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The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function

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Cancers
Authors:
Hideki Iwamoto at Kurume University
Hideki Iwamoto
Takashi Niizeki at Kurume University
Takashi Niizeki
Hiroaki Nagamatsu
Hiroaki Nagamatsu
Hiroaki Nagamatsu
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Kazuomi Ueshima
Kazuomi Ueshima
Kazuomi Ueshima
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Abstract and Figures

Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.
Flowchart illustrating the study inclusion and exclusion process. EHS, extrahepatic spread; MVI, macrovascular invasion; New-FP, fine-powder cisplatin and 5-fluorouracil; PVTT, portal vein tumor thrombus.
Flowchart illustrating the study inclusion and exclusion process. EHS, extrahepatic spread; MVI, macrovascular invasion; New-FP, fine-powder cisplatin and 5-fluorouracil; PVTT, portal vein tumor thrombus.
… 
Overall survival curves for patients in the New-FP and sorafenib groups. (A) New-FP (n = 418, red line) and sorafenib (n = 844, blue line), before propensity score matching. (B) New-FP (n = 198, red line) and sorafenib (n = 198, blue line), after propensity score matching. (C) Cohort 1 (no MVI or EHS), New-FP (n = 38, red line) and sorafenib (n = 38, blue line). (D) Cohort 2 (MVI with no EHS), New-FP (n = 78, red line), and sorafenib (n = 78, blue line). (E) Cohort 3 (EHS with no MVI), New-FP (n = 6, red line), and sorafenib (n = 6, blue line). (F) Cohort 4 (MVI and EHS), New-FP (n = 78, red line), and sorafenib (n = 78, blue line). HR, hazard ratio; MST, median survival time; New-FP, fine-powder cisplatin and 5-fluorouracil; EHS, extrahepatic spread; MVI, macrovascular invasion.
Overall survival curves for patients in the New-FP and sorafenib groups. (A) New-FP (n = 418, red line) and sorafenib (n = 844, blue line), before propensity score matching. (B) New-FP (n = 198, red line) and sorafenib (n = 198, blue line), after propensity score matching. (C) Cohort 1 (no MVI or EHS), New-FP (n = 38, red line) and sorafenib (n = 38, blue line). (D) Cohort 2 (MVI with no EHS), New-FP (n = 78, red line), and sorafenib (n = 78, blue line). (E) Cohort 3 (EHS with no MVI), New-FP (n = 6, red line), and sorafenib (n = 6, blue line). (F) Cohort 4 (MVI and EHS), New-FP (n = 78, red line), and sorafenib (n = 78, blue line). HR, hazard ratio; MST, median survival time; New-FP, fine-powder cisplatin and 5-fluorouracil; EHS, extrahepatic spread; MVI, macrovascular invasion.
… 
Therapeutic effects of New-FP and sorafenib in HCC with major PVTT. (A) Cohort 5, survival curves of patients with major PVTT-HCC before propensity score matching: New-FP (n = 177, blue line) and sorafenib (n = 114, red line). (B) Cohort 5, survival curves of patients with major PVTT-HCC after propensity score matching: New-FP (n = 78, blue line) and sorafenib (n = 78, red line). (C) Therapeutic response for New-FP in major PVTT-HCC. (D) Survival curves in the responder (red line, n = 57) and non-responder groups (blue line, n = 21) for New-FP. (E) Survival curves in different therapeutic response groups for New-FP: CR (red line, n = 13), PR (blue line, n = 44), SD (yellow line, n = 13), and PD (green line, n = 8).CR, complete response; HCC, hepatocellular carcinoma; HR, hazard ratio; MST, median survival time; PD, progressive disease; PR, partial response; PVTT, portal vein tumor thrombus; SD, stable disease.
Therapeutic effects of New-FP and sorafenib in HCC with major PVTT. (A) Cohort 5, survival curves of patients with major PVTT-HCC before propensity score matching: New-FP (n = 177, blue line) and sorafenib (n = 114, red line). (B) Cohort 5, survival curves of patients with major PVTT-HCC after propensity score matching: New-FP (n = 78, blue line) and sorafenib (n = 78, red line). (C) Therapeutic response for New-FP in major PVTT-HCC. (D) Survival curves in the responder (red line, n = 57) and non-responder groups (blue line, n = 21) for New-FP. (E) Survival curves in different therapeutic response groups for New-FP: CR (red line, n = 13), PR (blue line, n = 44), SD (yellow line, n = 13), and PD (green line, n = 8).CR, complete response; HCC, hepatocellular carcinoma; HR, hazard ratio; MST, median survival time; PD, progressive disease; PR, partial response; PVTT, portal vein tumor thrombus; SD, stable disease.
… 
Univariate and multivariate analyses for evaluating factors associated with overall sur- vival.
Univariate and multivariate analyses for evaluating factors associated with overall sur- vival.
… 
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Cancers2022,14,4873.https://doi.org/10.3390/cancers14194873www.mdpi.com/journal/cancers
Article
TheClinicalImpactofHepaticArterialInfusion
ChemotherapyNew‐FPforHepatocellularCarcinomawith
PreservedLiverFunction
HidekiIwamoto
1,2,
*,TakashiNiizeki
1
,HiroakiNagamatsu
3
,
KazuomiUeshima
4
,JojiTani
5
,TeijiKuzuya
6
,
KazuhiroKasai
7
,YouheiKooka
8
,AtsushiHiraoka
9
,RieSugimoto
10
,TakehiroYonezawa
11
,SatoshiTanaka
12
,
AkihiroDeguchi
13
,ShigeoShimose
1
,TomotakeShirono
1
,MiwaSakai
1
,HiroyukiSuzuki
1
,EtsukoMoriyama
1
,
HironoriKoga
1
,TakujiTorimura
14
,TakumiKawaguchi
1
,NewFPStudyGroupandKurumeLiverCancerStudy
GroupofJapan
1
DivisionofGastroenterology,DepartmentofMedicine,KurumeUniversitySchoolofMedicine,
Kurume830‐0011,Japan
2
IwamotoInternalMedicineClinic,Kitakyusyu802‐0832,Japan
3
DepartmentofGastroenterology,JuntendoUniversity,Bunkyo‐ku113‐8421,Japan
4
DepartmentofGastroenterologyandHepatology,FacultyofMedicine,KindaiUniversity,Osaka589‐8511,
Japan
5
DepartmentofGastroenterologyandNeurology,FacultyofMedicine,KagawaUniversity,Miki761‐0793,
Japan
6
DepartmentofGastroenterologyandHepatology,FujitaHealthyUniversity,Toyoake470‐1101,Japan
7
DivisionofGastroenterology,IMSSapporoDigestiveDiseaseCenterGeneralHospital,Sapporo063‐0842,
Japan
8
DivisionofHepatology,DepartmentofInternalMedicine,IwateMedicalUniversitySchoolofMedicine,
Iwate028‐3695,Japan
9
GastroenterologyCenter,EhimePrefecturalCentralHospital,Matsuyama790‐0024,Japan
10
DepartmentofHepato‐Biliary‐Pancreatology,NationalHospitalOrganizationKyushuCancerCenter,
Fukuoka811‐1395,Japan
11
DepartmentofGastroenterology,HachinoheRedCrossHospital,Aomori039‐1104,Japan
12
DepartmentofGastroenterologyandHepatology,NationalHospitalOrganizationOsakaNationalHospital,
Osaka162‐8655,Japan
13
DepartmentofGastroenterology,KagawaRosaiHospital,Marugame763‐8502,Japan
14
DepartmentofGastroenterology,OmutaCityHospital,Omuta836‐0861,Japan
*Correspondence:iwamoto_hideki@med.kurume‐u.ac.jp;Tel.:+81‐942‐35‐3311;Fax:81‐942‐31‐7747
SimpleSummary:New‐FPisaregimenofhepaticarterialinfusionchemotherapyforhepatocellu‐
larcarcinoma(HCC).Inthestudy,theregimensignificantlyprolongedthesurvivalofpatientswith
majorportalveintumorthrombus‐HCC.
Abstract:Background:Systemictreatmentsarerecommendedforadvancedhepatocellularcarci‐
noma(HCC)inpreservedliverfunction.However,theireffectsareunsatisfactoryinsometumor
conditions,particularlymacrovascularinvasion(MVI)includingmajorportalveintumorthrombus
(PVTT).Wecomparedtheefficacyofhepaticarterialinfusionchemotherapy(HAIC)regimens
New‐FPandsorafenibforvarioustumorconditionsinpreservedliverfunction.Methods:Weret‐
rospectivelycollectedthedataof1709patientswithHCCwhoweretreatedwithNew‐FPorsoraf‐
enib.Survivalwasassessedafterpropensityscorematching.Subgroupanalyseswereconducted:
cohort1(noMVIorextrahepaticspread(EHS)),cohort2(MVIonly),cohort3(EHSonly),cohort4
(MVIandEHS),andcohort5(majorPVTT).Results:TheNew‐FPgrouphadalongermediansur‐
vivaltime(MST)thanthesorafenibinthewholeanalysis(18vs.9months;p<0.0001).New‐FP
demonstratedalongerMSTcomparedwithsorafenibincohort2andcohort4.Incohort5,theMST
oftheNew‐FPgroupwas16months,whilethatofsorafenibwas6months(p<0.0001).Formajor
PVTT‐HCC,theresponserateofNew‐FPwas73.0%.TheMSTofpatientswhoachievedcomplete
responsewithNew‐FPwas59months.Conclusions:HAICusingNew‐FPispromisingforpatients
withMVI‐andmajorPVTT‐HCCinpreservedliverfunction.
Citation:Iwamoto,H.;Niizeki,T.;
Nagamatsu,H.;Ueshima,K.;Tani,
J
.;Kuzuya,T;Kasai,K;Kooka,Y;
Hiraoka,A;Sugimoto,R.;etal.The
ClinicalImpactofHepaticArterial
InfusionChemotherapyNew‐FPfor
HepatocellularCarcinomawith
PreservedLiverFunctionn.Cancers
2022,14,4873.https://doi.org/
10.3390/cancers14194873
AcademicEditor:QuirinoLai
Received:22August2022
Accepted:3October2022
Published:5October2022
Publisher’sNote:MDPIstaysneu‐
tralwithregardtojurisdictional
claimsinpublishedmapsandinstitu‐
tionalaffiliations.
Copyright:©2022bytheauthors.Li‐
censeeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsandcon‐
ditionsoftheCreativeCommonsAt‐
tribution(CCBY)license(https://cre‐
ativecommons.org/licenses/by/4.0/).
Cancers2022,14,48732of14
Keywords:hepaticarterialinfusionchemotherapy;sorafenib;propensityscorematching;retrospec‐
tivecohortstudy;systemictreatment
1.Introduction
Nowadays,systemictreatmenthasbeenremarkablydevelopedforhepatocellular
carcinoma(HCC)[1].Sorafenibwasthefirstmolecular‐targetedagent(MTA)approved
forHCCtreatment[2].Currently,atezolizumabplusbevacizumabhasbecomethe1st‐line
drug[3].However,sorafenibisstillanalternativechoicefor1st‐linetherapy[3].Systemic
treatmentisrecommendedforintermediate‐stageHCCrefractorytotranscatheterarterial
chemoembolizationandforadvanced‐stageHCC[4].
Macrovascularinvasion(MVI)andextrahepaticspread(EHS)aretwofactorsthat
defineadvanced‐stageHCC[5].HCCwithMVI(MVI‐HCC),andespeciallyHCCwith
portalveintumorthrombus(PVTT),isacriticalconditionthatcandirectlycausedeterio‐
rationofliverfunction.Althoughsystemictreatmentisrecommendedforadvanced‐stage
HCC,therapeuticeffectsarenotyetsatisfactoryforMVI‐HCC[6].Findingthebestthera‐
peuticstrategyrepresentsanunmetmedicalneed.
Locoregionaltreatmentshavetraditionallybeenadministeredinthetreatmentof
HCC.Hepaticarterialinfusionchemotherapy(HAIC)isafrequentlyadministeredtreat‐
mentforadvancedHCC[7,8].Recently,theguidelineregardingHAICwasalsoreported
[9].HAICdirectlyandconsecutivelydeliverschemotherapeuticdrugstothetumorusing
cathetertechniques.Accordingtopreviousreports,strongerlocalcontrol(withlesstox‐
icity)isanoutstandingfeatureofHAICascomparedwithsystemicchemotherapy[10].
However,HAICisnotastandardtreatmentrecommendedwithincurrentguidelinesdue
totherelativesparsityofgold‐standardclinicaltrialsconductedtodate[11].Recentclin‐
icaltrialshaveprovidedsomeevidencesupportingtheefficacyofHAICinthetreatment
ofHCC,andtheclinicalevidenceinregardtoHAIChasgraduallybeenincreasing[12,13].
Herein,wereportontheefficacyofaHAICregimen,“New‐FP”(i.e.,fine‐powdercispla‐
tin(DDP‐H,NipponKayakuCo.Ltd.,Tokyo,Japan)suspendedinlipiodoland5‐fluor‐
ouracil),inthetreatmentofadvancedHCC.Recently,weconductedalargemulticenter
retrospectivecohortstudycomparingtheefficacyofNew‐FPandsorafenibtoenhance
evidenceregardingthereproducibilityanduniversalityofNew‐FP[14].Thisstudyre‐
vealedtheusefulnessoflocoregionaltreatmentusingNew‐FP.However,questionsre‐
mainregardingtheimpactofliverfunctionandtumorcondition.Wenotedthatone‐third
oftheanalyzedpopulationincludedpatientswithChild‐PughClassBliverfunction.As
thecurrentlyapprovedsystemictreatmentstargetpatientswithpreservedliverfunction,
itisnecessarytocomparetheefficacyofNew‐FPandsorafenibinpatientswithpreserved
liverfunctioninordertodeterminethepreciseefficacyofthistreatmentmodality.
MajorPVTT,whichinvolvestumorinvasionintothe1stbranchandtrunkofthepor‐
talvein,isalife‐threateningtumorconditionwithashortsurvivalprognosis[15].Alt‐
houghsystemictreatmentsarerecommendedformajorPVTT‐HCC,theirtherapeuticef‐
fectsareunsatisfactory[16].Therefore,thereisaneedtoclarifytheefficacyoflocoregional
treatmentformajorPVTT‐HCC.
ThisstudyaimedtoclarifytheefficacyofNew‐FPinthetreatmentofHCCinpatients
withpreservedliverfunctionbycomparingtheoutcomesofNew‐FPandsorafenibusing
propensityscorematching(PSM)analysis.Additionally,weexaminedthedetailedther‐
apeuticeffectsofNew‐FPinpatientswithmajorPVTT‐HCC.Thegoalofthisstudywas
tosupporttheidentificationofthebesttherapeuticstrategyforMVI‐HCCandmajor
PVTT‐HCCinpatientswithpreservedliverfunction.
Cancers2022,14,48733of14
2.MaterialsandMethods
2.1.StudyDesign
Amulticenterretrospectivecohortstudywasconductedinthestudyforpatients
withHCC.ThepatientswithHCCwhowereinitiallytreatedwithNew‐FPorsorafenib
wereenrolled.ThepatientsweretreatedintheKurumeLiverCancerStudyGroupandat
eightotherhospitalsbetweenMarch2009andJune2019.HCCwasdiagnosedbybiopsy
orradiologicalevaluation.Theenrolledpatientswere>18years.Deathorend‐of‐study
censoring(June30,2019)wasthecompletefollow‐upperiod.Thepatientswhocouldnot
collectthedatawereexcluded.TheEthicsCommitteeoftheKurumeUniversitySchoolof
Medicineapprovedthestudy(No.19004).Thewritteninformedconsentwaswaivedow‐
ingtotheretrospectivestudydesign.
2.2.Patients
Informationoftheenrolledpatientswascollectedfrompatients’medicalrecords.
TheclinicalstagewasjudgedbytheBarcelonaClinicLiverCancer(BCLC)stagingsystem
[5].HAICwasmainlyadministeredforpatientswithupto7outinBCLC‐BorPVTTin
BCLC‐C.Incaseswithextrahepaticmetastasis,ifhepaticlesionswereprogressed,wecon‐
sideredadministrationofHAICtocontrolhepaticlesionsfirst.MVIwasdiagnosedby
enhancedcomputedtomographyormagneticresonanceimaging.MajorPVTTincludes
tumorinvasionintothe1stbranch(Vp3)andtrunk(Vp4)oftheporalvein.
2.3.EvaluationItems
Thefollowingitemswereevaluated:(i)overallsurvival(OS),beforeandafterPSM;
(ii)factorsassociatedwithpoorprognosisafterPSM;(iii)OSinfourcohortscategorized
bythepresenceofMVIandEHS(afterPSM),asfollows:cohort1(noMVIorEHS),cohort
2(MVIwithnoEHS),cohort3(EHSwithnoMVI),andcohort4(MVIandEHS);and(iv)
anOSandforestplotanalysisinpatientswithmajorPVTT‐HCC(regardlessofthepres‐
enceofEHS),beforeandafterPSM(cohort5).
2.4.PropensityScoreMatching
DifferentdistributionsofcovariatesbetweentheNew‐FPandsorafenibgroupswere
adjustedusingPSM.Thefollowingvariables:sex,age,HCCetiology,Child–Pughclass,
tumorsize,thepresenceofMVI,thepresenceofEHS,AFPlevel,andDCPlevelwereused
forPSM.Aone‐to‐onenearest‐neighbormatchingalgorithmwithanoptimalcaliperof
0.3withoutreplacementwasusedtogeneratepairsofpatientsineachanalysis.Ineach
medicationgroup(i.e.,bothsorafenibandNew‐FP),therewere198patientsenrolledin
theoverallanalysis,38patientsincohort1,76patientsincohort2,sixpatientsincohort
3,38patientsincohort4,and78patientsincohort5.
2.5.TreatmentProtocol
2.5.1.Sorafenib
Administrationofsorafenib(Nexavar;BayelCo.,Ltd.,Osaka,Japan)wasconducted
accordingtomanufacturerrecommendations.
2.5.2.New‐FP
Initially,DDP‐H(50mg/body)suspendedin5–10mLoflipiodolwasadministered
forpatientsunderangiography,and5‐FU(250mgbolusinjectionand1250mgcontinuous
injectionusinganinfusionballoonpump)wereadministered.ThedoseoftheNew‐FP
regimenwasdeterminedbythetherapeuticresponseandadverseevents.Therapeutic
responsewasassessedusingthemodifiedResponseEvaluationCriteriainSolidTumors
(mRECIST)criteria[17].Completeresponse(CR)isdisappearanceofintratumoralarterial
Cancers2022,14,48734of14
enhancement.Partialresponse(PR)isa>30%decreaseinviabletargetlesions.Stabledis‐
ease(SD)isneitherPRnorprogressivedisease(PD).PDisa>20%increaseinviabletarget
lesions.
2.6.StatisticalAnalyses
Datawereexpressedascountsormeansandstandarddeviations.Allstatisticalanal‐
yseswerecarriedoutusingJMPstatisticalanalysissoftware(JMPProversion14,SAS
InstituteInc.,Cary,NC,USA).OSwasestimatedbytheKaplan–Meiermethod.Factors
associatedwithprognosiswereevaluatedbyunivariateandmultivariateanalysisusing
Coxproportionalhazardsmodels.Variablesassociatedwithprognosis(p<0.10)onuni‐
variateanalysiswereenteredintothemultivariateregressionmodel.Statisticalsignifi‐
cancewassettoatwo‐tailedp‐valueof<0.05.
3.Results
3.1.PatientandTumorCharacteristics
TheflowdiagramforstudyenrollmentisshowninFigure1.Atotalof1709consec‐
utivelypresentingpatientsdiagnosedwithHCC,including671intheNew‐FPgroupand
1038inthesorafenibgroup,wereenrolledinthisstudy.Amongthem,436patientswere
excludedfromthepresentanalysisbecauseofChild–PughclassBorCliverfunctioncat‐
egorizations.Additionally,11patientswereexcludedbecauseofincompletedata.Finally,
1262patients,including418intheNew‐FPgroupand844inthesorafenibgroup,were
enrolledinthePSManalysis.
Figure1.Flowchartillustratingthestudyinclusionandexclusionprocess.EHS,extrahepaticspread;
MVI,macrovascularinvasion;New‐FP,fine‐powdercisplatinand5‐fluorouracil;PVTT,portalvein
tumorthrombus.
PatientcharacteristicsaresummarizedinTable1.Etiology,tumorsize,thepresence
ofMVIandEHS,BCLCstage,andmeanDCPlevelwerestatisticallysignificantlydifferent
betweenthetwogroupsbeforePSM.However,statisticaldifferencesdisappearedafter
PSM(Table1).

Cancers2022,14,48735of14
Table1.Patientcharacteristicsbeforeandafterpropensityscorematching.
BeforeMatchingn=1262AfterMatchingn=396
PatientCharacteris‐
tics
New‐FP
n=418
Sorafenib
n=844p‐ValueNew‐FP
n=198
Sorafenib
n=198
p‐
Value
Age(years)68.6±10.970.1±9.610.939866.6±10.965.3±10.70.8046
Sex(male/female)327/91677/1670.415462/1660/180.8127
HCV/HBV/non‐viral181/77/160465/154/225<0.000137/19/2227/28/230.8074
Child–Pughscore(5/6)251/167526/3170.0563 0.1263
Tumorcharacteristics
Tumorsize(cm)8.29±4.603.59±3.39<0.00017.62±4.217.26±4.750.8107
MVI(+/−)357/61605/239<0.0001143/55146/520.7342
SeverePVTT(+/−)177/180114/491<0.0001117/8178/1200.2304
EHS(+/−)76/342429/415<0.000124/5421/570.7385
BCLCstage(B/C)52/366305/532<0.000146/15250/1480.6390
AFP(ng/mL)27,729.0±
154,561.1
17,735.3±
110,114.80.188648,645.45±
248,475.48
52,073.81
±
163,296.82
0.6153
DCP(mAU/mL)23,513.0±
70,955.4
14,373.38±
71,899.80.033930,379.13±
95,631.52
27,714.78
±
61,755.77
0.8773
AFP,alpha‐fetoprotein;BCLC,BarcelonaClinicLiverCancer;DCP,des‐gammacarboxyprothrom‐
bin;EHS,extrahepaticspread;PVTT,portalveintumorthrombus;HBV,hepatitisBvirus;HCV,
hepatitisCvirus;MVI,macrovascularinvasion.
3.2.OverallSurvival
Figure2A,BshowsthesurvivalcurvesfortheNew‐FPandsorafenibgroupsbefore
andafterPSM.BeforePSM,theMSTforNew‐FPandsorafenibwas17and12months,
respectively.Astatisticallysignificantdifferencewasobservedbetweenthegroups(Fig‐
ure2A,hazardratio(HR)0.68,95%confidenceinterval(CI):0.59–0.79);p<0.0001).After
PSM,theMSTsforNew‐FPandsorafenibwere18and9months,respectively,withasta‐
tisticallysignificantdifferencebetweenthegroups(Figure2B,HR0.54;95%CI0.43–0.68,
p<0.0001).
Cancers2022,14,48736of14
Figure2.OverallsurvivalcurvesforpatientsintheNew‐FPandsorafenibgroups.(A)New‐FP(n=
418,redline)andsorafenib(n=844,blueline),beforepropensityscorematching.(B)New‐FP(n=
198,redline)andsorafenib(n=198,blueline),afterpropensityscorematching.(C)Cohort1(no
MVIorEHS),New‐FP(n=38,redline)andsorafenib(n=38,blueline).(D)Cohort2(MVIwithno
EHS),New‐FP(n=78,redline),andsorafenib(n=78,blueline).(E)Cohort3(EHSwithnoMVI),
New‐FP(n=6,redline),andsorafenib(n=6,blueline).(F)Cohort4(MVIandEHS),New‐FP(n=
78,redline),andsorafenib(n=78,blueline).HR,hazardratio;MST,mediansurvivaltime;New‐
FP,fine‐powdercisplatinand5‐fluorouracil;EHS,extrahepaticspread;MVI,macrovascularinva‐
sion.
3.3.PrognosticFactors
AfterapplyingPSM,prognosticfactoranalyseswereperformedfortheentiredataset
(Table2).AChild–Pughscoreof5,thepresenceofmajorPVTT,thepresenceofEHS,the
Cancers2022,14,48737of14
bettertherapeuticresponse,andNew‐FPtreatmentwereassociatedwithpatientprogno‐
sisonunivariateanalysis.MultivariateanalysisshowedthataChild–Pughscoreof5and
New‐FPwereeachindependentbetterprognosticfactors.ThepresenceofmajorPVTT
andEHSwereindependentpoorprognosticfactors.
Table2.Univariateandmultivariateanalysesforevaluatingfactorsassociatedwithoverallsur‐
vival.
Variable
UnivariateAnal‐
ysis
(p‐Value)
MultivariateAnalysis
(p‐Value)
HazardRatio
(95%CI)
Sex(male/female)0.1681
HBV(+/−)0.3909
HCV(+/−)0.1851
Child–Pughscore(5/6)0.00020.00680.72(0.57–0.91)
BCLCstage(B/C)0.2621
MVI(+/−)0.9679
MajorPVTT(+/−)0.02130.00021.57(1.24–1.99)
EHS(+/−)<0.00010.00111.76(1.37–2.26)
AFP(≥400ng/mL/<400
ng/mL)0.1811
Bettertherapeuticre‐
sponse<0.00010.7901
Treatment(New‐FP/so‐
rafenib)0.0350<0.00010.52(0.41–0.65)
AFP,alpha‐fetoprotein;BCLC,BarcelonaClinicLiverCancer;CI,confidenceinterval;EHS,extra‐
hepaticspread;HBV,hepatitisB;HBC,hepatitisC;MVI,macrovascularinvasion;New‐FP,fine‐
powdercisplatinand5‐fluorouracil.
3.4.SubgroupAnalyses
Subgroupanalyseswereconductedintheaforementionedfivecohorts(Figure2C–
F).
3.4.1.Cohort1:NoMVIorEHS
Patientandtumorcharacteristicsforcohort1areshowninSupplementaryTableS1.
BeforePSM,therewerestatisticallysignificantdifferencesinsex,etiology,andtumorsize
betweenthetwogroups.AfterPSM,thesestatisticaldifferencesdisappeared.TheOSin‐
cludingbothgroupsincohort1was19monthsTheMSTsintheNew‐FPandsorafenib
groupswere20and17months,respectively(Figure2C).Therewasnostatisticallysignif‐
icantdifferenceinOSbetweenthem(p=0.28,HR0.71,95%CI0.39–1.32).
3.4.2.Cohort2:MVIwithoutEHS
Patientandtumorcharacteristicsforcohort2areshowninSupplementaryTableS2.
BeforePSM,therewasastatisticallysignificantdifferenceintumorsizebetweenthetwo
groups.AfterPSM,thestatisticaldifferencedisappeared.TheOSincludingbothgroups
incohort2was12monthsTheMSTsintheNew‐FPandsorafenibgroupswere19and
eightmonths,respectively(Figure2D).New‐FPstatisticallysignificantlyprolongedsur‐
vivalcomparedwithsorafenib(p<0.0001,HR0.51,95%CI0.35–0.74).
3.4.3.Cohort3:EHSwithoutMVI
Patientandtumorcharacteristicsforcohort3areshowninSupplementaryTableS3.
BeforePSM,therewerestatisticallysignificantdifferencesinageortumorsizebetween
thetwogroups.AfterPSM,thestatisticaldifferencesdisappeared.TheOSincludingboth
Cancers2022,14,48738of14
groupsincohort3was11monthsTheMSTsforNew‐FPandsorafenibwere13and7.5
months,respectively(Figure2E).TherewasnostatisticallysignificantdifferenceinOS
betweenthetwogroups(p=0.095,HR1.34,95%CI0.37–4.82).
3.4.4.Cohort4:MVIandEHS
Patientandtumorcharacteristicsforcohort4areshowninSupplementaryTableS4.
BeforePSM,therewasastatisticallysignificantdifferenceintumorsizebetweenthetwo
groups.AfterPSM,thestatisticaldifferencebetweenthegroupsdisappeared.TheOSin‐
cludingbothgroupsincohort4was7months.TheMSTsoftheNew‐FPandsorafenib
groupswere8.8monthsand4months,respectively(Figure2F).New‐FPstatisticallysig‐
nificantlyprolongedsurvivalascomparedwithsorafenib(p=0.003,HR0.50,95%CI0.31–
0.82).
3.5.AssessmentinMajorPVTT‐HCC
3.5.1.ComparisonofOSinMajorPVTT‐HCC
Incohort5,theOSofpatientswithmajorPVTT‐HCCwascomparedbetweenthe
New‐FPandsorafenibgroups.Patientandtumorcharacteristicsforcohort5areshown
inSupplementaryTableS5.BeforePSM,therewerestatisticallysignificantdifferencesin
tumorsizeandthepresenceofEHSandDCPlevelsbetweenthetwogroups.AfterPSM,
thestatisticaldifferencesbetweenthegroupsdisappeared.TheMSTsoftheNew‐FPand
sorafenibgroupswere13andsixmonths,respectively,beforeapplyingPSM(Figure3A).
TheMSTsoftheNew‐FPandsorafenibgroupswere16andsixmonths,respectively,after
applyingPSM(Figure3B).
Cancers2022,14,48739of14
Figure3.TherapeuticeffectsofNew‐FPandsorafenibinHCCwithmajorPVTT.(A)Cohort5,sur‐
vivalcurvesofpatientswithmajorPVTT‐HCCbeforepropensityscorematching:New‐FP(n=177,
blueline)andsorafenib(n=114,redline).(B)Cohort5,survivalcurvesofpatientswithmajorPVTT‐
HCCafterpropensityscorematching:New‐FP(n=78,blueline)andsorafenib(n=78,redline).(C)
TherapeuticresponseforNew‐FPinmajorPVTT‐HCC.(D)Survivalcurvesintheresponder(red
line,n=57)andnon‐respondergroups(blueline,n=21)forNew‐FP.(E)Survivalcurvesindifferent
therapeuticresponsegroupsforNew‐FP:CR(redline,n=13),PR(blueline,n=44),SD(yellowline,
n=13),andPD(greenline,n=8).CR,completeresponse;HCC,hepatocellularcarcinoma;HR,haz‐
ardratio;MST,mediansurvivaltime;PD,progressivedisease;PR,partialresponse;PVTT,portal
veintumorthrombus;SD,stabledisease.
3.5.2.ForestPlotAnalysis
Weperformedaforestplotanalysistoshedlightonthefactorsassociatedwithprog‐
nosisinpatientswithmajorPVTT‐HCC(Figure4).Sorafenib,anAFPlevelof≥400ng/mL,
Cancers2022,14,487310of14
thepresenceofEHS,thepresenceofVp4(portalveininvasioninthemaintrunk),tumor
size≥5cm,andage≥65yearswerepoorprognosticfactorsinpatientswithmajorPVTT‐
HCC.
Figure4.Forestplotanalysisforfactorsassociatedwithpoorprognosisinpatientswithmajor
PVTT‐HCC.AFP,alpha‐fetoprotein;EHS,extrahepaticspread;HCC,hepatocellularcarcinoma;
Vp4,tumorinvasionintothetrunkoftheportalvein;PVTT,portalveintumorthrombus.
3.5.3.EfficacyofNew‐FPinMajorPVTT‐HCC
DataonthetherapeuticresponsetoNew‐FPformajorPVTT‐HCCareshowninFig‐
ure3C.TheCR,PR,SD,andPDrateswere16.6%,56.4%,16.7%,and10.3%,respectively.
Theobjectiveresponseratewas73.0%,andthediseasecontrolratewas89.7%.TheMSTs
ofrespondersandnon‐responderswere23andsixmonths,respectively(p=0.0043,HR
0.48,95%CI0.29–0.79,Figure3D).TheMSTsofpatientswhoachievedCR,PR,SD,and
PDwere59,17.2,8,and4months,respectively(p<0.0001,Figure3E).
4.Discussion
ThisstudydemonstratedtheefficacyofNew‐FPundervarioustumorconditionsin
patientswithpreservedliverfunction.New‐FPwasshowntobehighlyeffectiveinpa‐
tientswithMVIregardlessofthepresenceofEHS.Intheprognosticanalysisofthewhole
datasetconductedafterapplyingPSM,thefactorsassociatedwithbetterprognosiswere
aChild–Pughscoreof5andNew‐FP,andthefactorsassociatedwithpoorprognosiswere
thepresenceofmajorPVTTandEHS.New‐FPalsoshoweddramaticefficacyinpatients
withmajorPVTT‐HCC.TheobjectiveresponseratetoNew‐FPformajorPVTT‐HCCwas
>70%,andtheMSTfortheresponderswas>20months.Notably,16.6%ofpatientswith
majorPVTT‐HCCachievedCRonapplyingNew‐FP;theMSTofthepatientswho
achievedCRwas59months.
Thisstudyisthelargestretrospectivecohortstudycomparingtheefficacyofasingle
HAICregimenandsystemictreatmentforHCCinpatientswithpreservedliverfunction.
Inthisstudy,theefficacyofNew‐FPwasdrasticallyenhancedbyexcludingpatientswith
poorliverfunction.Ueshimaetal.similarlyreportedalarge‐scaleretrospectivecohort
Cancers2022,14,487311of14
studyexaminingtheefficacyofHAICandsorafenibforHCCinpatientswithpreserved
liverfunction[18].TheHAICregimensevaluatedintheirstudyincludedcisplatinmono‐
therapy,interferon‐α+5‐FU,andlow‐doseFP;theMSTsofpatientswithHCCwithMVI
andwithoutEHSwere10.6monthsforHAICand9.1monthsforsorafenib.HAICwas
statisticallysignificantlysuperiortosorafenibaloneforMVI‐HCC.Althoughadirectcom‐
parisonbetweenthereferencedreportandthecurrentstudycannotbemade,wenotethat
theMSTforNew‐FPwassuperiortothatofHAICinthispriorstudy.Recently,ourgroup
reportedacomparativestudybetweenNew‐FPandaconventionalHAICregimenoflow‐
doseFP[19];thestudyrevealedthatNew‐FPprolongedpatientsurvivalascomparedto
low‐doseFP.TheseresultssuggestthatapplyingaHAICregimenisimportantinthe
treatmentofHCC.
Inthisstudy,New‐FPshowedstrongefficacyforMVI‐HCC,regardlessofthepres‐
enceofEHS.SystemictreatmentisrecommendedforpatientswithHCCinvolvingEHS
[20].However,thedegreeofprogressionofhepaticlesionsoftendeterminestheprognosis
ofpatientswithHCCinvolvingEHS[21].Ourpreviousreportshowedthatprimarytu‐
morstageT4wasanindependentprognosticfactorinpatientswithHCCandEHS[22].
Therefore,locoregionaltreatmentisimportantevenforHCCwithEHS.Tofindtheap‐
propriatetherapeuticstrategyforHCCwithEHS,wehavetoproperlyassesstheprogres‐
sionofhepaticlesions.Then,weneedtoselectthebesttreatment.Furtheranalysesare
neededtoclarifytheclinicalquestionregardingtreatmentforHCCwithEHS.
TheprognosisforpatientswithmajorPVTT‐HCCisextremelypoor.Forexample,
thebasalprognosisofsuchpatientsisthreemonthsforVp4andsixmonthsforVp3(right
orleftportalveininvasion)[23].Thepreviouslyreportedprognosisofpatientswithmajor
PVTT‐HCCtreatedwithsorafenibwas6.5months[24].Theprognosisforother1st‐line
systemictreatments,suchaslenvatinibandatezolizumabplusbevacizumabcombination
therapy,isalsoapproximatelysixmonths[7,25].IntheSILIUStrial,arandomizedclinical
trialcomparingtheefficacyofsorafenibandsorafenibpluslow‐doseFPinthetreatment
ofHCC,additionallow‐doseFPshowedastatisticallysignificanteffectformajorPVTT‐
HCCascomparedwithsorafenib[26];theseresearchersalsoreportedthatobjectivere‐
sponsecouldbeanindependentprognosticfactorforOS[27].Inourcurrentstudy,re‐
sponderstoNew‐FPdemonstratedlongersurvival.Surprisingly,theMSTofCRcases
reachednearlyfiveyears.Achievingatherapeuticresponseiscriticallyimportantinthe
treatmentofmajorPVTT‐HCC,andevidenceindicatesthatNew‐FPshouldbeselected
forthesepatients.
Currently,weareinaneraofsystemictreatmentsforHCC,andsequentialdrugther‐
apyhasbecomemainstream[28].However,therearemanylocoregionaltreatmentsavail‐
ableforHCCaswell.Therefore,weneedtofindanoptimaltherapeuticstrategythatcom‐
binessystemicandlocoregionaltreatments.Inthestudy,themultivariateanalysisre‐
vealedthatthepoorprognosticfactorsoftheNew‐FP/HAICgroupbeforePSMwerea
Child–Pughscoreof6,thepresenceofmajorPVTT,andEHS,respectively.Tomanagethe
patientswiththesefactors,New‐FPmonotherapymightbenotenough.Ikedaetal.re‐
portedontheusefulnessofacombinationtherapy(cisplatinmonotherapyandsorafenib)
[29].WealsopreviouslyreportedontheefficacyofcombinationtherapywithTACEor
HAICandlenvatinib[30],andKudoetal.reportedontheimportanceofconversiontreat‐
mentafteratezolizumabplusbevacizumabcombinationtherapy[31].Thesereportssug‐
gestthatmultidisciplinarytreatmentcombiningsystemicandlocoregionaltreatments,in‐
cludingHAIC,mightbethebesttherapeuticstrategyforthemanagementofadvanced
HCC.Fromthisperspective,dataavailabletodatestronglysuggestthatNew‐FP,which
demonstratesahighresponserate,canbeaneffectivechoiceintheeraofmultisystemic
treatments.
AlthoughthestudyrevealedtheeffectivenessofNew‐FPforPVTT‐HCC,thebest
treatmentforBCLC‐Bstillremainsunclear.Inthestudy,cohort1istheanalysisforBCLC‐
B.TherewasnosignificantdifferenceintheMSTsbetweenNew‐FPandsorafenib.One
ofthereasonswhythereisnodifferenceisthattumorconditionsaretooheterogeneous.
Cancers2022,14,487312of14
TACEisrecommendedforBCLC‐B.However,thesystemictreatmentisalsorecom‐
mendedforTACEunsuitablecasesinBCLC‐B.Sofar,therehavebeennoclinicaltrials
whichdirectlycomparedwithTACE,HAIC,andthesystemictreatmentinthearea.What
weknowinthetreatmentofBCLC‐Bisthatachievingcompleteresponse/cancer‐freepro‐
longssurvivalandsequentialtherapy,e.g.,TACEtosystemictreatments,TACEtoHAIC,
orHAICtosystemictreatments,canprolongthetimetoprogressiontoBCLC‐C[32].Fur‐
theranalysesareneededtofindthebesttreatmentforBCLC‐B.
Thisstudyhasseverallimitations.First,thisstudywasretrospectiveinnature.Sec‐
ond,althoughPSMwasconducted,theratiooftumorconditions(suchasinregardto
MVI)mightbefavorableforNew‐FP;therefore,weperformedsubgroupanalyses.Third,
thenumberofpatientsincohort3wasverylow.Thereisapossibilitythatselectionbias
mighthaveaffectedtheoutcomesincohort3.Additionally,thedataregardingpost‐treat‐
mentswerenotcollectedbecauseoftheissueduetothemulticenterstudy.Influenceof
post‐treatmentssignificantlyaffectspatients’survival.Toovercometheselimitations,we
needtoperformarandomizedprospectivestudytocompareNew‐FPandvariousMTAs,
includingsorafenib,inthefuture.
5.Conclusions
Inconclusion,wefoundthatNew‐FPmeaningfullyprolongedtheOSofpatients
withHCCwithpreservedliverfunction,especiallypatientswithMVI‐HCC,regardlessof
thepresenceofEHS.Moreover,New‐FPshowedstatisticallysignificantefficacyinpa‐
tientswithmajorPVTT‐HCC.WeconcludethatNew‐FPisapromisingHAICregimen
thatcanprovideachanceofsurvivalformorethanfiveyearsevenforpatientswithmajor
PVTT‐HCC.
SupplementaryMaterials:Thefollowingsupportinginformationcanbedownloadedat:
https://www.mdpi.com/article/10.3390/cancers14194873/s1,TableS1:Patientcharacteristicsbefore
andafterpropensityscorematchingincohort1,TableS2:Patientcharacteristicsbeforeandafter
propensityscorematchingincohort2,TableS3:Patientcharacteristicsbeforeandafterpropensity
scorematchingincohort3,Patientcharacteristicsbeforeandafterpropensityscorematchingin
cohort4,Patientcharacteristicsbeforeandafterpropensityscorematchingincohort5.TableS4:
Patientcharacteristicsbeforeandafterpropensityscorematchingincohort4,TableS5:Patientchar‐
acteristicsbeforeandafterpropensityscorematchingincohort5.
AuthorContributions:Datacuration,H.N.,K.U.,J.T.,T.K.(TeijiKuzuya),K.K.,Y.K.,A.H.,R.S.,
T.Y.,S.T.,A.D.,S.S.,T.S.,M.S.,H.S.andE.M.;conceptualizationandwriting—originaldraftprepa‐
ration,H.I.;supervision,T.N.,H.K.,T.T.andT.K.(TakumiKawaguchi).Allauthorshavereadand
agreedtothepublishedversionofthemanuscript.
Funding:H.I.waspartlygrantedfromtheTakedaScienceFoundation,theShinnihonFoundation
ofAdvancedMedicalTreatmentResearch,andtheYasudaMedicalfoundation.
InstitutionalReviewBoardStatement:ThestudyprotocolwasapprovedbytheEthicsCommittee
oftheKurumeUniversitySchoolofMedicine(No.19004).Theethicalapprovednumbersineach
facilityareshownbelow.No.31‐9intheEhimePrefecturalCentralHospital,2019‐0159intheFujita
HealthUniversity,2021‐159inKagawaUniversity,19064intheOsakaNationalHospital,2019‐13
intheNationalHospitalOrganizationKyushuCancerCenter,H18‐154inJuntendoUniversity.Ad‐
ditionally,theopt‐outagreementregardingthestudyispresentedinthehomepageoftheKurume
UniversitySchoolofMedicine,inwhicharedescribedallfacilitiesregisteredinthestudy.
InformedConsentStatement:Allproceduresfollowedwereinaccordancewiththeethicalstand‐
ardsoftheresponsiblecommitteeonhumanexperimentation(institutionalandnational)andwith
theHelsinkiDeclarationof1975,asrevisedin2008.Therequirementforwritteninformedconsent
waswaivedowingtotheretrospectivestudydesign.
DataAvailabilityStatement:DataarecontainedwithinthearticleorSupplementaryMaterials.
Acknowledgments:TheauthorsthankthemembersoftheKurumeLiverCancerStudyGroupof
JapanandtheNew‐FPStudyGroup.HironoriKogaisarepresentativeofthisgroup.
Cancers2022,14,487313of14
ConflictsofInterest:Theauthorsdeclarethattheyhavenoconflictofinterest.
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32. Shimose,S.;Iwamoto,H.;Tanaka,M.;Niizeki,T.;Shirono,T.;Kajiwara,A.;Noda,Y.;Kamachi,N.;Okamura,S.;Nakano,M.;
etal.Multimolecular‐TargetedAgentsforIntermediate‐StageHepatocellularCarcinomaInfluenceTimetoStageProgression
andOverallSurvival.Oncology2021,99,756–765,https://doi.org/10.1159/000518612.
... MVI is a critical condition that directly impacts liver function and is associated with a poor prognosis and shorter survival time [32,33]. Previous studies have shown promise for using HAIC for patients with MVI [34,35]. Moreover, a meta-analysis has indicated that combining molecular-targeted agents with HAIC can improve OS compared to using molecular-targeted agents alone in patients with advancedstage HCC [36,37]. ...
Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching
Article
Full-text available
  • Sep 2023
  • INT J MOL SCI
This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group (n = 30) or the LEN monotherapy group (n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.
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... Several studies comparing HAIC to conventional therapy, including sorafenib, have reported the efficacy of HAIC in patients with advanced HCC, especially MVI [7][8][9]. More recently, among HAIC regimens, the efficacy of New-FP therapy using fine-powder cisplatin (CDDP) suspended in lipiodol and 5-fluorouracil (5-FU) in MVIand major PVTT-HCC has been reported, showing high response rates and prolonged survival [10]. We also previously reported that the combination of HAIC with New-FP therapy and radiotherapy has shown favorable outcomes for MVI-HCC, especially when combined with sorafenib post-treatment [11]. ...
Prognostic Value of Skeletal Muscle Loss in Patients with Hepatocellular Carcinoma Treated with Hepatic Arterial Infusion Chemotherapy
Article
Full-text available
  • Mar 2023
Simple Summary Although reduced skeletal muscle mass affects therapeutic efficacy and adverse events in various therapies for hepatocellular carcinoma (HCC), there are no reports on skeletal muscle mass or its changes and prognostic indications in patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). This is the first study to show the association between the presence of a decreased skeletal muscle index (SMI) and clinical outcomes in HAIC, with novel evidence having a strong impact. A decrease in the SMI immediately after the start of HAIC was significantly associated with poor progression-free survival and overall survival in patients with advanced HCC, whereas the pre-treatment SMI was not a significant factor. Additionally, patients with a decreased SMI after treatment had worse nutritional status and liver function and poor therapeutic effects. It is effective to monitor the SMI and evaluate the therapeutic effects by using computed tomography to evaluate general conditions and predict clinical outcomes. Abstract Sarcopenia-related factors, including the skeletal muscle index (SMI), are reportedly associated with prognosis in patients with hepatocellular carcinoma (HCC) receiving various treatments. However, there is no evidence relating to hepatic arterial infusion chemotherapy (HAIC). In this study, we investigated whether a low SMI was associated with worse clinical outcomes of HAIC. Seventy patients with advanced HCC were included. Clinical outcomes were compared between the decreased SMI (n = 27) and non-decreased SMI (n = 43) groups, which were classified according to changes in the SMI after 3 weeks of treatment. In the prognostic analysis, patients in the decreased SMI group had significantly shorter progression-free and overall survival (OS) than those in the non-decreased SMI group. In addition, poor nutritional status and liver function were associated with an immediate decrease in the SMI after HAIC. The therapeutic effect was worse in the decreased SMI group than in the non-decreased SMI group, although the incidence of adverse events did not significantly differ. In multivariate analysis, a decreased SMI at 3 weeks after HAIC was identified as a significant independent factor associated with OS. A decreased SMI in patients with advanced HCC undergoing HAIC was associated with poor prognosis. It is effective to monitor the SMI to evaluate general conditions and predict clinical outcomes.
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Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity
Article
Full-text available
  • Feb 2023
Recently, treatments for unresectable hepatocellular carcinoma (HCC) have undergone remarkable development. Various systemic chemotherapy drugs have been approved and are recommended by clinical guidelines worldwide. Although systemic treatments are effective and contribute to prolonged patient survival, their effects are unsatisfactory for some specific tumor conditions, such as macrovascular invasion. Hepatic arterial infusion chemotherapy (HAIC) is a traditional treatment for advanced HCC. As yet, there is no worldwide consensus recommending HAIC because no high-quality clinical trials have demonstrated its survival benefit. However, clinical evidence is gradually accumulating that shows its survival benefit, and it is recognized as an effective locoregional treatment for advanced HCC. Several HAIC regimens have been reported, including cisplatin monotherapy, cisplatin plus 5-fluorouracil (low-dose FP), lipiodol-suspended FP, and an oxaliplatin-based regimen. We have entered an era of chemo-diversity in the treatment of advanced HCC. This review aimed to clarify the relevance of HAIC in the era of chemo-diversity. We propose a multidisciplinary therapeutic strategy combining locoregional HAIC treatment with sequential drug therapy, with the aim of becoming cancer-free through conversion therapy.
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Clinical Practice Guidelines for Hepatic Arterial Infusion Chemotherapy with a Port System Proposed by the Japanese Society of Interventional Radiology and Japanese Society of Implantable Port Assisted Treatment
Article
Full-text available
  • May 2022
Hepatocellular carcinoma is one of the leading causes of cancer-related death not only in Japan, but also worldwide. In the advanced stage, hepatic arterial infusion chemotherapy (HAIC) is one of the most commonly used treatment options for liver cancer in Japan and implantation of a catheter system (called a port system) in the body is a treatment method that has evolved mainly in Japan. The Guideline Committee of the Japanese Society of Interventional Radiology and the Japanese Society of Implantable Port Assisted Treatment jointly developed clinical practice guidelines for HAIC with a port system to ensure its appropriate and safe performance and these were published in Japanese in 2018. We have now written an updated English version of the guidelines with the aim of making this treatment widely known to experts around the world. In this article, the evidence, method, indication, treatment regimen, and maintenance of the system are summarized.
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Changing the Treatment Paradigm for Hepatocellular Carcinoma Using Atezolizumab plus Bevacizumab Combination Therapy
Article
Full-text available
  • Oct 2021
Atezolizumab plus bevacizumab combination therapy was approved worldwide for use in 2020. A 30% objective response rate with 8% complete response (CR) was achieved in a phase 3 IMbrave150 trial. Here, the change in the treatment strategy for hepatocellular carcinoma (HCC) using atezolizumab plus bevacizumab combination therapy is reviewed. The phase 3 IMbrave150 clinical trial was successful because of the direct antitumor effect of bevacizumab, which shifted the suppressive immune microenvironment to a responsive immune microenvironment, in addition to its synergistic effects when combined with atezolizumab. The analysis of CR cases was effective in patients with poor conditions, particularly tumor invasion in the main portal trunk (Vp4), making the combination therapy a breakthrough for HCC treatment. The response rate of the combination therapy was 44% against intermediate-stage HCC. Such a strong tumor-reduction effect paves the way for curative conversion (ABC conversion) therapy and, therefore, treatment strategies for intermediate-stage HCC may undergo a significant shift in the future. As these treatment strategies are effective in maintaining liver function, even in elderly patients, the transition frequency to second-line treatments could also be improved. These strategies may be effective against nonalcoholic steatohepatitis-related hepatocellular carcinoma and WNT/β-catenin mutations to a certain degree.
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Clinical Importance of Regimens in Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Macrovascular Invasion
Article
Full-text available
  • Sep 2021
Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child–Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively (p < 0.05, p < 0.05). The complete response (29%) and objective response rate (76%) of New FP were significantly higher than those of LFP (p < 0.001, p < 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC.
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Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update
Article
Full-text available
  • May 2021
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other’s work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma
Article
Full-text available
  • Feb 2021
Backround: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. Methods: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. Results: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. Conclusions: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.
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AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma
Article
  • Mar 2022
  • GASTROENTEROLOGY
Background & Aims Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines. Methods The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. Results The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab. Conclusions The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.
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Sorafenib Plus Hepatic Arterial Infusion Chemotherapy versus Sorafenib for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis: A Randomized Trial
Article
  • Feb 2022
  • RADIOLOGY
Background The prognosis of hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (PVTT) is dismal after standard treatment with sorafenib. Hepatic arterial infusion chemotherapy (HAIC) has been suggested for patients with HCC and major PVTT. Purpose To compare the efficacy and safety of sorafenib plus 3cir-OFF HAIC versus sorafenib alone for advanced HCC with major PVTT. Materials and Methods This phase II trial recruited systemic treatment-naïve patients with HCC and major PVTT (portal vein invasion grade Vp3 [first branch] and Vp4 [main trunk]) between June 2017 and November 2019. Patients were randomly assigned (1:1 ratio) to receive sorafenib (400 mg twice daily) plus 3cir-OFF HAIC (35 mg/m2 oxaliplatin [hours 0-2] followed by 600 mg/m2 5-fluorouracil [hours 2-24], days 1-3) with a standardized percutaneous port catheter system or sorafenib alone (400 mg twice daily) every 4 weeks. The primary end point was overall survival (OS). The secondary end points were objective response rate, progression-free survival (PFS), and safety. OS and PFS were assessed using the Kaplan-Meier method and log-rank test. Results The intent-to-treat population included 64 patients, with 32 in each group. The median OS was 16.3 months (95% CI: 0.0, 35.5) with sorafenib plus HAIC and 6.5 months (95% CI: 4.4, 8.6) with sorafenib alone (hazard ratio [HR] = 0.28; 95% CI: 0.15, 0.53; P < .001). A higher objective response rate (41% [n = 13] vs 3% [n = 1], P < .001) and a longer median PFS (9.0 months vs 2.5 months; HR = 0.26; 95% CI: 0.15, 0.47; P < .001) were observed in the sorafenib plus HAIC group. Grade 3 or 4 adverse events were more frequent in the sorafenib plus HAIC group, including diarrhea (n = 7 [22%] vs n = 5 [16%]), hand-foot syndrome (n = 6 [19%] vs n = 2 [6%]), and thrombocytopenia (n = 7 [22%] vs n = 0). Conclusion Sorafenib plus 3cir-OFF hepatic arterial infusion chemotherapy may be a promising treatment in patients with hepatocellular carcinoma and major portal vein tumor thrombosis because of the improved survival and an acceptable safety profile. Clinical trial registration no. NCT03009461 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chung in this issue.
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Management of hepatocellular carcinoma patients with portal vein tumor thrombosis: A narrative review
Article
  • Dec 2021
  • HEPATOB PANCREAT DIS
Background: Hepatocellular carcinoma (HCC) is one of the main reasons for malignancy-related death. Portal vein tumor thrombosis (PVTT) is the most common form of macrovascular invasion related to HCC occurring in 10%-60% of patients. HCC with PVTT is usually characterized by worsening liver function, vulnerability to blood metastasis, higher incidence of complications associated with portal hypertension, and intolerance to treatment when compared with that without PVTT. If only treated with supportive care, the median survival of HCC with PVTT is about 2.7 months. In the past, sorafenib was the only recommended therapy by guidelines with limited effectiveness. This narrative review aimed to describe the current management options for HCC with PVTT. Data sources: We have reviewed literature from PubMed on the treatment of HCC with PVTT and compiled evidence-based facts on effective therapies available for different types of PVTT. Results: Sorafenib monotherapy is not much effective, but combining it with other methods can improve survival. Each type of PVTT can benefit from the combination of transarterial chemoembolization and sorafenib than sorafenib monotherapy. The tumor downstaging can be realized possibly after transarterial chemoembolization, but tumor invasion into the main trunk of the portal vein greatly impairs efficacy. Although surgery is a curative approach, it is often not recommended for Vp4 PVTT. Some new methods can broaden the indication, but further explorations are needed. Radiotherapy can decrease the possibility of Vp3 progression to Vp4, but building a forecast model of best radiation dose and response is necessary. Systemic chemotherapy, hepatic arterial infusion chemotherapy, radiofrequency ablation, portal stenting, and traditional Chinese medicine are also beneficial in Vp3-4 PVTT. The accurate diagnosis of PVTT can be made by radiomics, and prognostic classification models can be used to design personalized treatments. The application of new treatment methods such as the atezolizumab plus bevacizumab scheme may increase survival. Conclusions: HCC with PVTT is still a thorny problem, and effective therapeutics need to be explored.
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Multimolecular-Targeted Agents for Intermediate-Stage Hepatocellular Carcinoma Influence Time to Stage Progression and Overall Survival
Article
  • Sep 2021
Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage. Methods: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Results: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01). Conclusion: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS.
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Evidence-based management of HCC: Systematic review and meta-analysis of randomized controlled trials (2002-2020)
Article
  • Jun 2021
  • GASTROENTEROLOGY
Background and Aims Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality with a rapidly changing landscape of treatments. In the past 20 years, numerous randomized controlled trials (RCT) have aimed at improving outcomes across disease stages. We aimed at analyzing the current evidence and identifying potential factors influencing response to therapies. Methods We conducted a systematic review of phase III RCTs across disease stages (2002-2020). Meta-analysis was designed to examine the relationship between etiology and outcome after systemic therapies with either tyrosine-kinase inhibitor/antiangiogenic or immune checkpoint inhibitors (ICI) therapy. Results Out of 10,100 studies identified, 76 were phase III RCT. Among them, a rigorous screening algorithm identified 49 with high-quality including a total of 22,113 patients undergoing adjuvant (n=7) and primary treatment for early (n=2), intermediate (n=7) and advanced stage disease (first-line, n=21; second-line, n=12). Nine of these trials were positive, six treatments have been adopted in guidelines [sorafenib (2 RCTs), lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib and ramucirumab] but two did not (adjuvant CIK cells and sorafenib-hepatic arterial infusion with FOLFOX). Meta-analysis of 8 trials including 3739 patients revealed ICI therapy to be significantly more effective in patients with viral hepatitis when compared with non-viral related HCC whereas no differences related to etiology were observed in patients treated with TKI/anti-VEGF. Conclusions Among 49 high-quality RCTs conducted in HCC during 2002-2020, nine resulted in positive results. A meta-analysis of systemic therapies suggest that immunotherapies may be less effective in non-viral etiologies.
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