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Chapter9:Novel developments in MR assessment of treatment response
ADCmeasurementsarehighlyreproducible.Clearapprais­alsofADCmeasurementerrorenablechancevariationto be reliably distinguished from true treatmentresponse. Several studieshavedeterminedthecoecientofvariation,thatis,the rangeofADCmeasurementvariationthatisstatisticallyattrib­utabletomeasurementerrororinterobservervariability,tobe somewherebetween7.3%and14.7%.
17,18
Generallyspeaking, dierencesinADCvaluesoflessthan 15%aremorelikelyto reectdierencesinmeasurementtechniqueratherthantrue dierencesintreatmentresponse.
18
Tissue necrosis aer intra-arterial therapyalso manifests
asadecreaseincontrastenhancement.Contrastenhancement
therebydecreasingbotharterialandpeakenhancement.Since peakenhancementreectsboththearterialandportalvenous contribution to overall enhancement, arterial enhancement (the numerator) is reduced to a greater degree than peak enhancement(thedenominator).enetresultisadecrease intheAEF.Studieshaveshownthatdierencesexistbetween theAEFofHCCsandcirrhoticbackgroundliverparenchyma. Moreover,dierencesmaybeseenintheAEFoflesionsearly aer successful TACE. In one study, patients whose target lesions demonstrated AEF decreases of ≥ 35% at 3–4 weeks aertreatmenthadincreasedsurvivalat6months,1year,and 2yearscomparedwiththosewhodidnot.
22
isareectionoftumorviability;thisformsthebasisforitsuse asa functional biomarker in theEASLcriteria. Decreases in contrastenhancementareobservedearlierintheposttreatment periodthanareincreasesinADCvalue.isisnotsurprising, asdisruptionintumorarterialsupplyviaTACEisthesine qua nonfortumornecrosis.Decreasesintumorarterialenhance­mentmaybeseenimmediatelyaerTACEandaresustained forupto4 weeksaertherapy.10esealterationsin contrast enhancementaid in interpretationofapparentlyparadoxical decreases in ADC values within 24 hours and aer 4 weeks posttherapy.Inthesettingofdecreasedcontrastenhancement, decreasedADCvaluesobservedduringthesetimeperiodsare lesslikelytobeinterpretedasresistantorrecurrenttumor.MRI performedat1–2weeksaerTACEyieldsthemaximumdif­ferencein tumorenhancementandADCvaluescomparedto baseline.
10
Conventionaldual-phase CE-MRI enables early detection ofchangesintumorperfusionaerintra-arterialtherapy.In dual-phaseCE-MRI,abolusofcontrastisdeliveredandimage acquisition is performed utilizing T1-weighted sequences in thearterialandportal venousphases.istechniqueistobe distinguishedfromperfusionMR,whichrepresentsadistinct method of studying tumor microperfusion using a series of rapidlysuccessiveimage acquisitions.
19,20
CE-MRImaximizes liver lesion conspicuity by exploiting the basic principle of dual liver vascular supply;thatis, 20–25% of liverperfusion is supplied by the hepatic artery and 75–80% is suppliedby theportalvein.Hypervascularlivertumorsrecruittheirblood supplyexclusivelyfromthe hepatic artery suchthatthey are best visualized in thearterialphase (typically 20–30 seconds aeradministrationofthecontrastbolus).Asthebackground liverparenchymaenhancesin theportalvenousphase(typi­cally60–70secondsaeradministrationofthecontrastbolus), hypervascular lesionsblendintothe backgroundliverparen­chyma. By contrast, hypovascular lesions are best visualized ona background of maximallyenhancing liver parenchyma. Hepatocellular carcinoma, islet cell, and neuroendocrine neoplasms represent examplesof hypervascular tumors best visualizedinthearterialphase.Adenocarcinomaandcholan­giocarcinomarepresentexamplesofhypovasculartumorsbest visualizedintheportalvenousordelayedphases.
21
Alterations in contrast enhancement aer intra-arterial therapy may be quantied using the arterial enhancement fraction (AEF), orthe ratio of arterialenhancementto peak enhancement.SuccessfulTACEdisruptstumorarterialsupply,

The volumetric approach

DW- and CE-MRI are robust examples of functional bio­markersfor assessmentoftreatmentresponse.Bothmethods satisfy many of the criteria for an ideal imaging biomarker. Untilrecently,thesetwo functionalapproacheshaveshareda commonlimitation.is limitation is a vestigeoftraditional anatomic approaches to treatment response assessment and consistsofthefollowing.Traditionally,ADCandenhancement measurementshavebeenobtainedviaplacementofaregion ofintereston a single axial MRI slice. is regionofinterest mustserveasarepresentationofthelesionasawhole.ispre­supposesa certaindegreeoftumorhomogeneityor uniform­ity.However,wehaveseenthattumorsrepresentintrinsically complexandheterogeneousecosystemsandthatthisintrinsic complexityisreectedintheirtreatmentresponse.IfDW-and CE-MRIaretoprovesuperior metrics of treatmentresponse comparedwithtraditionalmetricsofresponseassessmentsuch asEASLandmRECIST,theymustovercomethislimitation.
RecentadvancesinMRIhavemadepossibletheapplication of DW- and CE-MRI technique in a three-dimensional set­ting.evolumetricapproachtofunctionalMRIenablesthese robustfunctionaltechniquestorepresentfullythecomplexity andheterogeneityoftumorsandtheirtreatmentresponse.Not onlydoesthisallowamorecomprehensiveassessmentoftreat­mentresponse,butitalsoenablesamoretargetedapproachto retreatment.
A brief discussion of volumetric functional MRI tech­nique suces for the purposes of our discussion.An entire targetlesionisidentiedandtreatedastheregionofinterest. Sophisticatedcomputersowareperformsvolumetricsegmen­tationofa lesiontothelevelof individualvoxels.Eachvoxel possesses unique anatomic and functional characteristics, includingspatialcoordinates,degreeofcontrastenhancement, and degree of diusion restriction. e functional informa­tionforeachvoxelis thenplottedon ahistogram.ehisto­gram provides a summary representation of the functional datacontainedinallvoxelsof a target lesion. e properties of the histogram depend entirely on the functional param­eteritrepresents.Ifthefunctionalparameterinquestionisan ADCvalue,thehistogramwillshowtherangeofADCvalues withinthetargetlesion,aswellastherelativenumberorfre­quency of voxelsforeach ADC valuewithin that range. e sameappliestocontrastenhancement,wheretheparameterin
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Section II:Principles of image-guided therapies
questionisthesignalintensity.Comparisonofpre-andpost­treatmenthistogramsprovidesusefulinformationabouttreat­mentresponse.Shisinthemean,distribution,andfrequency ofvoxelvaluespermitbroadappraisalsabouttheoverallmag­nitude and direction of treatment response. More detailed assessmentoftreatmentresponseisalsopossibleviavoxel-by­voxelcomparisonofpre-andposttreatmentvalues.espatial distributionofvoxelsofagivenADCvalueorsignalintensity isthenrepresentedasacolor-codedmapthatissuperimposed ontheoriginal lesioningrayscale.iseectivelyservesasa directionalmapfortargetedretreatmentofareasdemonstrat­ingsuboptimaltreatmentresponse.
Ample precedent exists for the volumetric approach to treatment response in computed tomography (CT), where therearedatasupportingitsuseinposttreatmentassessment of metastatic breast,23 lung,24 and head and neck25 cancers. WithintheeldofMR,functionalvolumetricassessmentof DW-MRIwithADCmappingandCE-MRIhavebeenapplied successfullyintheliverandbrain.26Overthepast3years,a numberofseminalpublicationshaveemergedsupportingits rolein treatment response assessmentof liver tumors aer TACE, including HCC,
26–28
 islet cell neoplasms,29 cholan­giocarcinoma,30andneuroendocrine31tumors.eresultsof these publications suggest that volumetric analysis of DW- andCE-MRIpossessesmanyofthecharacteristicsofanideal imagingbiomarker.
RecentstudieshaveshownthatthresholdvolumetricADC and CE alterations can be used to predict response to treat­ment in HCC (Figure 9.1). Volumetric alterations in ADC andvenousenhancement (VE) performedat3–4weeksaer TACEcanpredictchangesintumorsizeat6months,allowing earlystraticationofpatientsintomRECISTcategoriesbefore changesintumorsizeareevident.28ishasalsobeenshown inthecaseofmetastaticisletcelltumors,whereearlyincreases inADCaboveapredeterminedthresholdof0.16×10–3allow early prediction of RECIST response.29 More recent studies havedeterminedtheoptimalADCandVEthresholdsforpre­diction of patient survival in unresectable HCC aer TACE independentlyofmRECISTcriteria.Inarecentstudy,increases inADC of ≥ 25%and decreases in VE of≥ 65% resulted in dramaticstraticationofpatientswith respect to overallsur­vival at 11 months. Moreover, stratication of patients into dual-parameter, single-parameter, and non-responders also resultedindramaticallydierentsurvivalsforthethreegroups, with the 25% survival being 30 months for dual-parameter responders and only 6 and 5 months, respectively, for the remaining two categories.
26,27
 e superiority of volumetric analysis of DW- and CE-MRI over highly sensitive labora­torybiomarkerssuchasalpha-fetoprotein(AFP)hasalsobeen recentlydemonstrated.
27
e reproducibility of volumetric DW- and CE-MRI remainsanactiveareaofresearch.Recentstudiessuggestthat semiquantitative volumetric analysis of DW- and CE-MRI demonstratessuperiorreproducibilitycomparedwithmanual region-of-interest(ROI)-basedmeasurementsinunresectable HCCaerTACE.isisthoughttobeafunctionoftheintrin­sicheterogeneityofHCCs,which makes consistent selection
of a representative ROI challenging. Manual selection of an ROIrequiresselectionnotonlyofarepresentativeaxialslice, butalsoofarepresentativeROIwithinthatslice.Bothchoices heavily inuence the nal appraisal of treatment response, and both are highly subject to interobserver variability. e volumetric approach eliminates this potential for variability bymakingtheentirelesiontheregionofinterest.isenables amorecomprehensiveand accurate assessmentof treatment response.
32
Volumetricanalysis offunctionalbiomarkershasrecently beenperformedonneuroendocrinetumorsfollowingTACE, including carcinoid and pancreatic neuroendocrine tumors (Figure9.2).Onestudynotedthatpatientswithindexlesions demonstrating≥15%volumetricADCincreaseaerTACEhad improvedoverallsurvivalcomparedwithpatientsdemonstrat­ingsmallerADCincreases.Moreover,volumetricdecreasesin arterialandportalVEof≥25%and≥50%predictedimproved patientsurvivalcomparedwithsmallerdecreasesindual-phase contrastenhancement.UnlikeHCC,however,combiningvol­umetric alterations in ADC and contrast enhancement did not confer an additional prognostic benet. Dual-parameter responderswerejustaslikelytosurviveat40months,aswere single-parameter responders, irrespective of whether the enhancementchangesoccurredinthearterialorportalvenous
31
phase.
Nowhereisthechallengeofaccuratelyrepresentingtumor andresponseheterogeneitymoreonerousthaninthecaseof cholangiocarcinoma. Cholangiocarcinoma is a hypovascu­lar tumor with protean contrast enhancement characteris­tics in the hepatic arterial phase. e volumetric approach is particularly helpful in such cases, where selection of an ROI would be fraught with potential complications. One recentstudydemonstratedthatvolumetricanalysisofADC changes3–4weeksaerTACEispredictiveofoverallsurvival in patients with unresectable cholangiocarcinoma. Patients whosurvivedmorethan10monthsdemonstratedsignicant increases in the mean volumetric ADC at 3–4 weeks com­paredwith patientswho did not. Moreover,patientswhose index lesions demonstrated volumetric ADC increases of ≥45%or≥60%at3–4weekshad bettersurvivalandprog­nosisthanpatientswithADCincreasesbelowthese thresh­olds.Interestingly,volumetricchangesinhepaticarterialand venous phase enhancement were not predictive of survival aertreatment,probablyowingtothe intrinsicallycomplex enhancementcharacteristicsofthetumor,whichpersisteven aertreatment.30esuperiorityofvolumetricADCchanges overalterationsincontrastenhancementforpredictingover­allsurvivalaerTACEhasalsobeendemonstratedinthecase ofmetastaticisletcellneoplasms.
29

Conclusion

Volumetricanalysis of functional treatment responseparam­etersremainsanactiveareaofMRresearch.Wehavediscussed itsapplicationtotwo commonly utilized functional imaging techniques,DW-and CE-MRI. We have discussed thesupe­riority of functional over anatomic approachesin treatment responseassessment.Volumetricanalysisrepresentsafurther
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Chapter9:Novel developments in MR assessment of treatment response
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Figure 9.1 Hepatocellular carcinoma
in a 63-year-old-male. Volumetric functional magnetic resonance imaging metrics before (A–F) and after (G–L) transarterial chemoembolization. Volumetric apparent diffusion coefficient (ADC) map and histogram analysis at baseline (A, B) had mean value of 1.44 × 10–3 mm2/s. Notice shift of histogram towards higher values. At follow-up 6 weeks after therapy (G, H) the mean ADC value increased to 1.85 × 10–3 mm2/s. Volumetric enhancement map in the arterial phase had a mean value of 13% at baseline (C, D) and decreased to 2% at follow-up (I, J). Volumetric enhancement map in the venous phase had a mean value of 63% at baseline (E, F) and decreased to 12% at follow-up (K, L). Notice shift of both histograms towards lower values. These changes indicate a favorable response to therapy.
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Section II:Principles of image-guided therapies
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metastases in a 65-year-old-male. Volumetric functional magnetic resonance imaging metrics before (A–F) and after (G–L) transarterial chemoembolization. Volumetric apparent diffusion coefficient (ADC) map and histogram analysis at baseline (A, B) had mean value of 1.21 × 10–3 mm2/s. At follow-up 6 weeks after therapy (G, H), the mean ADC value increased to 1.88 × 10–3 mm2/s. Notice shift of histogram towards higher values. Volumetric enhancement map in the arterial phase had a mean value of 68% at baseline (C, D) and decreased to 15% at follow-up (I, J). Volumetric enhancement map in the venous phase had a mean value of 91% at baseline (E, F) and decreased to 36% at follow-up (K, L). Notice shift of both histograms towards lower values. These changes indicate favorable response to therapy.
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82
Chapter9:Novel developments in MR assessment of treatment response
renement of these functional techniques by enabling more comprehensive assessments of treatment response. e suc­cessful applicationofvolumetricanalysis in this settingpor­tendssuccessinitsbroaderapplicationtoarangeoffunctional MRItechniques.Moreresearchisneededtosupportfurther thepromisingpreliminaryresultsofthis approach.Itisclear fromtherstanalysisthatvolumetricDW-andCE-MRIhold great promise as metrics of treatment response by enabling early,comprehensive,andreproducibleassessmentswithpow­erfulprognosticsignicance.

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Section III
Organ-specific cancers – primary liver cancers
Chapter

Assessment and triage of hepatocellular carcinoma

10
Riccardo Lencioni

Summary

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Unlike most solid cancers, future incidence and mortality rates for HCC were projected to largely increase in several regions around the world over the next decade. Given the complexity of the disease and the common association of HCC and cirrhosis, careful multidisci­plinary assessment of tumor stage, liver function, and physical status is required for proper staging and therapeutic planning. Patients with early-stage HCC should be considered for any of the available curative therapies, including liver transplantation, surgical resection, and image-guided ablation.
Transcatheter arterial chemoembolization is recommended as the standard of care for the treatment of large or multinodu­lar non-invasive tumors in patients who have neither evidence of hepatic decompensation nor extrahepatic spread of the dis­ease, i.e., those cases classied as intermediate stage according to the Barcelona Clinic for Liver Cancer (BCLC) staging sys­tem. Radioembolization with yttrium-90 (Y90) microspheres is increasingly used to treat patients at more advanced tumor stages, including those with portal vein invasion. e multitar­geted tyrosine kinase inhibitor sorafenib is the only systemic treatment currently available for HCC patients unsuitable for surgical or interventional therapies. Despite the recent advances and renements in therapeutic strategies, tumor recurrence remains a challenge in patients with HCC. Several clinical trials investigating dierent combinations of locoregional and sys­temic treatments for preventing early recurrence and improv­ing long-term outcomes are ongoing.
proper diagnostic approach. Conrmation of tiny nodules as true HCC may be challenging, as pathologic changes inher­ent in cirrhosis– such as regenerative or dysplastic nodules– mimic a small tumor.8 Treatment choice is also dicult, given the complexity of the disease and the large number of poten­tially useful therapies, and requires careful multidisciplinary assessment of tumor stage, liver function, and physical status.
5–7

Assessment of hepatocellular carcinoma

Diagnostic criteria
In the setting of a patient with known hepatitis B or cirrhosis of other etiology, a discrete nodular lesion found during imaging surveillance– typically by ultrasound– has a high likelihood of being HCC. However, it has been shown by pathologic studies that nearly half of the tiny nodules that are detected in cirrhotic livers do not correspond to HCC.9 e dierential diagnosis between small HCC and non-malignant hepatocellular lesions may be challenging. Percutaneous image-guided biopsy is the most straightforward approach. Unfortunately, biopsy of small nodular lesions is exposed to sampling error. Moreover, it may be dicult to distinguish HCC from dysplastic nodules on small biopsy specimens. erefore, a positive biopsy– as assessed by an expert pathologist – is helpful, but a negative biopsy can never be taken as the sole criterion to rule out malignancy.
Current guidelines recommend to investigate nodules detected during surveillance by using contrast-enhanced com­puted tomography (CT) and/or contrast-enhanced magnetic resonance imaging (MRI).
5–7
In fact, one of the key pathologic
factors for dierential diagnosis that is reected in dynamic

Introduction

HCC is the third leading cause of cancer-related death world­wide.1 Unlike most solid cancers, future incidence and mortal­ity rates for HCC were projected to largely increase in several regions around the world over the next decade, mostly as a result of the dissemination of hepatitis B and C virus infec-
2–4
tion.
Patients with cirrhosis are at the highest risk of devel­oping HCC and should be monitored every 6 months with imaging techniques to diagnose the tumor at an early, asympto­matic stage.
5–7
Lesions detected by imaging surveillance require
imaging studies is the vascular supply to the lesion. rough the progression from regenerative nodule, to low-grade dys­plastic nodule, to high-grade dysplastic nodule, to frank HCC, one sees loss of visualization of portal tracts and development of new arterial vessels, termed non-triadal arteries, which become the dominant blood supply in overt HCC lesions. It is this neovascularity that allows HCC to be diagnosed and is the key for imaging cirrhotic patients.
8
A rational diagnostic protocol should be structured accord­ing to the actual risk of malignancy and the possibility of achiev­ing a reliable diagnosis. Since the prevalence of HCC among
Interventional Oncology, Second Edition, ed. Jean-François H.Geschwind and Michael C.Soulen. Published by Cambridge University Press. ©Cambridge University Press2016
85
Section III:Primary liver cancers
HCC
Stage 0
PST 0, Child-Pugh A PS 0-2, Child-Pugh A-B PST >2, Child-Pugh C
Very early
stage (0)
Single <2 cm
Carcinoma in situ
Single
Portal pressure/
bilirubin
Increased
Normal
Resection
Median OS >60 mo; 5-yr survival: 40%–70%
Liver transplantation
(CLT/LDLT)
Curative treatment (30%–40%)
Early
stage (A)
Single or 3 nodules ≤3 cm,
PS 0
3 nodules ≤3 cm
Associated diseases
No Ye s
Stage A-C Stage D
Intermediate
stage (B)
Multinodular,
PS 0
RF/PEI TACE Sorafenib
Ta rget: 20%
OS: 20 mo (45–14)
Advanced
stage (C)
Portal invasion
N1, M1, PS 1-2
Target: 40%
OS: 11 mo (6–14)
Terminal
stage (D)
Best supportive
care
Target: 10%
OS: <3 mo
Figure 10.1 Barcelona Clinic for
Liver Cancer (BCLC) staging system for hepatocellular carcinoma (HCC). PST = performance status test; PS = performance status; N = node; M = metastasis; CLT = cadaveric liver transplantation; LDLT = living donor liver transplantation; RF = radiofrequency; PEI = percutaneous ethanol injection; TACE = transarterial chemoembolization; OS = overall survival. (Adapted from European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943.)
small nodules detected in cirrhotic livers is related to the size of the lesion, the recommended diagnostic workup depends on the size of the lesion.
5–7
Lesions smaller than 1cm in diameter have a low likelihood of being HCC. erefore, these nodules only need careful follow-up in order to timely detect growth suggestive of malignant transformation. Areasonable protocol is to repeat imaging every 3months. When the nodule exceeds 1cm in size, the lesion is more likely to be HCC and diagnostic conrmation should be aggressively pursued. It is accepted that the diagnosis of HCC can be made without biopsy in a nodule that shows characteristic vascular features of HCC– i.e., arte­rial hypervascularity with portal venous or late-phase wash­out – even in patients with normal alpha-fetoprotein value but with established cirrhosis. Such lesions should be treated as HCC, since the positive predictive value of the clinical and radiological ndings is extremely high, provided that the examinations are conducted by using state-of-the-art protocols and interpreted by radiologists with extensive expertise in liver imaging.8 For lesions ranging from 1 to 2cm, some guidelines recommend that typical imaging ndings are conrmed by two coincident dynamic imaging modalities.
6
If the imaging ndings are not typical or the vascular pro­le is not coincidental between techniques, biopsy is recom­mended. In this regard, it is important to point out that neither the absence of arterial hypervascularity nor the absence of con­trast washout allows HCC to be ruled out. HCC tumors at a very early stage may not exhibit the characteristic vascular features of overt HCC. Delaying the diagnosis of HCC until imaging detec­tion of arterial hypervascularity or washout could reduce the chances of radical cure, since the incidence of microscopic vas­cular invasion and satellite nodules signicantly increases when tumor develops imaging-detectable neoangiogenetic changes.
Alternate approaches, particularly the use of diusion MRI or liver-specic MRI contrast agents, are expected to improve the ability to characterize small lesions. However, prospective investigation, with meticulous imaging-pathology correlation on explanted livers, is warranted before any alternate crite­rion is endorsed as the standard diagnostic approach for HCC. Also, it has to be pointed out that non-invasive criteria based on imaging ndings can be applied only in patients with estab­lished cirrhosis. For nodules detected in non-cirrhotic livers, biopsy conrmation is recommended.
Clinical staging
In most solid malignancies, tumor stage at presentation deter­mines prognosis and treatment management. Most patients with HCC, however, have two diseases– liver cirrhosis and HCC– and complex interactions between the two have major implications for prognosis and treatment choice.10 erefore, the tumor–node–metastasis (TNM) system has limited useful­ness in the clinical decision-making process, because it does not take into account hepatic functional status. Several scoring systems have been developed in the past few years in attempts to stratify patients according to expected survival.
e most popular staging system so far has been the BCLC staging system.6 e BCLC includes variables related to tumor stage, liver functional status, physical status, and cancer-related symptoms and provides an estimation of life expectancy that is based on published response rates to the various treatments (Figure 10.1). In the BCLC system, early-stage HCC (stage A) includes patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0, preserved liver func­tion (Child–Pugh class Aor B), and solitary tumor or up to three nodules smaller than 3 cm in size, in the absence of
86
Chapter10:Assessment and triageofHCC
macroscopic vascular invasion and extrahepatic spread. If the patient has Child–Pugh class Acirrhosis and a solitary tumor smaller than 2 cm in size, the stage is dened as very early (stage 0). Patients with multinodular HCC with neither vascu­lar invasion nor extrahepatic spread are classied as intermedi­ate stage, provided that they have a performance status of 0 and Child–Pugh class A or B cirrhosis. Patients with portal vein invasion or extrahepatic disease belong to the advanced stage. e terminal stage includes patients who have either severe hepatic decompensation (Child–Pugh classC) or performance status greater than2.
Several alternate staging systems for HCC have been pro­posed over the past few years. In particular, a group of inves­tigators from Hong Kong has recently presented a new, HKLC staging system for HCC that seems to provide better prognos­tic dierentiation with respect to the BCLC in Asian patients.11 e authors postulate that the dierence might stem from the etiology of the underlying liver disease. In the West, hepatitis C is the dominant liver disease causing HCC, while in Hong Kong, as well as in several Asian countries (except Japan), the dominant liver disease is hepatitis B.Patients with hepatitis B who develop HCC generally have better liver function than those with hepatitis C, because hepatitis B disease frequently inactivates before the development of HCC, allowing some recovery to occur, whereas hepatitis C remains active through­out the disease course.12 Of importance, the new HKLC staging system highlights one of the ongoing controversies that sur­rounds the BCLC classication, by showing that more aggres­sive treatment may be warranted, particularly in patients with some degree of vascular invasion.13 Nevertheless, the HKLC staging system will require external validation both in Asia and elsewhere before being introduced more widely.

Triage of hepatocellular carcinoma

Patients with HCC should be evaluated in referral centers by multidisciplinary teams involving hepatologists, oncologists, diagnostic and interventional radiologists, surgeons, radiation oncologists, and pathologists to guarantee careful selection of candidates for each treatment option and ensure the expert application of these treatments.
6
Earlystage
Patients with early-stage HCC can benet from curative thera­pies, including liver transplantation, surgical resection, and percutaneous ablation, and have the possibility of long-term cure, with 5-year survival gures ranging from 50% to 75%.14 However, there is no rm evidence to establish the optimal rst-line treatment for early-stage HCC because of the lack of randomized controlled trials (RCTs) comparing radical therapies.
Liver transplantation
Liver transplantation is the only option that provides cure of both the tumor and the underlying chronic liver disease. It is recognized as the best treatment for patients with solitary HCC smaller than 5cm in the setting of decompensated cirrhosis
and for those with early multifocal disease (up to three lesions, none larger than 3cm). However, for patients with a solitary small tumor in well-compensated cirrhosis, the optimal treat­ment strategy is still under debate.14 e reported outcomes of patients who actually underwent transplantation are bet­ter than those of patients submitted to resection, especially if the substantially lower rates of tumor recurrence– less than 10–20% at 5years– are considered.14 Overall survival, however, decreases on an intention-to-treat perspective. In fact, because of the lack of sucient liver donation, there is always a wait­ing period between listing and transplantation, during which the tumor may grow and develop contraindications to trans­plantation (vascular invasion, extrahepatic spread). e rate of dropouts may be as high as 25% if the waiting list is longer than 12months.14 Most groups perform interventional treatments– including transcatheter arterial chemoembolization (TACE), Y90 radioembolization, and percutaneous ablation– to achieve local control of the tumor during the waiting time. Living donor liver transplantation is a viable option to expand the number of available livers. However, it requires a highly skilled group of senior liver surgeons, increases surgery-related morbidity, and carries the risk of donor mortality. In addition, the applicability of the technique is low, and only about one-fourth of potential recipients eventually undergo the procedure.
14
Surgical resection
Resection is the treatment of choice for HCC in non-cirrhotic patients, who account for less than 10% of the cases in Western countries. However, in patients with cirrhosis, candidates for resection must be carefully selected to reduce the risk of post­operative liver failure. It has been shown that a normal bili­rubin concentration and the absence of clinically signicant portal hypertension are the best predictors of excellent out­comes aer surgery.14 In experienced hands, such patients have treatment-related mortality of less than 1–3% and may achieve a 5-year survival higher than 70%.14 In contrast, survival drops to less than 50% at 5years in patients with signicant portal hypertension, and to less than 30% at 5years in those with both adverse factors (portal hypertension and elevated bilirubin). Anatomic resections – guided by intraoperative ultrasound techniques– are preferred to wedge resections as they include any microsatellite lesions possibly located in the same hepatic segment as the main tumor. In fact, it is known that neoplastic dissemination occurs at very early stages in HCC via the inva­sion of small peripheral portal vein branches.9 Aer resection, tumor recurrence rate exceeds 70% at 5years, including recur­rence due to dissemination and de-novo tumors developing in the remnant cirrhotic liver. e most powerful predictors of recurrence are the presence of microvascular invasion and/or additional tumor sites besides the primary lesion.
14
Image-guided ablation
Image-guided ablation is recommended for patients with early-stage HCC when surgical options are precluded. radiofrequency ablation (RFA) has been the most popular tech-
15,16
nique,
several alternate technologies – including thermal
and non-thermal methods– have recently attracted attention,
5–7
While
87
Section III:Primary liver cancers
http://internalmedicinebook.com
since they appear to be able to overcome some specic limita­tions of RFA.
17–22
Whatever the ablative modality, the ablation of appropriate margins beyond the visible borders of the tumor is necessary to achieve therapeutic results similar to those achieved with surgery. Ideally, a 360°, 0.5–1-cm-thick ablative margin should be produced all around the target tumor. is cu would ensure that the peripheral portion of the lesion as well as any microscopic invasions located in its close proximity have been eradicated.
An open question is whether ablation can compete with surgical resection as rst-line treatment.23 RCTs failed to pro­vide an unequivocal answer.
24–26
In a recent meta-analysis, the pooled results of RCTs demonstrated no signicant dierence between RFA and resection for 1- and 3-year overall survival and recurrence-free survival.27 e 5-year overall survival and recurrence-free survival, however, were lower with RFA than with resection. On the other hand, the complication rate was lower and hospital stays were shorter with RFA than with resection.27 us, at this point, there are no unequivocal data to back up RFA as a replacement of resection as rst-line treat­ment for patients with early-stage HCC. Importantly, however, non-randomized investigations have consistently reported similar results for resection and RFA in very-early-stage tumors– i.e., single HCC smaller than or equal to 2 cm in diameter – suggesting that RFA has potential to stand as rst-line therapy for these patients.14 As progress continues to be made, ablation is gradually being used to treat HCC patients who could have been resected according to broader eligibil-
provide a combined ischemic and cytotoxic eect locally with low systemic toxic exposure.
30
In a recent Cochrane meta-analysis, the evidence support­ing the benets of TACE has been questioned. e authors of the Cochrane review state that, contrary to current clinical practice, there is absence of evidence of TACE or transarte­rial embolization having a benecial eect on survival in par­ticipants with unresectable HCC.31 However, several experts have questioned such a conclusion and have expressed con­cern over this Cochrane review.
32,33
It has been pointed out that the analysis included a trial undertaken in patients with early HCC, in whom bland arterial embolization (not TACE) was assessed in combination with local ablation. On the other hand, the Cochrane assessment excluded two major trials that found improved survival because of risk of bias, accord­ing to Cochrane criteria.
32,33
e data recently collected in the GIDEON, the largest global observational study completed in the eld of HCC so far, show that TACE is by far the most widely used treatment for HCC worldwide.
28
Y90 radioembolization is increasingly used to treat patients at more advanced tumor stages, including those with portal vein invasion. In fact, due to the minimally embolic eect of Y90 microspheres, treatment can be safely used in patients with portal vein thrombosis. e ecacy and safety of Y90 radioembolization have been documented in several phase I–II clinical studies.
34–37
Several phase III trials aimed at showing the survival benet or radioembolization versus sorafenib or in combination with sorafenib are currently ongoing.
38
ity criteria for surgery. e availability of an eective alternate local treatment has allowed progressive renements in surgi­cal criteria, restricting the indication to patients who truly can benet from resection.
14
Intermediate–advancedstage
Despite the widespread implementation of surveillance pro­grams, more than half of the patients with HCC are diagnosed late, when curative treatments cannot be applied.28 In addition, in a high proportion of cases the disease recurs aer a radical therapy. Patients with intermediate–advanced HCC are con­sidered for transarterial regional hepatic therapy or systemic treatment with sorafenib.
Transarterial treatment
e most common methods of image-guided transcatheter tumor therapy used in HCC treatment are TACE and Y90 radi­oembolization. TACE is the recommended option for patients presenting with large or multinodular HCC and relatively pre­served liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread. most popular TACE technique has been the administration of an anticancer-in-oil emulsion followed by embolic agents.29 e key component of this procedure is Lipiodol, which is used both as a vehicle to carry and localize the chemothera­peutic agent inside the tumor and as a microembolic agent for tiny tumor vessels. e introduction of embolic, drug-eluting beads has provided an alternative to Lipiodol-based regimens. Clinical experiences have suggested that drug-eluting beads
5–7
e
Systemic treatment
e multitargeted tyrosine kinase inhibitor sorafenib is the only systemic treatment currently available for HCC. Sorafenib blocks several key modulators of angiogenesis, including cell surface tyrosine kinase receptors (vascular endothelial growth factor and platelet-derived growth fac­tor receptors), but also some intracellular serine/threonine kinases (Raf-1 and B-Raf). Two RCTs, the SHARP trial, conducted mainly in America and Europe39 and a similar trial conducted in Asia,40 reported improved survival with sorafenib compared with placebo, thus establishing sorafenib as the standard of care for patients unsuitable for surgical or interventional therapies.
However, most patients progress aer initial response, likely because of activation of additional pathways and resist­ance to sorafenib. In addition, sorafenib therapy has been asso­ciated with toxicity, such as hand–foot skin reaction, diarrhea, and fatigue, and may lead to dose reductions and interruptions in treatment. us, alternative or second-line treatments with prolonged ecacy and more tolerable safety proles are neces­sary to further improve patient outcomes. With new genomic technologies, several molecular targets have been identied in HCC, facilitating the development of numerous targeted thera­pies. Unfortunately, none of the drugs tested so far have shown positive results in the rst-line (brivanib, sunitinib, erlotinib, and linifanib) or second-line (brivanib, everolimus) setting aer sorafenib progression and, thus, sorafenib remains the only approved systemic drug forHCC.
41
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