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)
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