1. HCC Guidelines and recommendation 2013

2. Typical feature (wash in/wash out) New mass/nodule NoYes Alternative imaging technique Atypical featureTypical feature Biopsy Increase (Ø ≥ 1 cm) NoYes US 3 months Ø < 1cm TC/RM/CEUS* Ø ≥1cm Increase (Ø ≥ 1 cm) US 3 months (for 12 months) No US 6 months Yes Other diagnosis HCC Inconclusive Diagnostic algorithm US, Ultrasound; MRI, Magnetic resonance imaging; CT, computed tomography; CEUS, contrast-enhanced ultrasonography *Since magnetic resonance imaging (MRI) or computed tomography (CT) would be performed for hepatocellular carcinoma staging after detection of a nodule by ultrasonography, the most cost-effective approach is to prescribe in first line MRI or CT and to resort to contrast-enhanced ultrasonography (CEUS) in case of inconclusive diagnosis at MRI and/or CT. Position paper AISF DLD 2013 45(2013) 712-723

3. 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

4. Treatment algorithm – AISF guidelines * : each TACE; ** : with cTACE, MRI is preferred to CT *** : Response must be assessed by modified RECIST criteria Position paper AISF DLD 2013 45(2013) 712-723 sorafenib HCC not amenable to curative treatments Child Pugh class A or B7 Performance Status ≤1 No portal/hepatic vein invasion (except segmental or subsegmental portal branches)) 1 st treatment (cTACE or DEB-TACE) 2 nd treatment (cTACE or DEB-TACE) MRI or CT** at 1 month No complete response Partial responseNewly developed HCC Complete response MRI or CT every 3 months Desease recurrence Consider another course of cTACE or DEB- TACE (and/or ablation techniques) Liver failure or severe adverse events* Yes No Resolution Palliation Desease progression or stable desease

5. Systemic therapies – AISF guidelines Position paper AISF DLD 2013 45(2013) 712-723

6. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2013; Available from: www.nccn.org Accessed on 09-May 2013.www.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  Systemic chemotherapy  Intra-arterial chemotherapy Clinical trial Locoregional therapy RT (conformal or stereotactic) (category 2B) Supportive care Options: Sorafenib (Child–Pugh Class A [category 1] or B) Clinical trial Locoregional therapy RT (conformal or stereotactic) (category 2B) Supportive care Options: Sorafenib (Child–Pugh Class A [category 1] or B) Supportive care Clinical trial SurveillanceTreatmentClinical 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 or Extensive liver burden Treatment algorithm – NCCN guidelines

7. Treatment algorithm - 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

8. Kudo et al. Dig Dis 2011;29:339–364 Consensus-based treatment algorithm - 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

9. 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 Treatment algorithm - AASLD guidelines

10. 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 Treatment algorithm – EASL, EORTC guidelines Target: 40% OS: 11 mo (6-14) Target: 20% OS: 20 mo (45-14) BSC Target: 10% OS: <3 mo

11. 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 Systemic therapies – EASL, EORTC guidelines

12. Levels of evidence and grade of recommendation 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

13. 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