11.4%,vs. p< proportion the ofpatients experiencingultrasound surveillance66.7%vs.modality ultrasou (76.2% for was significantThere nota difference inpropo the SurveillanceModality Flow Diagram Hepatocellular of CarcinomaSurveilla

Accepted ArticleBenefits Physicaland ofHepatocellular Harms Carc

Hepatology Hepatology rtion ofHCC detected rtion at earlyan stageby relatedphysical significantlywasharm higher nd and AFPand nd respectively,p=0.53);however, 0.001). inoma Surveillance,inoma byStratified

nce Benefits and Harmsand ainBenefits nce

1. References

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Accepted 2012;27(7):861-867. Jul Article

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g yas 5. . 5. . 5. . 0.95 8.6 54.3 ± 9.7 54.3 ± 9.4 54.3 ± (years)Age Characteristic ofsurveillancerelatedoccurrence physical harm Presence of ascites (%) 270 (39.7) 204 (41.4) 66 (3 66 (41.4) 204 care (39.7) 270 ofhepatologyReceipt ofascites Presence (%) encephalopathy(%) ofhepatic Presence Child CPugh Child BPugh Child PughA classChild Pugh Other NASH Alcoholrelated Hepatitis B Hepatitis C Liver DiseaseEtiologyof BMI ≥35 0.59 BMI– 30 34.9 BMI– 25 29.9 (66.3) 124 BMI <25 MassBodyIndex(BMI) (64.1) 316 Other/Unknown (64.7) 440 Hispanic Black NonHispanic White Race/Ethnicity Sexmale)(% Table1:

Accepted Article Patientsociodemographic clinicaland characteris

This article isprotected by copyright. All rights reserved. AllPatients 388 (57.1)388 (29.8)203 (25.7)175 (56.2)382 (19.0)129 (23.3)158 (33.2)225 (24.5)166 (42.1)286 (22.9)156 (32.5)221 4 6.) 0 6.) 3 7.) 0.01 (73.2) 134 0.74 (62.7) 307 (23.5) 44 (65.5)441 (22.3) 110 (22.7)154 89 (13.1)89 (11.6)79 (n=680) 22 (3.2)22 22 (3.2)22 (2.5)17

Hepatology Hepatology

PhysicalHarm 135 (27.4)135 (53.7)265 203 (41.2)203 (22.1)109 (34.1)168 282 (57.2)282 (30.0)148 122 (24.8)122 (32.7)161 (24.6)121 59 (12.0)59 63 (12.8)63 88 (17.9)88 Patients without (n=493) 18 (3.6)18 16 (3.3)16 13 (2.6)13

tics, overalltics, and stratified by Patients with 117 (62.6)117 106 (56.7)106 Physical 20 (10.7)20 (21.4)40 83 (44.4)83 (25.1)47 (28.4)53 26 (13.9)26 (29.4)55 41 (22.0)41 (19.4)36 (34.4)64 (24.2)45 (n=187) 4 (2.1)4 (3.2)6 4 (2.1)4 Harm

.) 0.15 5.3) value* 0.30 0.49 0.93 0.38 p- Page 20of24 Page 21of24 ALT (U/L) 58 ± 50 53 ± 45 73 ± 61 < 0.001 < 61± 73 0.001 0.002 (72.2) 135 89± 92 0.05 45± 53 (56.8) 277 (88.2) 165 64± 73 – alanine ALT aminotransferase; AST aspartate– ami 50± 58 (61.0) 412 (81.9) 399 72± 78 (83.7) 564 35 U/L> ALT (U/L)ALT 35 U/LAST > AST (U/L) * pvalue comparing* patientswith withoutandany s steatohepatitis hepatocellularcarcinoma; international – INRnorma

Accepted 0.65 0.4 1.3 ± 0.08 (8.0) 15 0.5 1.3 ± 0.3 0.4 1.3 ± 2.1 1.6 ± (12.8) 63 Article(11.5) 78 2.8 1.9 ± 0. 2.6 1.8 ± 0.5 0.9 ± ofHCC Number 0 INR (86.5) 160 Bilirubin(mg/dL) 0.9 1.1 ± (74.8) 362 0.8 1.0 ± (78.0) 522 Creatinine(mg/dL) Thrombocytopenia 10count(*Platelet 9 L 10±6 14±6 13±5 0.06 53± 103 67± 114 64± 110 /L) This article isprotected by copyright. All rights reserved. Hepatology Hepatology urveillancerelated physicalurveillancerelated harm lizedNASH – nonalcoholicratio; notransferase;HCC – .001 02 5

n am 1 2 6* 56 63* 22 51* Any Harm Characteristic Result Surveillance,byStratified ModalitySurveillance a included both ingroups patients7 with* physicalharm po related to false Hepatic angiogram (n) Biopsy ofliver (n)mass SevereHarm 4phaseCT MRI and Multiple MRI Multiple CT 4phase Moderate(n)Harm Single MRI Single 4phase CT (n)Mild Harm Table2:

Accepted Article Mild, SevereandModerate,Physical ofHepatHarms

Falsepositive 26 16 3 1 0 1 4 AlphaFetoprotein

Hepatology Hepatology (n=640)

Indeterminate sitiveand ultrasound AFP were

nd FalsePositivend Indeterminatevs. 18 2 0 0 0 1 1

ocellularCarcinoma Falsepositive 32 11 6 0 2 5 7

Ultrasound (n=523)

Indeterminate 28 10 10 7 0 0 1

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Accepted Hepatocellular of FlowDiagram SurveillanCarcinoma Article

ce Benefits and Harms in a in Harms a with Cohortceand Benefits Patients of

Accepted Article

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