HCC screening and surveillance
HCC biomarkers and thecurrent role in patients at risk for
hepatocellular carcinoma (HCC)Robert G. Gish MDSenior Medical
Director Liver Program St Josephs Medical Center, Phoenix,
AzClinical Professor of Medicine (Adjunct): University of Nevada,
Las VegasMedical Director Hepatitis B Foundation, Doylestown,
PA
HCC Biomarkers and Surveillance:OutlineBiomarkers for HCC are
not being used primarily to establish a diagnosis of cancerHCC
biomarkers can be used as risk tests in surveillance protocols to
determine who may develop HCC and to guide changes in imaging
method selection and timingAlpha beta-protein (AFP) is not FDA
cleared as a single test for the diagnosis or risk of HCCDCP and
AFPL3% are the only biomarkers that are cleared by the FDA with the
intended use as risk markers for HCCAFP as a single test: for
Diagnosis of HCC? (no): Poor Diagnostic Tool due toLow sensitivity
and/or specificityTumor heterogeneityPatient heterogeneity
Combined use of AFP, AFP-L3 and DCP significantlyImproves the
performance characteristics as risk markers for HCCKey Challenges
and Uses of Biomarkers in Clinical PracticeCP1245754Roberts,
LRmls/so10-9-2006Surveillance Guidelines for High-Risk Patients
Approval/Clearance And Reimbursement for HCC Biomarkers
USAFDA ClearanceCanada
Health CanadaEuropeCE MarkJapanMHLWAFPNot cleared for
HCCReimbursedYesYes
YesReimbursedAFP-L3Yes ReimbursedYes
Yes
YesReimbursedDCPYesReimbursedYes
Yes
YesReimbursedThe biomarkers have been already approved in almost
every region of the globe.Inclusion of AFP-L3 and DCP Biomarkers
Enable More Comprehensive Surveillance StrategiesKumada T, et al. J
Hepatol 1999;30:125-30.Makuuchi M, et al. Hepatol Res.
2008;38:37-51.Koike Y, et al. Cancer 2001;91:561-9.AFP-L3DCPAFP is
a glycoprotein with a single asparagine-linked complex-type
carbohydrate chain on each molecule.
AFP-L3 is an isoform of AFP which has an additional fucose
residue.
Elevation of AFP-L3 is indicative of greater malignant potential
of HCC and is correlated to shorter doubling time of tumor volume
and increased hepatic arterial supply.1 DCP is a precursor form of
prothrombin, a coagulation protein.
HCC cells lack the carboxylase protein to change DCP to
prothrombin.
DCP has been reported to be a specific marker for microinvasion
and a high DCP level is associated with development of portal vein
invasion.2,3HCC biomarkers: Intended useAFP-L3 and DCP are intended
for and FDA Cleared for in vitro diagnostic use as an aid in the
risk assessment of patients with chronic liver diseases for
development of HCC in conjunction with other laboratory findings,
imaging studies, and clinical assessment. The combined use of these
biomarkers has been shown to be more sensitive and effective for
the early detection of HCC through surveillance.4-6
1. Shimauchi Y, et al. Oncol Rep.2000;7:249-56.2. Toyoda H, et
al. Clin Gastroenterol Hepatol 2006;4:111-7.3. Volk ML, et al.
Cancer Biomarkers 2007;3:79-87.Inclusion of AFP-L3 & DCP
Improves Early DetectionPrimary
ToolSensitivitySpecificityConclusionsColli et al
(2006)1Ultrasound48%
(95% CI 34-62%)97%
(95% CI 95-98%)Ultrasound isinsufficiently sensitive to detect
HCC in many cirrhotics or to support an effective surveillance
program.Singal et al (2012)2Ultrasound43.9%91.5%Ultrasound is
suboptimal when used aloneVolk et al (2007)3AFP, AFP-L3 & DCP
84%94%Combined use of AFP, AFP-L3 and DCP results in enhanced
detection of HCC with minimal false positivesHann et al (2013)4AFP,
AFP-L3 & DCP 83%91%Colli A, et al. Am J Gastroenterol
2006;101:513-23. Singal et al. Cancer Epidemiol Biomarkers Prev.
2012;21:793-9Volk ML, et al. Cancer Biomarkers 2007;3:79-87Hann HW,
et al. DDW 2013 Poster Tu 1048Colli: Pooled 14 out of 2,524 studies
using stringent criteria
Not suggesting that U/S be replaced by the biomarkers should be
used in conjunction
Low sensitivity leads to patients who are not diagnosed, or who
are diagnosed at a later stage. Low specificity leads to more false
positives and additional expenses related to unnecessary
testing.
8Biomarkers Supplement Ultrasound and Provide an opportunity for
earlier HCC detection Surveillance strategyCost per
test1AdvantagesDisadvantagesNo surveillance $0No expenditureNo
chance of diagnosisUltrasound$185Widely used , low costPoor
sensitivityUltrasound + AFP$216Widely usedPoor sensitivity,
particularly in early stage HCCUltrasound + AFP, AFP-L3,
DCP$361Earlier and more sensitive detection of HCCAdditional costs
of AFP-L3 and DCPCT$640High sensitivityHigh cost, limited accessYu
NC, et al. Clin Gastroenterol Hepatol 2011;9:161-7.Semiannual CT is
sensitive in HCC detection but costs are very high. Adding AFP-L3
and DCP to regular practice is not very expensive but is very
effective to aid in early diagnosis of HCC. Detecting HCC early
enough to undergo resection improves incremental cost-effectiveness
of HCC treatments.
9Earlier Detection of HCC May Improve Opportunity for
Cost-Effective InterventionsTreatments (Stage I)Mean years
survivedMean cumulative expendituresICERs (Incremental
cost-effectiveness ratios)No treatment
1.06$35,390N/AChemotherapy1.29$68,824Insignificant difference
Radiation1.47$65,09874,404Liver directed (Ablation and/or TACE
)2.67$95,56625,345Resection4.51$123,80715,303Transplant5.98$207,47355,066Shaya
FT, et al. Pharmacoeconomics. 2013 Nov 29.Resection, classified by
the AASLD Guidelines as curative therapy, is also the most cost
effective.Shaya et al. reported that resection at an earlier stage
was the most effective for incremental cost-effectiveness ratios
(ICERs) considering life years and cumulative medical
expenditures.
10Costs and Performance of HCC Surveillance ToolsSurveillance
testsCost per test1ReferencesSensitivitySpecificityUltrasound
$185Singal, et al. (2012)244%92%AFP only$31Volk, et al.
(2007)369%91%3 biomarkers (AFP, AFP-L3, DCP)$176
$88 (AFP, AFP-L3) + $88 (DCP)Volk, et al. (2007)388%91%Hann, et
al. (2013)483%91%Yu NC, et al. Clin Gastroenterol Hepatol
2011;9:161-7.Singal et al. Cancer Epidemiol Biomarkers Prev.
2012;21:793-9Volk ML, et al. Cancer Biomarkers 2007;3:79-87Hann HW,
et al. DDW 2013 Poster Tu 1048Costs1 : CT, $640; MRI, $140011AFP-L3
and DCP Are Reimbursed By Various Insurance Providers AFP-L3 and
DCP are covered by a number of public and commercial payers (data
on file)
Medicare Clinical Laboratory Fee Schedule1 AFP-L3 (CPT 82107):
$88.54DCP (83951): $88.54
Some Examples of Health Plan
CoverageMedicareMedicaidTricareHighmark Blue Cross Blue
ShieldEmblemHealthCapital Blue CrossTufts Health PlanBlue Cross
Blue Shield of DelawarePriority Health Centers for Medicare and
Medicaid Services. Clinical Laboratory Fee Schedule. 2013.Liver
Dedicated Surveillance Ultrasound (US)+ HCC biomarkers in at-risk
patients*Poor/Fairquality USOr abnormal biomarkersGood/Excellent
quality US and normal HCC biomarkers#gadoxetate disodium MRI (Or
dynamic CT)US surveillance q6 months with biomarkersNegative
MRIAbnormal US orincreasing biomarkersblood tests AFP-L3%/DCP (HCC
serum biomarkers); *AASLD Guidelines 2009; # see LI-RADS.AASLD =
American Association for the Study of Liver Diseases; AFP =
alpha-fetoprotein; CT = computed tomography;DCP = des-gamma-carboxy
prothrombin; HCC = hepatocellular carcinoma; LI-RADS = Liver
Imaging Reporting and Data System;MRI = magnetic resonance imaging;
US = ultrasound.Proposed Liver Ultrasound AlgorithmGish, R.
,Gastroenterology & Hepatology, 2014; 10;2:121-123. Gish RG.
Early Detection of Hepatocellular Carcinoma Through Surveillance
Using Biomarkers. Gastroenterology and Hepatology, 2014. Volume 10,
Issue 2;
121-123.http://www.gastroenterologyandhepatology.net/index.php/archives/february-2014/early-detection-of-hepatocellular-carcinoma-through-surveillance-using-biomarkers/.13HCC
Biomarkers Utility ExamplesRemember: Not all HCC make all
biomarkersPatient number of AFP-L3, DCP and AFP in those with known
HCC (n=685)Toyoda et al. Clin Gastro and Hep 2006;4:111-117AFP >
20 ng/mLDCP > 40mAU/mLAFP-L3 > 10%9611093153451415159 (23%)
all negative15Combined Biomarker Testing Identifies a Greater
Number of Positive tests in Patients with Known HCC1AFP-L3
Positive15(20.3%)DCP Positive3(4.1%)AFP
Positive8(10.8%)7(9.5%)15(20.3%)4(5.4%)15(20.3%)All
Negative7(9.5%)FDA submission data for uTASWako i30 If HCC
biomarkers are used prior to imaging: In this study of 74 patients,
the use of AFP alone would have detected 45 HCC cases and missed 29
cases of HCCCut-off pointPositive casesAFP 20 ng/mL45
(60.8%)AFP-L310 %49 (66.2%)DCP 7.5 ng/mL
29 (39.2%)Combination ofAFP, AFP-L3, and DCPSame as above67
(90.5%)Cant predict in advance which biomarker will be most
effective, so need to run all three tests.
Both biomarkers are highly specific for HCC and complement each
other.15 Therefore, when both markers are measured in tandem, the
sensitivity is improved while the high specificity is
maintained.16,17 In other words, the combination measurement of
three HCC biomarkers will identify a greater number of patients at
risk of developing HCC during surveillance than with each marker
alone.
The diagram shows that if you were to run AFP alone, you would
miss:7 patients that were DCP positive but not AFP positive 19
patients that were AFP-L3 positive but not AFP positive 4 patients
that were positive for both DCP and AFP-L3, but negative for total
AFP - Of the 74 patients in this study, 26 patients with HCC would
have been missed if only AFP were used16Utility when biomarkers are
used in combination in patients without HCC: False Positives, True
Negative, True Positives (in the colored circles)AFP-L3%DCPAFP2
(0.5%)3 (0.7%)9 (2.2%)15 (3.7%)26 (6.5%)81(20.2%)True Negative258
(64%)7 (1.7%)False PositiveAFP: 25%AFP-L3%: 7%DCP: 9%N = 401FDA
submission data for LiBASys17This is looking at G4 (no HCC) but
they tested positive for the marker (false positives). If using
only AFP there is a 24.6% false positive rate. That is the highest
of all three markers. By adding in the other markers you lower the
possibility of having false positives. There is only a 0.5% chance
that someone without HCC would test positive for all three
markers.
But lets keep looking at AFP since it is the bench mark. If a
doctor adds in DCP- only 7 out of 401 pts tested positive for both
of these. Or L3 + AFP- only 9 out of 401 tested positive for both
of these. All the more reason to use- there is such a low
likelihood of false positives when more than one marker is
elevated. rule out the possibility of a false positive.Predictors
of HCC Development in Patients with Chronic Hepatitis CEl-Serag, et
al. 2014
The development of HCC in patients with HCV and cirrhosis can be
predicted based on: high AFP levels high ALT levels low platelet
levels older age at AFP testAFP = -fetal protein; ALT = alanine
aminotransferase.El-Serag HB, Kanwal F, Davila JA, Kramper J,
Richardson P. Laboratory-based algorithm to predict development of
hepatocellular carcinoma in patients with hepatitis C and
cirrhosis. Gastroenterol. 2014;146;1249-1255.
18Case 1 Risk assessment of HCC development by AFP-L3
0.17 ng/mLAFP-L3 Normal: