1. HCC Guidelines and recommendation 2012

2. Diagnostic algorithm and recall policy.*One imaging technique only recommended in centers of excellence with high-end radiological equipment.**HCC radiological hallmark: arterial hypervascularity and venous/late phase washout Mass/nodule on US <1cm 1-2cm>2cm 4-phase CT or Dynamic Contrast enhanced MRI 4-phase CT/Dynamic Contrast enhanced MRI Repeat US at 4 mo Growing/Changing Character Stable 1 or 2 positive techniques*: HCC radiological Hallmarks** 1 positive technique: HCC radiological Hallmarks** YesNo HCC Biopsy Investigate according to size Inconclusive YesNo HCC Biopsy Diagnostic algorithm EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdfhttp://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

3. Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on www.webaisf.orgwww.webaisf.org Available on: http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf Accessed on 30-March 2012http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf Typical feature (wash in/wash out) New mass/nodule NOSì Other contrast enhanced technique Atypical featureTypical feature Biopsy Growing Ø NOSì US 3 months Ø < 1cm TC/RM/CEUS Ø ≥1cm Growing Ø US 3 months (for 12 months) NO US 6 months Sì Other diagnosis HCC No diagnosis Diagnostic algorithm US, Ultrasound

4. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2012; Available from: www.nccn.org Accessed on 30-March 2012www.nccn.org. Imaging every 3–6 months for 2 years, then every 6-12 months AFP, if initially elevated, every 3-6 months for 2 years, then every 6-12 months See relevant pathway (HCC-2 through HCC-7) if disease recurs Options: Sorafenib (Child–Pugh Class A [category 1] or B) Chemotherapy + RT only in the context of a clinical trial Locoregional therapy RT (conformal or stereotactic) (category 2B) Supportive care Systemic or intra-arterial chemotherapy in clinical trial Options: Sorafenib (Child–Pugh Class A [category 1] or B) Clinical trial Locoregional therapy RT (conformal or stereotactic) (category 2B) Supportive care Sorafenib (Child–Pugh Class A [category 1] or B) Supportive care Clinical trial Surveillance Treatment Clinical presentation Refer to liver transplant center Consider brige therapy as indicated Transplant candidate Inadequate hepatic reserve Tumor location Evaluate whether patient is a candidate for transplant (See UNOS criteria under Surgical Assessment HCC-5) Not a transplant candidate Extensive liver disease Unresectable Inoperable by perfomance status or comorbidity, local disease or local disease with minimal extrahepatic disease only Metastatic disease

5. APASL guidelines APASL recommendations on HCC, Omata M, et al. Hepatol Int. 2010;4:439–474 Sorafenib or systemic therapy trial Confined to the liver Main portal vein patent HCC Extrahepatic metastasis Main portal vein tumor thrombus Resectable Child–Pugh A/B Child–Pugh C YesNo Solitary tumor < 5 cm < 3 tumors < 3 cm No venous invasion Tumor > 5 cm > 3 tumors Invasion of hepatic / portal vein branches Child–Pugh AChild–Pugh BChild–Pugh CChild–Pugh A/BChild–Pugh C Resection/RFA (for < 3 cm HCC) Local ablation TransplantationTACESupportive care

6. Kudo et al. Dig Dis 2011;29:339–364 Consensus-based treatment algorithm for HCC proposed by JSH HCC YesNo Child-Pugh A/BChild-Pugh CChild-Pugh B/CChild-Pugh A SorafenibPalliative care *1, *2 YesNo Exceeding Milan criteria or age >65 Within Milan *7 criteria or age ≤65 Transplantation TACE/ablation for Child-Pugh C Patient *10 HAIC (Vp3,4) *8 Sorafenib (vp3,4) *8 TACE (Vp1,2) *9 Resection(Vp1,2) *9 TACE *5 HAIC *5 Resection *6 Ablation *6 Resection TACE TACE+ Ablation *4 Sorafenib *5 (TACE refractory,child-pugh A) Resection Ablation Intensive follow up Ablation TREATMENT SIZE NUMBER VASCULAR INVASION LIVER fUNCTION EXTRAHEPATIC SPREAD No Hypovascular Early HCC *3 Single Yes 1-3 ≤3 cm>3 cm ≥4

7. Portal pressure/ bilirubin HCC RFASorafenib Stage 0 PS 0, Child–Pugh A Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 End stage (D) Liver transplantationTACEResection Symptomatic treatment Curative treatments Palliative treatments Associated diseases YesNo 3 nodules ≤ 3 cm Increased Normal 1 HCC Stage D PS > 2, Child–Pugh C Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1–2 Stage A–C PS 0–2, Child–Pugh A–B PS, performance status; TACE, transarterial chemoembolization. Adapted from Bruix J, Sherman M. HEPATOLOGY, Vol. 53, No. 3, 2011. Available on: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf AASLD guidelines

8. Portal pressure/ bilirubin HCC PEI/RFASorafenib Stage 0 PS 0, Child–Pugh A Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 End stage (D) Liver transplantationTACEResection Curative treatments (30%) 5-year survival (40–70%) Associated diseases YesNo 3 nodules ≤ 3 cm Increased Normal 1 HCC Stage D PS > 2, Child–Pugh C Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1–2 Stage A–C PS 0–2, Child–Pugh A–B PS, performance status; TACE, transarterial chemoembolization; BSC, Best Supportive Care EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf. HCC guidelines Target: 40% OS: 11 mo (6-14) Target: 20% OS: 20 mo (45-14) BSC Target: 10% OS: <3 mo

9. Levels of evidence and grade of raccomandation Adjuvant therapy after resection OLT-extended Neoadjuvant therapy in waiting list LDLT Downstaging Internal radiation Y90 Resection Levels of evidence (NCI) Grade of recommendation (GRADE) 1 2 3 2 (weak) 1 (strong) RF (<5 cm), RF/PEI (<2 cm) Chemoembolization External/palliative radiotherapy Sorafenib ACB ACB OLT-Milan EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdfhttp://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

10. Algorithm for resection in HCC patients Segmentectomy or bisegmentectomy Segmentectomy or limited resection Major hepatectomy (up to 4 segment) Risk of IPLF>15% in all types of hepatectomy MELD score 9 - 10 Serum sodium level Cirrhotic: patient eligible for liver resection ≥ 140 mEq/L< 140 mEq/L >10 <9 Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on www.webaisf.orgwww.webaisf.org Available on: http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf Accessed on 30-March 2012http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf

11. * : each TACE; ** : with cTACE, MRI is preferred to CT *** : Response must be assessed by modified RECIST criteria [CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progression Disease]. TACE candidate No portal vein thrombosis (accepted segmental thrombosis) No extra-epatic spread; Child Pugh A or B7 Liver deterioration, major complication* CR *** MRI or CT Every 3 months Relapse*** PR *** Resolution No BSC Sì Progression Disease (PD) *** or Stable Disease(SD) *** New nodule Growth of target nodule or SD*** Consider SORAFENIB Consider other treatment (cTACE or DEB-TACE) cTACE or DEB-TACE MRI or CT ** (at 1 month) cTACE or DEB-TACE MRI or CT ** (at 1 month) Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on www.webaisf.orgwww.webaisf.org Available on: http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf Accessed on 30-March 2012http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf Treatment algorithm for the repetition of TACE in intermediate stage HCC patients

12. Trial design strategies and control groups EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdfhttp://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711