20° CONGRESSO NAZIONALE DELLE MALATTIE DIGESTIVE
FISMAD
Napoli 20 Marzo 2014
Mostra d’oltremare
“Screening possibili, probabili e impossibili
in gastroenterologia oncologica”
Fegato
Mauro Borzio MD
U.O.C. Gastroenterologia
A.O. Melegnano –
Mauro.borzio@gmail.com
SCREENING: perchè
Sopravvivenza a 5 anni
HCC sintomatico (fase avanzata)
0-10%
HCC precoce ( < 3 cm)
50 %
Llovet et al . Sem Liv Dis 1999
Surveillance for cancer: “lead time” bias
Cancer diagnosis
Cancer
Symptoms
Screening test
Spurius benefit:
anticipated diagnosis
Symptoms
Lead time
Survival time
Survival with surveillance
Screening test
death
Real benefit:
Increased OS
Symptoms
death
Survival with surveillance
18,816 patients with HBsAg-positive chronic hepatitis
9,373
AFP + US (semi-annual)
9,443
No surveillance
86
HCC
67
36
No of deaths for HCC
54
83/100,000
Total mortality
for HCC
HCC mortality rate ratio:
0.63 (95% CI: 0.41-0.98)
Adherence 58%
No OLT available
131/100,000
Surveillance for HCC in cirrhosis: unfeasibility of
RCT when informed consent is given
205 cirrhotic patients (child-Pugh A/B)
This topic can be only
addressed by carefully
conducted cohort
studies
Decision aid
paper
6 mo. US + 3 mo. AFP
vs
No surveillance
204 pts. (99.5%)
Declined randomization
181
chose
surveillance
21
continued their
usual care
2
were
undecided
Poustchi H et al. Hepatology 2010; 54:1998
2010
2012
2012
Screening dell’HCC
• Cosa si aspetta il decisore
– Appropriatezza e sostenibilità economica dello
screening (cost/effectiveness ratio)
• Cosa si aspetta il cittadino
– Prevenzione mediante procedure semplici e sicure
(adherence/compliance)
• Cosa si aspettano i sanitari
– Efficacia in termini di aumentata sopravvivenza
(overall survival benefit)
Recommendation for HCC
surveillance
Cost/utility analyses
Basic prerequisite of cost-effectiveness:
disease frequency in the target population should
be high enough
•The annual incidence of the disease in the target
population should be > 0.2%
•For HCC surveillance in liver cirrhosis: the annual
incidence should be > 1.5 %/yrs
(due to the cirrhosis-related mortality
[“overdiagnosis”] and treatment restraint)
Sarasin 1996, Ardeguas 2003, Yuen 2003
Changes in Age-adjusted mortality rates in men for primary liver
cancer by European Country from 2000 to 2010
Bertuccio et al, Ann Oncol 2013; 24:1667
Croat ia
Sweden
net herlands
Un Kingdom
Port ugal
Romania
Czech Rep
Slovenia
Germany
Aust ria
Belgium
Russia
greece
Slovakia
France
Years
HCC X 100,000
Spain
It aly
2000-2003
2006-2008
Hungary
6.08
4.02
lit uania
est onia
-100
0
100
200
300
Epidemiologia del tumore epatico primitivo in Italia
Registro AIRTUM (aggiornato 2011)
Complete prevalence (per 100 000) at 1 January 2003 and
prevalent cases in Europe at 2003, by cancer site and age
Gatta et al; Ann Oncol 2013;24:1660
Categories of adult patients in whom surveillance for
HCC is recommended
AASLD, AISF, EASL-EORTC guidelines
1.Cirrhotic patients, Child-Pugh stage A and B* (2-2,5 %
incidence)
2.Cirrhotic patients, Child-Pugh stage C awaiting liver
transplantation**
3.Non-cirrhotic HBV carriers with active hepatitis or
inactive carriers with family history of HCC and HBVDNA > 10.000 UI *** ( > 0.2 % incidence)
4.Non-cirrhotic patients with chronic hepatitis C and
advanced liver fibrosis F3 **** (> 1.5 % incidence)
Surveillance is recommended for the above patients if they do not have
contraindications to radical or palliative treatments
* evidence 3A, strength B1;
** evidence 3D, Strength B1
*** evidence 1B, strength A1 for Asian patients; evidence 3D, strength C1 for
Westewrn patients
**** evidence 3D, strength B1 for Asian patients; evidence 3D strength B2 for
Western patients
Surveillance strategy according to the risk of HCC
Surveillance Recommended
Threshold Incidence for Efficacy of
Surveillance (>0.25 LYG)(%/year)
Population Group
Incidence of HCC (%/year)
Asian male hepatitis B carriers over age 40
0.2
0.4-0.6
Asian female hepatitis B carriers over age 50
0.2
0.3-0.6
Hepatitis B carrier with family history of HCC
0.2
African/North American Blacks
0.2
Incidence higher than without
family history
HCC occurs at a younger age
Cirrhotic hepatitis B carriers
Hepatitis C cirrhosis
Stage 4 primary biliary cirrhosis
Genetic hemochromatosis
0.2-1.5
1.5
1.5
1.5
3-8
3-5
3-5
Unknown, but probably >1.5
1.5
Unknown, but probably >1.5
Alpha 1-antitripsin deficiency
Other cirrhosis
1.5
Surveillance Benefit Uncertain
Hepatitis B carriers younger than 40 (males)
or 50 (females)
Hepatitis C and stage 3 fibrosis
Noncirrhotic NAFLD
HCC, hepatocellular carcinoma; LYG, life years gained; NAFLD,
Unknown
0.2
<0.2
1.5
1.5
nonalcoholic fatty liver disease.
<1.5
<1.5
Sherman M. Sem Liver Dis 2010
Surveillance for HCC: how?
Guide-lines recommendations
1. Surveillance for HCC should be performed
using ultrasonography every 6 months
2. Surveillance with US should be performed
by an experienxed operator
3. AFP as a unique test for surveillance is not
recommended due to its suboptimal
performance.
4. The combination of AFP to US does not
provide any additional benefit
AASLD, Hepatology 2005
AISF 2012, www.webaisf.org
EASL-EORTTC, J Hepatol 2012
Predictivity of different AFP serum
levels according to tumor prevalence
AFP cut-off
Retrospective analysis
170 cases with HCC and CLD
170 cases with CLD no HCC
Sensitivity 60,
specificity 90.6
HCC prevalence
PPV
NPV
20 ng/mL
50
10
5
84.6
41.5
25.1
69.4
95.3
97.7
100 ng/mL
50
10
5
96.4
74.6
58.2
58.9
92.8
96.5
200 ng/mL
50
10
5
97.4
80.9
66.7
56.1
92.0
96.1
400 ng/mL
50
10
5
96.7
76.3
60.4
54.5
91.5
95.8
Trevisani et al. J Hepatol 2001;34:570-5.
Surveillance for HCC: how
Pooled sensitivity (meta-regression) of Ultrasound
for early stage HCC
Singal et al . Aliment Pharmacol Ther 2009; 30:37
Semi-annual
0.70 (0.56-0.81)
For HCC at any stage
0.94 (083-0.98)
AFP as a surveillance test
Pooled sensitivity (meta-regression) of US (left) or US+ AFP (right) for early stage HCC
Singal et al . Aliment Pharmacol Ther 2009; 30:37
Sensitiv.
False +
PPV
cost for each
small HCC detected
(USA $)
US
84 %
2,9 %
6.6 %
1,980
US + AFP
92 %
7.5 %
3.0 %
3,640 ( +84%)
AFP
68 %
5,0 %
3.3 %
3,030 (+ 53 %)
Semiannual surveillance
in 9,783 patients with
HBsAg + or with chronic
hepatitis
Zang B et al J Med Screen1999; 6:108
Doubling time (months) of small
HCC
6.5 ± 5.7
Range 1-19
Ebara (Japan)
22 HCC < 3 cm
6.6 ± 4.2
Range 1-20
Barbara (Italy)
59 HCC < 5 cm
Survival according to the surveillance interval
(6 vs 12 months)
Santi ey al J Hepatol 2010;53:291
Retrospective study on 634 patients with
Child-Pugh class A/B cirrhosis
Observed survival
Corrected (for lead time) survival
Sensitivity analysis: semi-annual is superior to annual time
interval in patiens with a tumor doubling time ≤ 147 days
Surveillance for HCC in cirrhosis:survival
in cohort studies
cirrhosis
Kemp 2005
3-Years survival rate
HCV,HBV,
alcohol
Retrospective
US 6-12 mo
41
56
38%
19%
Toyoda 2006
Japan
HCV, HBV
Retrospective
US+AFP +
DCP
1,050
591
36 %
19%
Strawitz2008
USA
HCV,
alcohol
Retrospective
US 12 mo
172
107
40%
13%
Kuo 2010
HBV, HCV
Retrospective
US≤ 12 mo
318
1118
59%
29%
Australia
329 days
(median)
916 days
(median)
Taiwan
Kemp W et al J Gastroenterol Hepatol 2005, Toyoda H et al; Clin Gastroenterol Hepatol 2006; Stravitz RT et al Am J
Med 2008; Kuo Y-H et al, Eur J Cancer 2010
Impact of regular (6-12 months) US surveillance on HCC
presentation and outcome
from EpaHCC-AIGO database (1113 cases at November 2013)
Surveillance
6-12 mo
> 12 mo
No
Single
2-3 nodules
4 or more
617 (55%)
405 (66%)
143 (23%)
69 (11%)
496 (45%)
244 (49%)
126 (25%)
126 (26%)
< 20 mm
192 (31%)
56 (11%)
21-30 mm
> 30 mm
200 (32%)
225 (37%)
94 (19%)
346 (70%)
Milan Criteria in
447 (72%)
194 (39%)
< 0.001
Curative treatment
(OLT, Rx, Ablation)
341 (55%)
168 (34%)
< 0.02
mean (95% CI) OS (months) 1yr
Surveillance 6-12 Mo
> 12 Mo
34 (29.4-38.6)
20 (16.3-23.7)
74 %
52 %
< 0.02
< 0.01
2 yr
3 yr
55 %
40 %
42 %
36 %
Screening e sorveglianza dell’HCC
1. Sebbene in Italia e più in generale in Europa si assista
ad una riduzione di incidenza e mortalità per HCC, i
programmi di screening e sorveglianza sono ancora
giustificati e cost-effective
2. Le linee guida europee raccomandano di limitare lo
screening e la sorveglianza ai gruppi ad alto rischio
(prevalenza > 0.2/100,000, incidenza 2.5%/anno)
3. Gli ultrasuoni applicati ad intervalli regolari (6 mesi)
sono il test migliore per lo screening e la sorveglianza
4. Studi di cohorte ben disegnati ( in assenza di RCTs)
confermano l’efficacia dello screening (maggiori
diagnosi precoci) e un favorevole impatto sui surrogati
di outcome (trattamenti curativi, survival 3-5 anni)