5/26/10. Oren Fix, MD, MSc Transplant Hepatology Division of Gastroenterology University of California San Francisco

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1 Oren Fix, MD, MSc Transplant Hepatology Division of Gastroenterology University of California San Francisco Epidemiology Surveillance Biomarkers Biopsy Treatment local regional therapy, systemic chemotherapy, transplant Liver criteria, drop- out, expanded criteria, down- staging >600,000 people worldwide 6 th most common cancer Deaths incidence 3 rd most common cause of cancer- related death Incidence is increasing due to hepa@@s C and non- alcoholic faoy liver disease Parkin et al. CA Cancer J Clin 2005 El- Serag. Gastroenterol

2 reduce mortality or provide meaningful improvement in survival 37% in HCC- related mortality with AFP + ultrasound every 6 months in hepa@@s B in China Cost- effec@ve using Markov modeling Bruix, Sherman. Hepatology 2005 Zhang et al. J Cancer Res Clin Oncol 2004 Hepa11s B carriers Asian males 40 years Asian females 50 years All cirrho@c hepa@@s B carriers Family history of HCC Africans >20 years Pa@ents with high HBV DNA and those with ongoing hepa@c inflammatory ac@vity Non- hepa11s B cirrhosis Hepa@@s C Alcoholic cirrhosis Gene@c hemochromatosis Primary biliary cirrhosis Alpha- 1- an@trypsin deficiency* Non- alcoholic hepa@@s* Autoimmune hepa@@s* *These groups have increased risk of HCC but data are lacking that show benefit with surveillance Bruix, Sherman. Hepatology 2005 Ultrasonography Sensi@vity 65-80%, specificity >90% Operator- dependent, cirrhosis, obesity AFP has poor sensi@vity and specificity 20 ng/ml = 60% sensi@vity 200 ng/ml = 22% sensi@vity PPV of 20 ng/ml = 25% (5% prevalence) PPV of 400 ng/ml = 60% Bruix, Sherman. Hepatology 2005 Trevisani et al. J Hepatol

3 Des- gamma carboxyprothrombin Lens culinaris- of AFP Glypican- 3 Pancrea@@s- associated an@gen P16 methyla@on Human hepatocyte growth factor Cytokera@n- 19 Transforming growth factor beta- 1 Lipoprotein a Erythrocyte binding polyamine Tissue polypep@de specific an@gen C- reac@ve protein P53 an@bodies CD24 gene Telomerase ac@vity Prothymosin alfa Microsatellite DNA analysis HCC- associated gene 1 Epidermal growth factor receptor Marrero. Clin Liver Dis 2005 May be more sensi@ve/specific than AFP for differen@a@ng HCC from chronic liver disease Sensi@vity diminishes with points AFP and DCP complementary but neither are sufficiently accurate for surveillance Marrero et al. Hepatology 2003 Lok et al. Gastroenterol 2010 Diagnosis PPV of AFP >200 ng/ml in a cirrho@c pa@ent with a liver mass is high Prognosis AFP and DCP predict post- transplant recurrence High DCP associated with microvascular invasion and poor differen@a@on Trevisani et al. J Hepatol 2001 Yao et al. Am J Transpl 2005 Fujiki et al. Am J Transpl

4 Different vascular supply of normal liver parenchyma and HCC CT imaging findings arterial phase enhancement Decreased on portal venous phase Similar MR findings T2 hyperintensity Pseudocapsule is Taouli, Krinsky. Liver Transpl 2006 OPTN database analysis 44.1% accuracy compared to pathologic stage Understaging = overstaging 21% of pa@ents given priority for transplant for HCC had no tumor on pathology Accuracy improved in older pa@ents, staging <90 days before transplant, stage >1 Understaging associated with higher risk of recurrence Freeman et al. Liver Transpl 2006 Shah et al. Transplanta@on 2006 Con Most lesions >2 cm can be diagnosed noninvasively 10% risk of false nega@ve diagnosis Accuracy decreases with smaller lesions Risk of progression for small lesions is low Bleeding Needle track seeding: 0-5.1% S@gliano, Burroghs. J Hepatol

5 Pro May allow priority for transplant High false rate of radiologic staging leads to unnecessary transplants Risk of tumor seeding is low and outcome usually not affected Tumor predict recurrence and may help select for transplant Marsh, Dvorchik. J Hepatol 2005 Marshall et al. Liver Transpp 2010 Yao et al. Am J Transpl 2005 Surgical resec@on Local regional therapy (LRT) Percutaneous ethanol abla@on (PEI) Radiofrequency abla@on (RFA) Transcatheter arterial chemoemboliza@on (TACE) and Drug- Elu@ng Beads (DEB) Radioemboliza@on (Y- 90) Systemic chemotherapy Liver transplanta@on Available to 5% of pa@ents Single, small lesion ( 5 cm) No liver disease of Child class A cirrhosis No portal hypertension (normal platelets) Normal bilirubin Rust, Gores. Clin Liver Dis 2001 Llovet et al. Hepatol

6 No difference in recurrence or survival in RCT comparing surgical with PEI No difference in overall survival and disease- free survival for small HCC in RCT comparing surgical and RFA Huang et al. Ann Surg 2005 Chen et al. Ann Surg 2006 Survival benefit demonstrated by several RCTs and meta- analysis China Europe TACE 1- yr: 57% 3- yr: 26% 1- yr: 82% 3- yr: 29% Control 1- yr: 32% 3- yr: 3% 1- yr: 63% 3- yr: 17% Meta- analysis: OR 0.42, 95% CI Lo et al. Hepatology 2002 Llovet et al. Lancet 2002 Llovet et al. Hepatology 2003 Improved 3- year survival in transplant who received LRT compared to no LRT (79% vs 75%, P=.03) UCSF analysis: improved survival with LRT (94% vs 81%, P=.049) review at UPenn: no survival benefit (84% vs 91%, P=.6) Freeman et al. Am J Transpl 2008 Yao et al. Am J Transpl 2005 PorreO Liver Transpl

7 YOrium- 90: pure beta emioer Half life 64 hours Range mm Biodegradable glass microspheres with diameters of μm Can treat with more advanced liver disease and portal vein thrombosis No RCTs Riaz et al. Q J Nucl Med Mol Imaging 2009 Sorafenib Oral mul@kinase inhibitor Blocks tumor cell signal transduc@on, prolifera@on, angiogenesis Approved for unresectable HCC 11/2007 First approved systemic drug for HCC Only medica@on proven to significantly improve overall survival in HCC Llovet et al. NEJM 2008 Median overall survival Sorafenib 10.7 months Placebo 7.9 months HR 0.69, 95% CI , P<.001 No difference in to symptoma@c progression (4.1 vs 4.9 mo) Side effects: diarrhea, weight loss, hand- foot skin syndrome, hypophosphatemia Llovet et al. NEJM

8 HCC considered the clearest 6 of first 7 pa@ents transplanted for hepa@c malignancy Early case series 9/11 (82%) developed recurrence in 1 year Only 1 survived 17 months Incidental HCC in 12 pa@ents: 11 survived 4 months to >15 years without recurrence Starzl et al. Ann Int Med 1966 Iwatsuki et al. Ann Surg 1985 BeOer outcomes in a concurrent series HCCs cm, 12 with mul@ple tumors ranging from 8-15 cm Recurrence in 24/37 (65%) 2- year survival 38% Disappoin@ng yet some pallia@on and a few long- term cures O Grady et al. Ann Surg 1988 German case series of 52 pa@ents Many pa@ents with large tumors >5 cm to 23 cm Tumor invasion of portal vein, extrahepa@c spread Median survival 9 months Median survival 10 yrs in 4 pa@ents with stage II Ringe et al. Ann Surg

9 Mazzaferro et al. NEJM 1996 criteria: Single tumor 5 cm 2-3 tumors, each 3 cm No tumor invasion of blood vessels or lymph nodes 4- year recurrence- free survival 83% 4- year overall survival 75% 1 lesion 5 cm 2 to 3, none >3 cm + Absence of Macroscopic Vascular Invasion Absence of Extra- hepa1c Spread Mazzaferro et al. NEJM 1996 Milan Criteria T1 1 lesion <2 cm T2 1 lesion 2-5 cm 2 or 3 lesions, none >3cm UNOS Policy 3.6 9

10 Urgency for transplant risk of death Urgency for transplant = risk of progression beyond stage II MELD for T1 MELD for T Wiesner et al. Gastroenterol 2004 Freeman et al. Am J Transpl 2008 Inten@on- to- treat analysis of resec@on vs transplanta@on Mean wai1ng 1me 2- year survival days 84% days 54% Llovet et al. Hepatology 1999 Inten@on- to- treat analysis of resec@on vs transplanta@on Mean wai1ng 1me 2- year survival 2- year post- transplant survival days 84% 84% days 54% 80% Difference in survival due to 23% drop- out rate Llovet et al. Hepatology

11 Low drop- out rate <6 months increase thereazer Higher risk of drop- out with tumors >3 cm and presence of 3 tumors of diagnosis or lis@ng Few pa@ents with HCC can be successfully maintained on the wai@ng list beyond 1 year Yao et al. Liver Transpl 2002 Yao et al. Liver Transpl 2003 Uncontrolled trials suggest LRT may reduce risk of drop- out No RCTs of LRT and drop- out Sorafenib? High- risk donors (cab+, HCV) Living donor liver transplanta@on Expanded criteria Down- staging Vitale et al. Hepatology 2010 Yao et al. Liver Transpl 2002 Yao et al. Liver Transpl 2003 Graziadei et al. Liver Transpl 2003 Milan criteria may be too restric@ve Some expansion of criteria demonstrates post- transplant outcomes comparable to Milan criteria UCSF Up- To- 7 Total Tumor Volume Marsh, Schmidt. Liver Transpl 2010 Yao et al. Hepatology 2001 Yao et al. Am J Transpl 2007 Mazzaferro et al. Lancet 2009 Toso et al. Liver Transpl

12 Milan UCSF* 1 lesion 5 cm 6.5 cm 2-3 lesions Each 3 cm Each 4.5 cm No vascular invasion No extrahepa1c spread *Total tumor diameter 8 cm 5- year recurrence- free probabili@es Milan 90.1% UCSF 93.6% Yao et al. Hepatology 2001 Yao et al. Am J Transpl = number of nodules + size (cm) of largest nodule 5- year overall survival: Milan 73.3% Up- to- 7: 71.2% Based on pathologic analysis Mazzaferro et al. Lancet 2009 The further the distance the greater the price Cri@cs: Expansion of criteria will lead to higher drop- out and recurrence rates, unfair to non- HCC pa@ents on wai@ng list Should all selec@on criteria be compared to Milan? Should the goal be a minimum acceptable post- transplant survival? Llovet et al. Sem Liver Dis 2005 Yao. Am J Transpl

13 Response to LRT may be a beoer predictor of recurrence than tumor stage 8 cm Down- staging Transplant? Outcome? Chapman et al. Ann Surg 2008; OOo et al. Liver Transpl 2006 Yao et al. Liver Transpl 2005; Yao et al. Hepatology 2008 Number of Lesions Size of Each Lesion (cm) Total Tumor Diameter (cm) 1 >5 but No vascular invasion on imaging Tumor size and number mee@ng T2 criteria OR Complete tumor necrosis without residual tumor (equivalent to oblitera@on of tumor) AND Minimum follow- up period of 3 months azer down- staging before liver transplanta@on 13

14 N=88 Kaplan- Meier Probabili1es 84.1% 61.3% Follow- up in Years n=50 Kaplan- Meier Probabili1es 97.6% 83.8% Follow- up in Years n=50 Kaplan- Meier Probabili1es 97.8% 95.0% Follow- up in Years 14

15 Pretransplant imaging criteria Organ (MELD) Role of LRT as a bridge to transplant Role of resec@on Expanded criteria Down- staging Pomfret et al. Liver Transpl HCC incidence is increasing, mortality is high, and it is a leading cause of cancer death 2. Surveillance of HCC in at- risk popula@ons improves survival 3. Biomarkers, including AFP, are not sensi@ve or specific to be used alone for surveillance, but have u@lity in diagnosis and prognosis 4. Radiologic imaging may be almost 50% inaccurate leading to both over- and understaging 5. Biopsy of liver masses is ozen unnecessary to establish diagnosis of HCC but may be useful in the future for pa@ent selec@on for transplant 6. LRT improves survival and may reduce drop- out and post- transplant recurrence 15

16 7. Liver is the most therapy for highly selected 8. Even for eligible drop out due to tumor progression limits access to transplant 9. Current transplant criteria for HCC based on tumor staging may be too 10. criteria are evolving and UCSF is at the forefront of the movement to expand criteria and down- stage 11. BeOer predictors of tumor biology and behavior are needed 12. Response to LRT are surrogates for tumor biology that allow of with HCCs with a lower risk of recurrence Management of HCC requires a mul@disciplinary approach that involves all aspects of HCC diagnosis and therapy Early referral to a hepatologist who is part of a mul@disciplinary HCC group is essen@al to improving survival in this otherwise devasta@ng disease 16