1 HEPATOCELULAR CARSINOMA

7232019 1 HEPATOCELULAR CARSINOMA

httpslidepdfcomreaderfull1-hepatocelular-carsinoma 17

Hindawi Publishing CorporationBioMed Research InternationalVolume 983090983088983089983091 Article ID 983091983089983088983092983090983095 983094 pageshttpdxdoiorg983089983088983089983089983093983093983090983088983089983091983091983089983088983092983090983095

Review ArticleClinical Significance of AFP and PIVKA-II Responses forMonitoring Treatment Outcomes and Predicting Prognosis inPatients with Hepatocellular Carcinoma

Hana Park 12 and Jun Yong Park 345

983089 Department of Internal Medicine CHA Bundang Medical Center CHA University Seongnam-si Republic of Korea983090 Institute of Gastroenterology CHA Bundang Medical Center CHA University Seongnam-si Republic of Korea983091 Department of Internal Medicine Yonsei University College of Medicine 983089983091983092 Sinchon-dong Seodaemun-gu Seoul Republic of Korea983092 Institute of Gastroenterology Yonsei University College of Medicine Seoul Republic of Korea983093 Yonsei Liver Cancer Special Clinic Yonsei University College of Medicine Seoul Republic of Korea

Correspondence should be addressed to Jun Yong Park drpjyyuhsac

Received 983090983089 November 983090983088983089983091 Accepted 983097 December 983090983088983089983091

Academic Editor Mohammad Ahmad al-Shatouri

Copyright copy 983090983088983089983091 H Park and J Y Park Tis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Aim Recently the utility o tumor markers in the hepatocellular carcinoma (HCC) 1047297eld has received a good deal o attention Here

we review and summarize the results o studies on the roles played by the -etoprotein (AFP) and prothrombin induced by theabsence o vitamin K or antagonist-II (PIVKA-II) responses in terms o the monitoring o outcomes and prediction o prognosisafer various HCC treatments Methods Studies lodgedin PUBMED and that satis1047297ed our inclusion criteria were reviewed ResultsWe reviewed 983089983090 studies measuring both AFP and PIVKA-II responses in HCC patients treated in various ways Te results arepresented by treatment modality Conclusion Measurement o AFP and PIVKA II marker levels beore and afer HCC treatment isclinically useul in monitoring o treatment outcomes and prognosis and in predicting recurrence and survival

1 Introduction

Although treatments and surveillance have improved hepa-tocellular carcinoma (HCC) remains difficult to cure partic-ularly when the disease is progressive Because only limited

treatment options are available the prognosis is poor [983089]Tus early diagnosis or detection o disease progressionafer treatment remains key to effective control o HCCImaging assessment remains the gold standard or evaluationo responses afer various HCC treatments [983090ndash983092] Howeverradiological analysis o HCC patients with vascular invasionor multiple lesions may not yield clear data on diseasedevelopment especially in cirrhotic patients In additionextensive desmoplastic and in1047298ammatory reactions andischemic changes and tissue edema develop afer transar-terial chemoembolization (ACE) or radiotherapy and may mask improvement in tumor size that is normally detectableby conventional imaging modalities including radiology [983093]

One possible way to deal with this limitation is via mea-surement o tumor markers yielding inormation ancillary toimaging data Such markers have been studied previously [983094983095] Measurement o -etoprotein (AFP) level is simple and isalready used widely or routine surveillance and noninvasive

diagnosis o HCC and to evaluate prognosis and monitorrecurrence ollowing treatment [983093 983094] However AFP serumlevels can also be increased in patients with other nontumor-ous hepatic disorders including acute and chronic hepatitiso any type cirrhosis andor massive hepatic necrosis andmay re1047298ect (general) hepatic in1047298ammatory and regenerativeactivity [983094 983096 983097] However serum prothrombin inducedby the absence o vitamin K or antagonist-II (PIVKA-II)measurement not only more speci1047297cally differentiates HCCrom other hepatic diseases [983089983088 983089983089] but PIVKA-II levels arenot also usually correlated with those o AFP [983089983090 983089983091] Tusmeasures o PIVKA-II and AFP are independent Althoughthe AFP serum level re1047298ects the intrahepatic tumor burden



983090 BioMed Research International

assessment o serum PIVKA-II level re1047298ects the extent o vascular invasion including portal vein thrombosis andextrahepatic disease extension [983089983092] and is regarded as com-plementary to serum AFP measurement Tus measuremento both PIVKA-II and AFP levels may yield useul inorma-tion on treatment response and prognosis in HCC patients

Because thehal-lives o the two serum markers are only a ew weeks [983089983093] changes in serum AFP andPIVKA-II levels beoreand afer treatment may provide clinically useul inormationon both treatment outcome and prognosis Te clinical utility o simultaneous AFP and PIVKA-II measurement was 1047297rstreport by Aoyagi et al in 983089983097983097983094 [983089983094] Since then many studieshaveocusedon use o a combination othe levelso these twomarkers to assess treatment response to predict prognosisand indeed to diagnose HCC [983089983095ndash983090983091]

Multimodal treatment is mandatory in HCC patientsand the prognostic cutoff values and predictive powers o AFP and PIVKA-II levels will differ according to the chosentreatment modality Tereore we reviewed and summarized

the results o studies on the utilities o AFP and PIVKA-IIlevels in monitoring o treatment outcomes and predictingprognosis

2 Methods

983090983089 Search Strategy A computerized English-languagesearcho PUBMED was perormed in September 983090983088983089983091 Studiespublished at any time were included Afer a preliminary search o the MeSH database we used the terms ldquoAFP andPIVKA-IIrdquo ldquoAFP and DCPrdquo ldquocombination tumor markersrdquoldquoHCCrdquo ldquotreatment responserdquo and ldquoprognosisrdquo to search titlesandor abstracts

983090983090 Study Eligibility and Critical Appraisal We careully reviewed all studies on AFP and PIVKA-II markers in theHCC context and selected studies (983089) dealing with both AFPand PIVKA-II (983090) eaturing measurement o both tumormarkers beore and afer treatment o HCC and (983091) ocusingon the roles played by both tumor markers in assessingtreatment outcomes or predicting prognosis and survival Weound 983089983090 studies that met these criteria when investigating theutilities o various HCC treatment modalities (able 983089)

3 Results

983091983089 Serum AFP and PIVKA-II Levels in Patients Who Under-went Curative Hepatic Resection to Treat HCC Six studiesmeasured both AFP and PIVKA-II levels in patients whounderwent curative hepatic resection [983090983088 983090983092ndash983090983096]

983091983089983089 Monitoring Treatment Outcomes Yamamoto et alreported that the avorable predictive values o pretreatmentAFP and PIVKA-II levels in terms o postoperative recur-rence had AUROCs o 983088983095983097 and 983088983097983089 respectively [983090983094] Tesensitivity and speci1047297city o recurrence detection improvedsimultaneously when both AFP and PIVKA-II levels weremeasured (sensitivity 983094983094983095 speci1047297city 983092983095983097) compared to

those obtained when AFP levels alone (sensitivity 983094983088983089speci1047297city 983092983093983090) or PIVKA-II levels alone (sensitivity983094983090983097 speci1047297city 983092983095983097) [983090983088] were assessed Patients withhigh pretreatment levels o AFP and PIVKA-II experienced asigni1047297cantly higher incidence o tumor recurrence afer cura-tive treatment [983090983088 983090983093] associated with the more unavorable

tumor characteristics o patients with higher levels o AFPand PIVKA-II [983090983088 983090983089] Chon et al ound that pretreatmentAFP and PIVKA-IIlevels were signi1047297cantly higher in patientswith microscopic vessel invasion or multiple tumors com-pared to others [983090983088] Te roles played by tumor markers inre1047298ecting microscopic vessel invasion or tumor multiplicity can compensate or limitations o current prognostic systems

Te concern was whether changes in tumor markerlevels afer treatment would yield additional inormationon patients who underwent curative resection [983090983088 983090983092 983090983093983090983096] Changes in tumor marker levels afer curative hepaticresection provide inormation on both the pattern andprobability o recurrence In one study high preoperativeserum AFP and PIVKA-II levels were associated with early recurrence (within 983094 months) afer curative resection [983090983094]Such patients had higher preoperative AFP and PIVKA-II

values than did those who developed recurrences gt983094 monthsafer surgery Also patients experiencing extrahepatic recur-rences had higher preoperative marker levels than did thosewith intrahepatic recurrences

983091983089983090 Prediction of Survival Serum AFP and PIVKA-II levelswere also predictive o survival in many studies [983090983088 983090983092ndash983090983095]Changes in tumor marker levels 983091 months afer operationsigni1047297cantly predicted HCC recurrence [983090983088] I marker levelsdid not all recurrence was likely [983090983088 983090983092 983090983093] Patients

with high AFP and PIVKA-II levels afer curative treatmentexperienced signi1047297cantly poorer overall survival than thosewith normal marker levels [983090983093] In addition not only highlevels o markers per se but also shorter doubling times o increases in marker levels were linked to signi1047297cantly poorerdisease-ree and overall survival [983090983095] Tus rapid elevation o marker levels re1047298ects aggressive behavior o remnant tumorsafer curative treatment

Upon multivariate analysis to evaluate the predictive values o marker levels in terms o survival elevated serumlevels o AFP andor PIVKA-II both beore and afer surgery independently predicted disease-ree or overall survival asdid tumor size tumor number and the existence o vascular

invasion [983090983088 983090983092 983090983093] Te numbers o markers elevated beoreoperation and shorter doubling times o marker values werealso predictive o survival [983090983093 983090983095]

983091983090 Serum AFP and PIVKA-II Levels in Patients with TACEwo studies have examined the kinetics o both AFP andPIVKA-II levels in HCC patients treated via transarterialchemoembolization (ACE) [983090983090 983090983097]

983091983090983089 Monitoring Treatment Outcomes Radiological mor-phology afer ACE is sometimes nonhomogenous andinconsistent because o irregular uptake o lipiodol and



BioMed Research International 983091

983137983138983148983141 983089 Studies regarding both AFP and PIVKA-II in the patients who underwent various treatment modalities or HCC

Author Year Number o

patientsreatmentmodality

umormarker

Cutoff value o markers

De1047297nition o tumormarker response

(change rom baseline)

oyoda et al [983090983092] 983090983088983089983090 983089983095983091 Curative

resection

AFPAFP-L983091

PIVKA-II

983090983088 ngdL983093

983092983088 mAUmL

mdash

Chon et al [983090983088] 983090983088983089983090 983090983094983095 Curative

resectionAFP

PIVKA-II983090983088 ngdL

983092983088 mAUmL mdash

Nanashima et al [983090983093] 983090983088983089983089 983092983095983088 Curative

resectionAFP

PIVKA-II

983090983088 ngmL983090983088983088ngmLdagger

983092983088 mAUmL983092983088983088 mAUmLdagger

mdash

Yamamoto et al [983090983094] 983090983088983088983097 983095983089983092 Curative

resectionAFP

PIVKA-II983090983088 ngmL


Masuda et al [983090983095] 983090983088983089983088 983090983089983088 Curative

resectionAFP




resectionAFP



Lee et al [983090983090] 983090983088983089983091 983089983089983093 ACE AFPPIVKA-II

983090983088 ngmL983092983088 mAUmL

ge983093983088 reduction

Park et al [983090983097] 983090983088983089983090 983091983090983095 ACE AFP


983092983088 mAUmL ge983093983088 reduction

Lee et al [983090983091] 983090983088983089983090 983094983088

983094983095HAICCCR

AFPPIVKA-II

983090983088 ngmL983090983088 mAUmL


Park et al [983089983092] 983090983088983089983091 983089983089983089 CCR AFP

PIVKA-II983090983088983088ngmL


Kuzuya et al [983091983088] 983090983088983089983089 983092983096 Soraenib AFP

PIVKA-II mdashDagger mdash

Nakazawa et al [983091983089] 983090983088983089983091 983093983097 Soraenib AFP


983092983088 mAUmLge983090983088 increase woold

increasedaggerPatients were divided into 983091 groups with low and high cutoff values o tumor markers in this studyDaggerumor marker ratio was evaluated in this study

necrosis evident on ollow-up imaging and this can com-promise imaging-based measurements o tumor responses[983091983090 983091983091] Lee et al and Park et al evaluated the serumlevels o AFP and PIVKA-II in efforts to overcome thislimitation [983090983090 983090983097] Radiological responses were assessedusing the modi1047297ed Response Evaluation Criteria in Solidumors (mRECIS) and each patient was considered toshow a complete response (CR) a partial response (PR)stable disease (SD) or progressive disease (PD) as describedin previous reports [983091] When the percentage declines intumor makerlevels afertreatment(rom pretreatmentlevels)were evaluated the reductions in both AFP and PIVKA-IIlevels in patients exhibiting a CR or PR were signi1047297cantly greater than in those with SD or PD [983090983097] In addition a strongassociation between the radiological response and serumAFP and PIVKA-II levels was evident [983090983097] However such anassociation was questioned in another study [983090983090] Te AFPserum level was signi1047297cantly correlated with the radiologicalresponse but the serum level o PIVKA-II was not

983091983090983090 Prediction of Survival Park et al ound signi1047297cantdifferences in median overall survival times between tumor

marker responders and nonresponders [983090983097] Upon mul-tivariate analysis the PIVKA-II and AFP responses weresigni1047297cant indicators o overall survival independent o hosttumor and serological actors when pretreatment valueswere compared with those 983091 and 983094 months afer treatmentLee et al ound that pretreatment AFP levels indepen-dently predicted progression-ree survival but pretreatmentPIVKA-II levels did not In terms o overall prediction o survival the pretreatment PIVKA-II level the presence o cirrhosis the tumor number and the AFP response were all

independent predictors [983090983090] Te cited authors perormed asubanalysis to determine whether a combination o the AFPand PIVKA-II responses would improve the prognostic valueo either alone Afer stratiying patients with AFP andorPIVKA-II responses into combined tumor marker respon-ders and those without AFP and PIVKA-II responses intocombined tumor marker nonresponders overall survival wassigni1047297cantly longer in the ormer than the latter group (983091983097983088

versus 983090983089983093 months log-rank test 1038389 = 0011) In additionthe combined tumor marker response was an independentpredictor o overall survival together with tumor size andthe presence o cirrhosis However in terms o prediction o progression-ree survival no difference was evident between




the two groups Tus the combined tumor marker responsedid not independently predict progression-ree survival uponmultivariate analysis

983091983091 Serum AFP and PIVKA-II Levels Patients Receiving HAIC or CCRT to Treat HCC wo studies examined the

kinetics o both AFP and PIVKA-II levels in HCC patientsundergoing hepatic artery inusional chemotherapy (HAIC)or concurrent chemoradiation therapy (CCR) [983089983092 983090983091]

983091983091983089 Monitoring Treatment Outcomes Lee et al evaluatedthe clinical utilities o AFP and PIVKA-II levels as predictorso treatment outcomes in patients with advanced HCCreceiving HAIC (1103925 = 60) or CCR (1103925 = 67) [983090983091] Inpatients who underwent HAIC the overall response (bothCR and PR according to WHO criteria) was signi1047297cantly higher in AFP responders than nonresponders (983091983094983088 versus983096983094 1038389 = 0009) and also in PIVKA-II responders thannonresponders (983093983088983088 versus 983090983093 1038389 lt 0001) However nodifference in disease control rate (the total o CR PR andSD according to WHO criteria) between AFP or PIVKA-II responders and nonresponders was evident In patientswho underwent CCR only the overall response rate o PIVKA-II responders was signi1047297cantly better than that o PIVKA-II nonresponders (983092983090983090 versus 983089983091983094 1038389 = 0019)neither the overall response nor the disease control rate o AFP responders differed rom those o AFP nonrespondersAnother study on the clinical utilities o AFP and PIVKA-II levels in patients undergoing CCR (1103925 = 1 1 1) ocusedon whether a combination o AFP and PIVKA-II markerlevels could be used to subdivide patients into prognosticgroups [983089983092] Four groups were de1047297ned AdarrPdarr [AFP response(+) and PIVKA-II response (+)] AdarrPuarr [AFP response (+)and PIVKA-II response (minus)] AuarrPdarr [AFP response (minus) andPIVKA-II (+)] AuarrPuarr [AFP response (minus) and PIVKA-II (minus)]Not only the overall response but also the disease control ratewas the best in the AdarrPdarr group ollowed (in order) by theAdarrPuarr AuarrPdarr and AuarrPuarr groups Notably this study showedthat treatment outcome and prognosis differed signi1047297cantly among patients varying in the PIVKA-II response even whenpatients exhibited an AFP response In addition a combina-tion o the responses o both tumor markers predicted thepattern o disease progression extrahepatic versus intrahep-atic Extrahepatic disease occurred more requently in theAdarrPuarr group and intrahepatic disease more requently in theAuarrPdarr group (983093983088983088 versus 983090983096983094 or extrahepatic disease

983093983088983088 versus 983095983089983092 or intrahepatic disease respectively 1038389 =0001) Tis is because the serum AFP level re1047298ects the tumorburden whereas the serum PIVKA-II level re1047298ects the extento vascular invasion (portal vein thrombosis andextrahepaticdisease extension) [983091983092]

983091983091983090 Prediction of Survival In patients who underwentHAIC AFP responders experienced signi1047297cantly better over-all survival than did AFP nonresponders (983089983095983091 versus 983094983092months 1038389 lt 0001) whereas the survival o PIVKA-IIresponders did not differ rom that o PIVKA-II nonre-sponders [983090983091] Similar results were seen in patients whounderwent CCR Te overall survival o AFP responders

was signi1047297cantly longer than that o AFP nonresponders (983089983095983094 versus 983096983095 months 1038389 = 0014) but PIVKA-II respondersand nonresponders did not signi1047297cantly differ in this contextRather PIVKA-II responders among CCR-treated patientsshowed signi1047297cantly better progression-ree survival than didnonresponders (983097983090 versus 983091983089 months 1038389 lt 0001) Multi-

variate analysis revealed that the AFP response was indepen-dently predictive o overall survival in patients treated withHAIC or CCR whereas the PIVKA-II response predictedonly progression-ree survival in patients treated with CCRPark et al ound that the prognoses o AFP responders couldbe urther divided in terms o whether such patients werealso PIVKA-II responders [983089983092] Patients in the AdarrPdarr grouphad signi1047297cantly longer progression-ree and overall survivalthan did those o the AdarrPuarr group (983089983094983090 versus 983093983089 months1038389 = 0009 983090983094983091 versus 983095983091 months 1038389 = 0017 resp) [983089983092] Inaddition o patients who showed a discordant tumor markerresponse (AdarrPuarr or AuarrPdarr)those othe AuarrPdarr group who wereAFP nonresponders had better progression-ree and overallsurvival than did AdarrPuarr patients (983089983088983089 versus 983093983089 months 1038389 =0038 983090983090983092 versus 983095983091 months 1038389 = 0038 resp) Te predictivepower (in terms o survival) o the two combined tumormarkers was betterthan that o AFP alone andcomparable tothat o the radiological response according to the mRECIScriteria

983091983092 Serum AFP and PIVKA-II Levels in Patients GivenSorafenib to Treat HCC wo studies investigated the kineticso both AFP and PIVKA-II afer administration o soraenibto patients with advanced HCC [983091983088 983091983089]

983091983092983089 Monitoring Treatment Outcomes Kuzuya et al [983091983088]measured tumor marker ratios (the concentrations o tumormarkers 983090 and 983092 weeks afer treatment divided by the valuesbeore treatment) At 983090 weeks the AFP (but not the PIVKA-II) ratio was signi1047297cantly higher in patients with PD than inthose withPR or SD At983092 weeks both ratios were signi1047297cantly higher in patients with PD than in those with PR or SDTe median AFP level did not change by either 983090 or 983092weeks afer commencement o soraenib in the PR + SDgroup but a signi1047297cant increase was evident in the PD groupSimilarly Nakazawa et al ound an early increase in AFPlevel (more than 983090983088 that o the baseline value) within983092 weeks afer commencement o soraenib in PD patients[983091983089] However median PIVKA-II levels did not all afer

commencement o soraenib even in the PR + SD group intwo studies [983091983088 983091983089] Rather the median PIVKA-II levels atboth 983090 weeks and983092 weeks increasedsigni1047297cantly over baselinein both the PR + SD and PD groups [983091983088] Such elevation o PIVKA-II levels even in patients who are responding wellhad been reported in previous studies [983091983093 983091983094] One possibleexplanation is that soraenib-mediated inhibition o angio-genesis rendered tumor cells hypoxic increasing PIVKA-II production [983091983088 983091983094] Tereore the elevated PIVKA-IIlevels seen afer administration o soraenib may indicate notonly tumor progression but also tumor responsiveness andcaution must be exercised when interpreting changes in AFPand PIVKA-II levels together




983091983092983090 Prediction of Survival Kuzuya et al assessed the cumu-lative time to progression (using the RECIS criteria) andcumulative overall survival afer dividing patients into twogroups those with low and high tumor marker ratios 983092 weeksafer treatment [983091983088] First the median time to progressionwas signi1047297cantly longer in the low than the high AFP ratio

group (983091983093 versus 983090983089 months 1038389 = 0021) and the medianoverall survival tended to be higher in the ormer than thelatter group but the difference was not statistically signi1047297cant(983097983091 versus 983093983089 months 1038389 = 0089) In terms o PIVKA-II levels no signi1047297cant difference in either cumulative timeto progression or overall survival was evident between thelow and high PIVKA-II ratio groups Nakazawa et al oundthat pretreatment PIVKA-II levels over 983089983088983088983088 mAUmL andan early increase in AFP level were independent predictorso poor overall survival Further an early rise in AFP levelwas the only independent predictor o poor progression-reesurvival [983091983089]

4 Summary and PerspectivesTe clinical utilities o tumor markers o HCC remaincontroversial Te potential roles played by tumor markerstend to be underrated in western reports being consideredo greater value in eastern settings Recently a combinationo AFP and PIVKA-II levels has been recommended ordiagnosis o HCC malignancy in Japan [983089983095] Most priorwork on tumor markers ocused on their possible diagnosticutility However as we have shown measurement o markerlevels both beore and afer HCC treatment is clinically valu-able to monitor treatment outcomes (in combination withradiological analysis) and to predict prognosis recurrenceand survival Serum biomarkers demonstrate great potentialor use in monitoring therapeutic effects and or predictingoutcomes early in HCC treatment Earlier studies useddifferent ldquonormalrdquo values o AFP and PIVKA-II levels and

variously de1047297ned measures o tumor response It is necessary to standardize these measures during uture evaluation o theimportance o tumor markers in patients treated or HCCIn addition HCC patient subdivision into groups de1047297ned by simultaneous consideration o AFP and PIVKA-II levels may yield interesting results

In conclusion measurement o a combination o tumormarkers beore and afer HCC treatment is clinically valuablein terms o monitoring treatment outcomes (together withradiological analysis) and to predict prognosis recurrence

and survival

Abbreviations

HCC Hepatocellular carcinomaAFP -FetoproteinPIVKA-II Prothrombin induced by the absence o

vitamin K or antagonist-IIACE ransarterial chemoembolizationAUROC Areas under the receiver operating

characteristicsmRECIS Modi1047297ed Response Evaluation Criteria in

Solid umors

HAIC Hepatic artery inusional chemotherapy CCR Concurrent chemoradiation therapy

Conflict of Interests

Te authors declare that they have no con1047298ict o interests

Acknowledgment

Tis study was supported by a grant rom the KoreaHealthcare technology RampD Project Ministry o Health andWelare Republic o Korea (HI983089983088C983090983088983090983088)

References

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[983090] J M Llovet A M di Bisceglie J Bruix et al ldquoDesign andendpoints o clinical trials in hepatocellular carcinomardquo Journal of the National Cancer Institute vol 983089983088983088 no 983089983088 pp 983094983097983096ndash983095983089983089983090983088983088983096

[983091] E A Eisenhauer P Terasse J Bogaerts et al ldquoNew responseevaluation criteria in solid tumours revised RECIS guideline(version 983089983089)rdquo European Journal of Cancer vol 983092983093 no 983090pp983090983090983096ndash983090983092983095 983090983088983088983097

[983092] J Furuse H Ishii K Nakachi E Suzuki S Shimizu and KNakajima ldquoPhase I study o soraenib in Japanese patients withhepatocellular carcinomardquo Cancer Sciencevol983097983097no983089pp983089983093983097ndash983089983094983093 983090983088983088983096

[983093] B K Kim S H Ahn J S Seong et al ldquoEarly -etoproteinresponse as a predictor or clinical outcome afer localizedconcurrent chemoradiotherapy or advanced hepatocellular

carcinomardquo Liver International vol 983091983089 no 983091 pp 983091983094983097ndash983091983095983094 983090983088983089983089[983094] P J Johnson ldquoTe role o serum alpha-etoprotein estimationin the diagnosis and management o hepatocellular carcinomardquoClinics in Liver Disease vol 983093 no 983089 pp 983089983092983093ndash983089983093983097 983090983088983088983089

[983095] Y Inagaki W ang M Makuuchi K Hasegawa Y Sug-awara and N Kokudo ldquoClinical and molecular insightsinto the hepatocellular carcinoma tumour marker des-907317-carboxyprothrombinrdquo Liver International vol 983091983089 no 983089 pp 983090983090ndash983091983093 983090983088983089983089

[983096] J R Bloomer A Waldmann K R McIntire andG Klatskinldquoalpha-etoprotein in noneoplastic hepatic disordersrdquo Journal of the AmericanMedical Associationvol983090983091983091no983089pp983091983096ndash983092983089983089983097983095983093

[983097] J R Bloomer A Waldmann K R McIntire andG KlatskinldquoSerum etoprotein in patients with massive hepatic necrosisrdquo

Gastroenterology vol 983095983090 no 983091 pp 983092983095983097ndash983092983096983090 983089983097983095983095[983089983088] K Hamamura Y Shiratori S Shiina et al ldquoUnique clinical

characteristics o patients with hepatocellular carcinoma whopresent with high plasma des-gamma-carboxy prothrombinand low serum alpha-etoproteinrdquo Cancer vol 983096983096 no 983095 pp983089983093983093983095ndash983089983093983094983092 983090983088983088983088

[983089983089] Y Koike Y Shiratori S Sato et al ldquoDes-gamma-carboxy prothrombin as a useul predisposing actor or the develop-ment o portal venous invasion in patients with hepatocellularcarcinoma a prospective analysis o 983090983090983095 patientsrdquo Cancer vol983097983089 no 983091 pp 983093983094983089ndash983093983094983097 983090983088983088983089

[983089983090] L Zhou J Liu and F Luo ldquoSerum tumor markers or detectiono hepatocellular carcinomardquo World Journalof Gastroenterology vol 983089983090 no 983096 pp 983089983089983095983093ndash983089983089983096983089 983090983088983088983094




[983089983091] G Malaguarnera M Giordano I Paladina M Berretta ACappellani and M Malaguarnera ldquoSerum markers o hepato-cellular carcinomardquo Digestive Diseases and Sciences vol 983093983093 no983089983088 pp 983090983095983092983092ndash983090983095983093983093 983090983088983089983088

[983089983092] H ParkS U Kim JYPark et al ldquoClinical useulness o doublebiomarkers AFP and PIVKA-II or subdividing prognosticgroups in locally advanced hepatocellular carcinomardquo Liver International 983090983088983089983091

[983089983093] K Kishi Sonomura K Mitsuzane et al ldquoime courses o PIVKA-II and AFP levels afer hepatic artery embolizationand hepatic artery inusion against hepatocellular carcinomarelationbetween the time course and tumor necrosisrdquo Radiation Medicine vol 983089983088 no 983093 pp 983089983096983097ndash983089983097983093 983089983097983097983090

[983089983094] Y Aoyagi M Oguro M Yanagi et al ldquoClinical signi1047297canceo simultaneous determinations o alpha-etoprotein and des-gamma-carboxy prothrombin in monitoring recurrence inpatients with hepatocellular carcinomardquo Cancer vol 983095983095 no 983097pp 983089983095983096983089ndash983089983095983096983094 983089983097983097983094

[983089983095] N Kokudo and M Makuuchi ldquoEvidence-based clinical practiceguidelines or hepatocellular carcinoma in Japan the J-HCCguidelinesrdquo Journal of Gastroenterology vol 983092983092 no 983089983097 pp 983089983089983097ndash983089983090983089 983090983088983088983097

[983089983096] Nakagawa Seki Shiro et al ldquoClinicopathologic signi-icance o protein induced vitamin K absence or antagonist IIand -etoprotein in hepatocellular carcinomardquo International Journal of Oncology vol 983089983092 no 983090 pp 983090983096983089ndash983090983096983094 983089983097983097983097

[983089983097] F Yamashita M anaka S Satomura and K anikawa ldquoProg-nostic signi1047297cance o Lens culinaris agglutinin Amdashreactive -etoprotein in small hepatocellular carcinomasrdquo Gastroenterol-ogy vol 983089983089983089 no 983092 pp 983097983097983094ndash983089983088983088983089 983089983097983097983094

[983090983088] Y E Chon G H Choi M H Lee et al ldquoCombined mea-surement o preoperative -etoprotein and des-907317-carboxy prothrombin predicts recurrence afer curative resection inpatients with hepatitis-B-related hepatocellular carcinomardquo

International Journal of Cancer vol 983089983091983089 no 983089983088 pp 983090983091983091983090ndash983090983091983092983089983090983088983089983090

[983090983089] S H Kang Y Kim do S M Jeon et al ldquoClinical characteristicsand prognosis o hepatocellular carcinoma with different setso serum AFP and PIVKA-II levelsrdquo European Journal of Gastroenterology amp Hepatology vol 983090983092 no 983095 pp 983096983092983097ndash983096983093983094 983090983088983089983090

[983090983090] Y K Lee S U Kim Y Kim doet al ldquoPrognostic value oalpha-etoprotein and des-gamma-carboxy prothrombin responses inpatients with hepatocellular carcinoma treated with transarte-rial chemoembolizationrdquo BMC Cancer vol 983089983091 article 983093 983090983088983089983091

[983090983091] M H Lee S U Kim D Y Kim et al ldquoEarly on-treatmentpredictions o clinical outcomes using alpha-etoprotein anddes-gamma-carboxy prothrombin responses in patients withadvanced hepatocellular carcinomardquo Journal of Gastroenterol-

ogy and Hepatology vol 983090983095 no 983090 pp 983091983089983091ndash983091983090983090 983090983088983089983090[983090983092] H oyoda Kumada ada et al ldquoPrognostic signi1047297cance

o a combination o pre- and post-treatment tumor markers orhepatocellular carcinoma curatively treated with hepatectomyrdquo Journal of Hepatology vol 983093983095 no 983094 pp 983089983090983093983089ndash983089983090983093983095 983090983088983089983090

[983090983093] A Nanashima N aura Abo et al ldquoumor marker levelsbeore and afer curative treatment o hepatocellular carcinomaas predictors o patient survivalrdquo Digestive Diseases and Sci-ences vol 983093983094 no 983089983088 pp 983091983088983096983094ndash983091983089983088983088 983090983088983089983089

[983090983094] K Yamamoto H Imamura Y Matsuyama et al ldquoSigni1047297-cance o alpha-etoprotein and des-907317-carboxy prothrombin inpatients with hepatocellular carcinoma undergoing hepatec-tomyrdquo Annals of Surgical Oncology vol 983089983094 no 983089983088 pp 983090983095983097983093ndash983090983096983088983092 983090983088983088983097

[983090983095] Masuda Beppu K Horino et al ldquoPreoperative tumormarker doubling time is a useul predictor o recurrence andprognosis afer hepatic resection o hepatocellular carcinomardquo Journal of Surgical Oncology vol 983089983088983090 no 983093 pp 983092983097983088ndash983092983097983094 983090983088983089983088

[983090983096] A Nanashima Y Sumida S obinaga et al ldquoPostoperativechanges in protein-induced vitamin K absence or antagonistII levels afer hepatectomy in patients with hepatocellularcarcinomarelationship to prognosisrdquo HPBvol983096no983090pp983089983091983095ndash983089983092983089 983090983088983088983094

[983090983097] W H Park J H Shim S B Han et al ldquoClinical utility o des-gamma-carboxyprothrombin kinetics as a complement toradiologic response in patients with hepatocellular carcinomaundergoing transarterial chemoembolizationrdquo Journal of Vas-cular and Interventional Radiology vol 983090983091 no 983095 pp 983097983090983095ndash983097983091983094983090983088983089983090

[983091983088] Kuzuya Y Asahina K suchiya et al ldquoEarly decrease in-etoprotein but not des-907317-carboxy prothrombin predictssoraenib efficacy in patients with advanced hepatocellularcarcinomardquo Oncology vol 983096983089 no 983091-983092 pp 983090983093983089ndash983090983093983096 983090983088983089983089

[983091983089] Nakazawa H Hidaka J akada et al ldquoEarly increase in

alpha-etoprotein or predicting unavorable clinical outcomesin patients with advanced hepatocellular carcinoma treatedwith soraenibrdquo European Journal of Gastroenterology amp Hep-atology vol 983090983093 no 983094 pp 983094983096983091ndash983094983096983097 983090983088983089983091

[983091983090] A Riaz K Memon F H Miller et al ldquoRole o the EASLRECIS and WHO response guidelines alone or in com-bination or hepatocellular carcinoma radiologic-pathologiccorrelationrdquo Journal of Hepatology vol 983093983092 no 983092 pp 983094983097983093ndash983095983088983092983090983088983089983089

[983091983091] M M Arnold L Kreel A C Wallace and A K C LildquoDistribution o lipiodol and evidence or tumor necrosis inhepatocellular carcinomardquo American Journal of Clinical Pathol-ogy vol 983097983095 no 983091 pp 983092983088983093ndash983092983089983088 983089983097983097983090

[983091983092] K Yamamoto H Imamura Y Matsuyama et al ldquoAFP AFP-L983091

DCP and GP983095983091 as markers or monitoring treatment responseand recurrence and as surrogate markers o clinicopathological variables o HCCrdquo Journal of Gastroenterology vol 983092983093 no 983089983090pp 983089983090983095983090ndash983089983090983096983090 983090983088983089983088

[983091983093] Nakazawa S Adachi M Kitano et al ldquoPotential prognosticbene1047297ts o radiotherapy as an initial treatment or patients withunresectable advanced hepatocellular carcinoma with invasionto intrahepatic large vesselsrdquo Oncology vol 983095983091 no 983089-983090 pp 983097983088ndash983097983095 983090983088983088983096

[983091983094] K Murata H Suzuki H Okano Oyamada Y Yasuda andA Sakamoto ldquoHypoxia-induced des-907317-carboxy prothrombinproduction in hepatocellular carcinomardquo International Journal of Oncology vol 983091983094 no 983089 pp 983089983094983089ndash983089983095983088 983090983088983089983088



Submit your manuscripts at

httpwwwhindawicom




assessment o serum PIVKA-II level re1047298ects the extent o vascular invasion including portal vein thrombosis andextrahepatic disease extension [983089983092] and is regarded as com-plementary to serum AFP measurement Tus measuremento both PIVKA-II and AFP levels may yield useul inorma-tion on treatment response and prognosis in HCC patients

Because thehal-lives o the two serum markers are only a ew weeks [983089983093] changes in serum AFP andPIVKA-II levels beoreand afer treatment may provide clinically useul inormationon both treatment outcome and prognosis Te clinical utility o simultaneous AFP and PIVKA-II measurement was 1047297rstreport by Aoyagi et al in 983089983097983097983094 [983089983094] Since then many studieshaveocusedon use o a combination othe levelso these twomarkers to assess treatment response to predict prognosisand indeed to diagnose HCC [983089983095ndash983090983091]

Multimodal treatment is mandatory in HCC patientsand the prognostic cutoff values and predictive powers o AFP and PIVKA-II levels will differ according to the chosentreatment modality Tereore we reviewed and summarized

the results o studies on the utilities o AFP and PIVKA-IIlevels in monitoring o treatment outcomes and predictingprognosis

2 Methods

983090983089 Search Strategy A computerized English-languagesearcho PUBMED was perormed in September 983090983088983089983091 Studiespublished at any time were included Afer a preliminary search o the MeSH database we used the terms ldquoAFP andPIVKA-IIrdquo ldquoAFP and DCPrdquo ldquocombination tumor markersrdquoldquoHCCrdquo ldquotreatment responserdquo and ldquoprognosisrdquo to search titlesandor abstracts

983090983090 Study Eligibility and Critical Appraisal We careully reviewed all studies on AFP and PIVKA-II markers in theHCC context and selected studies (983089) dealing with both AFPand PIVKA-II (983090) eaturing measurement o both tumormarkers beore and afer treatment o HCC and (983091) ocusingon the roles played by both tumor markers in assessingtreatment outcomes or predicting prognosis and survival Weound 983089983090 studies that met these criteria when investigating theutilities o various HCC treatment modalities (able 983089)

3 Results

983091983089 Serum AFP and PIVKA-II Levels in Patients Who Under-went Curative Hepatic Resection to Treat HCC Six studiesmeasured both AFP and PIVKA-II levels in patients whounderwent curative hepatic resection [983090983088 983090983092ndash983090983096]

983091983089983089 Monitoring Treatment Outcomes Yamamoto et alreported that the avorable predictive values o pretreatmentAFP and PIVKA-II levels in terms o postoperative recur-rence had AUROCs o 983088983095983097 and 983088983097983089 respectively [983090983094] Tesensitivity and speci1047297city o recurrence detection improvedsimultaneously when both AFP and PIVKA-II levels weremeasured (sensitivity 983094983094983095 speci1047297city 983092983095983097) compared to

those obtained when AFP levels alone (sensitivity 983094983088983089speci1047297city 983092983093983090) or PIVKA-II levels alone (sensitivity983094983090983097 speci1047297city 983092983095983097) [983090983088] were assessed Patients withhigh pretreatment levels o AFP and PIVKA-II experienced asigni1047297cantly higher incidence o tumor recurrence afer cura-tive treatment [983090983088 983090983093] associated with the more unavorable

tumor characteristics o patients with higher levels o AFPand PIVKA-II [983090983088 983090983089] Chon et al ound that pretreatmentAFP and PIVKA-IIlevels were signi1047297cantly higher in patientswith microscopic vessel invasion or multiple tumors com-pared to others [983090983088] Te roles played by tumor markers inre1047298ecting microscopic vessel invasion or tumor multiplicity can compensate or limitations o current prognostic systems

Te concern was whether changes in tumor markerlevels afer treatment would yield additional inormationon patients who underwent curative resection [983090983088 983090983092 983090983093983090983096] Changes in tumor marker levels afer curative hepaticresection provide inormation on both the pattern andprobability o recurrence In one study high preoperativeserum AFP and PIVKA-II levels were associated with early recurrence (within 983094 months) afer curative resection [983090983094]Such patients had higher preoperative AFP and PIVKA-II

values than did those who developed recurrences gt983094 monthsafer surgery Also patients experiencing extrahepatic recur-rences had higher preoperative marker levels than did thosewith intrahepatic recurrences

983091983089983090 Prediction of Survival Serum AFP and PIVKA-II levelswere also predictive o survival in many studies [983090983088 983090983092ndash983090983095]Changes in tumor marker levels 983091 months afer operationsigni1047297cantly predicted HCC recurrence [983090983088] I marker levelsdid not all recurrence was likely [983090983088 983090983092 983090983093] Patients

with high AFP and PIVKA-II levels afer curative treatmentexperienced signi1047297cantly poorer overall survival than thosewith normal marker levels [983090983093] In addition not only highlevels o markers per se but also shorter doubling times o increases in marker levels were linked to signi1047297cantly poorerdisease-ree and overall survival [983090983095] Tus rapid elevation o marker levels re1047298ects aggressive behavior o remnant tumorsafer curative treatment

Upon multivariate analysis to evaluate the predictive values o marker levels in terms o survival elevated serumlevels o AFP andor PIVKA-II both beore and afer surgery independently predicted disease-ree or overall survival asdid tumor size tumor number and the existence o vascular

invasion [983090983088 983090983092 983090983093] Te numbers o markers elevated beoreoperation and shorter doubling times o marker values werealso predictive o survival [983090983093 983090983095]

983091983090 Serum AFP and PIVKA-II Levels in Patients with TACEwo studies have examined the kinetics o both AFP andPIVKA-II levels in HCC patients treated via transarterialchemoembolization (ACE) [983090983090 983090983097]

983091983090983089 Monitoring Treatment Outcomes Radiological mor-phology afer ACE is sometimes nonhomogenous andinconsistent because o irregular uptake o lipiodol and







umormarker





resection

AFPAFP-L983091

PIVKA-II

983090983088 ngdL983093

983092983088 mAUmL

mdash


resectionAFP




resectionAFP

PIVKA-II

983090983088 ngmL983090983088983088ngmLdagger


mdash


resectionAFP




resectionAFP




resectionAFP




983090983088 ngmL983092983088 mAUmL


Park et al [983090983097] 983090983088983089983090 983091983090983095 ACE AFP



Lee et al [983090983091] 983090983088983089983090 983094983088

983094983095HAICCCR

AFPPIVKA-II

983090983088 ngmL983090983088 mAUmL


Park et al [983089983092] 983090983088983089983091 983089983089983089 CCR AFP

PIVKA-II983090983088983088ngmL



































and survival

Abbreviations




Solid umors




Acknowledgment


References
















































httpwwwhindawicom







umormarker





resection

AFPAFP-L983091

PIVKA-II

983090983088 ngdL983093

983092983088 mAUmL

mdash


resectionAFP




resectionAFP

PIVKA-II

983090983088 ngmL983090983088983088ngmLdagger


mdash


resectionAFP




resectionAFP




resectionAFP




983090983088 ngmL983092983088 mAUmL


Park et al [983090983097] 983090983088983089983090 983091983090983095 ACE AFP



Lee et al [983090983091] 983090983088983089983090 983094983088

983094983095HAICCCR

AFPPIVKA-II

983090983088 ngmL983090983088 mAUmL


Park et al [983089983092] 983090983088983089983091 983089983089983089 CCR AFP

PIVKA-II983090983088983088ngmL



































and survival

Abbreviations




Solid umors




Acknowledgment


References
















































httpwwwhindawicom























and survival

Abbreviations




Solid umors




Acknowledgment


References
















































httpwwwhindawicom









and survival

Abbreviations




Solid umors




Acknowledgment


References
















































httpwwwhindawicom



































httpwwwhindawicom




httpwwwhindawicom

Documents

1 HEPATOCELULAR CARSINOMA