1. Diagnosing and Managing Cancers of the Liver and Bile Ducts Jeffrey S. Weinstein, MD Medical Director of Liver Transplantation Methodist Dallas Medical Center April 25, 2015

2. Types of Malignant Liver Tumors Metastatic tumors (most common) Hepatocellular carcinoma (HCC) Cholangiocarcinoma (CCA) Combined HCC/CCA Fibrolamellar carcinoma Hepatoblastoma Cystadenocarcinoma Epitheliod hemangioendothelioma Angiosarcoma

3. Hepatobiliary Anatomy

4. Hepatocellular (HCC) Clinical features Diagnostic studies Staging Treatment options Role of transplant

5. Clinical Features of HCC Usually occur in background of chronic liver disease and cirrhosis Small tumors usually cause no symptoms Larger tumors can be associated with: - abdominal pain - loss of appetite and weight loss - worsening liver function - fever - jaundice - intra-abdominal bleeding

6. Diagnostic studies for HCC Labs - AFP tumor marker Radiologic studies - Ultrasound - Multiphase MRI - Multiphase CT Biopsy

7. AFP Limitations and Uses Limitations - may be elevated with chronic hepatitis - elevated in HCC in only about ~ 40% Uses - level > 20 useful for screening but adds to costs and false positive rates - level > 400-500 about 99% specific - level > 400-500 have worse prognosis

8. Non-Invasive Radiologic Studies Used for HCC Ultrasound - screening and staging Multiphase contrast enhanced CT or MRI of abdomen and pelvis - screening, diagnosis, and staging Chest CT +/- Bone scan - staging

9. Invasive Studies Used for HCC Ultrasound or CT guided biopsy - diagnosis and staging Endoscopic ultrasound - diagnosis and staging Angiography - diagnosis and treatment

10. HCC findings on Contrast Enhanced MRI or CT Requires dedicated 4-phase study - Early and late arterial phases - Portal venous phase - Late venous phase Typical HCC - early arterial enhancement - late venous washout

11. MRI Appearance of HCC Arterial phase Portal venous phase Late venous phase

12. Diagnostic Approach to HCC Mass < 1cm on Ultrasound Repeat Ultrasound every 3- 6 months for 2 years 0r MRI/CT x 1 No growth Resume surveillance every 6 months Growth in mass Contrast enhanced CT or MRI Typical vs. Atypical for HCC

13. Diagnostic Approach to HCC Mass < 1cm on MRI/CT Typical for HCC Treat for HCC Growth in mass Repeat MRI/CT Atypical for HCC Check CA 19-9, biopsy or resect mass Monitor with U/S q 3 months

14. Diagnostic Approach to HCC Mass > 1cm on MRI/CT Typical for HCC Treat for HCC Obtain other study MRI/CT Atypical for HCC Check CA 19-9, biopsy or resect mass

15. Tumor Staging for HCC Critical for determining treatment options Based on: 1) Size and number of tumors 2) Extension of tumor into adjacent structures 3) Presence of metastases 4) Severity of underlying liver disease 5) Overall physical condition of the patient

16. Staging Severity of Liver Disease Child Pugh Score AscitesBilirubin level Hepatic encephalopathyAlbumin level Prothrombin time/INR MELD score Prothrombin time/INRBilirubin level Serum creatinine Signs of Portal Hypertension VaricesLow platelets AscitesEnlarged spleen

17. Treatment Options for HCC Surgical resection Liver transplant (OLTx) Microwave or radiofrequency ablation Transarterial chemoembolization (TACE) Transarterial radioembolization Radiation and stereotactic radiotherapy Systemic chemotherapy Cryoablation Percutaneous alcohol ablation

18. Surgical Resection for HCC Non-cirrhotic liver or well-compensated liver disease Lesion size and location amenable to surgery Tumor confined to the liver No invasion of large vessels

19. UNOS Guidelines for OLTx & HCC Tumor < 5cm or three tumors all < 3cm Surgical resection not possible Tumor confined to liver No invasion of large vessels or lymph nodes Cirrhotic liver No other contraindications to OLTx Candidates allocated MELD score of 22 MELD upgrade every 3 months if UNOS criteria remain fulfilled

20. OLTx and HCC Bridging therapies if waiting time expected to be 6 months or more - MWA or RFA for tumors < 3 cm - TACE or Radioembolization for larger or multiple tumors About 20% will be removed from list for tumor progression before OLTx 5 year survival after OLTx ~ 75%

21. Locoregional Therapies for HCC MWA or RFA for tumors < 3cm TACE, Radioembolization and Stereotactic radiotherapy for larger or multiple tumors Tumor or tumors confined to liver Absence of severe liver dysfunction Reduce tumor burden before resection Bridging therapy before OLTx Primary treatment for those who are not candidates for surgery or OLTx

22. Systemic Therapies for HCC For advanced tumors and intact liver function Vascular endothelial growth factor inhibitors - Sorafenib* - Bevacizumab Epidermal growth factor inhibitors - Erlotinib - Cetuximab Chemotherapy - Gemcitabine + Cisplatin or Oxaliplatin - Low dose Doxorubicin or Capecitabine

23. Cholangiocarcinoma (CCA) Diagnostic studies Staging Treatment options Unique issues related to PSC Role of liver transplant (OLTx)

24. Anatomic Classification for CCA Intrahepatic 10% - arise from intrahepatic biliary tree Distal 40% - arise below the cystic duct insertion Perihilar 50% (most common in PSC) - Bismuth-Corlette classification - Klatskin tumor any involvement of hepatic duct bifurcation

25. Anatomic Classification for CCA

26. CCA and PSC Incidence of 0.6 to 1.5% per year Lifetime risk 5 t0 15% Younger age of onset ~ 30-50 than with CCA not associated with PSC ~ 50-70 Most tumors are perihilar 1/3 of cases diagnosed within 2 years of when PSC is first diagnosed Smoking and alcohol use may increase risk

27. When to Suspect CCA in Patients with PSC Rapid deterioration in clinical condition for those with PSC Jaundice, dark urine, pale stools, itching Dull RUQ pain Weight loss Rising Alkaline phosphatase and bilirubin Elevated CA 19-9 (> 100)

28. Diagnosing CCA Clinical and laboratory abnormalities Elevated tumor markers – CA 19-9 Radiologic changes on MRCP, MRI/CT or PET scan Endoscopic findings on ERCP or EUS Tumor cells identified on brushings or biopsy Findings at time of Laparoscopy or Surgery

29. Studies Used to Diagnose CCA Serum tumor markers - CA 19-9 Radiologic studies - Ultrasound (U/S), MRCP, CT, MRI, and PET scans Interventional studies - ERCP and Endoscopic Ultrasound (EUS) - Percutaneous cholangiogram (PTC) - CT/MRI guided biopsies

30. CA 19-9 Limitations and Uses Limitations - cannot be detected in 5-10% of patients - may be elevated in other conditions pancreatic CA, acute cholangitis, or biliary obstruction Uses - level > 1000 correlated with advanced tumors - level > 37 useful for screening but poor specificity - level > 100-129 useful for screening or in patients with suspicious stricture - monitoring response to therapy

31. Non-Invasive Radiologic Studies Used for CCA Ultrasound +/- doppler screening and staging MRCP screening, diagnosis, and staging Contrast enhanced multiphase CT or MRI diagnosis and staging PET/CT scan diagnosis and staging

32. Radiologic Changes in PSC with Suspected CCA Stricture progression “Dominant stricture” Increased dilation of the biliary tree proximal to stricture Polypoid mass within the bile duct

33. Radiologic Changes in PSC with Suspected CCA CCA Changes on MRCP

34. Radiologic Procedures and Interventions for CCA Percutaneous cholangiography - diagnose & stage tumor, alleviate obstruction - assess, brush, biopsy, and stent strictures - more difficult to do in PSC CT/MRI guided biopsies - confirm lymph node involvement with tumor - confirm suspected primary tumor* * risk of tumor seeding with biopsies

35. Endoscopic Procedures and Interventions for CCA ERCP +/- cholangiography or intraductal U/S - diagnose & stage tumor, alleviate obstruction - assess extent of tumor in and around bile duct - visualize, brush, and biopsy suspected tumors - stent obstructing tumors - has risk for infection (cholangitis) Endoscopic ultrasound - diagnose & stage tumor - assess tumor extent, regional lymph nodes and vessels - biopsy tumor* or regional lymph nodes * risk of tumor seeding when tumor biopsied

36. CCA Changes on ERCP

37. CCA on Cholangiography Ulcerated stricture Ulcerated and nodular stricture

38. Diagnostic Challenges Related to CCA in Patients with PSC Symptoms of PSC progression can mimic that of tumor CA 19-9 may be elevated from acute cholangitis or benign causes for impaired biliary excretion Mass lesions less common Biliary dilation proximal to point of obstruction is less common

39. Tumor Staging for CCA Critical for determining treatment options Based on: 1) Extent of tumor 2) Severity of underlying liver disease 3) Overall physical condition of the patient Laparoscopy and/or open surgery often required to complete the staging process

40. Treatment Options for Extrahepatic CCA Surgery for patients without PSC Transplant for select patients with PSC Chemoradiotherapy Systemic chemotherapy Intra-arterial chemotherapy Intra-arterial radiotherapy Photodynamic therapy

41. CCA and PSC What’s the Difference? 1) Bile duct damage present in all patients 2) Underlying liver disease present in most patients Diagnostic challenges - benign vs. malignant bile duct stricture - similar lab, radiologic, & endoscopic abnormalities Surgical limitations - recurrent infections - cirrhosis and liver dysfunction Cancer screening for CCA possible in PSC

42. Treatment of CCA in Patients With PSC Stage and diagnose tumor with radiologic and endoscopic studies For large, locally advanced or metastatic tumors - Nonsurgical treatments as for patients without PSC - OLTx not recommended For suspected tumor that is small and confined - Needle biopsy should be avoided - Refer to transplant center with protocol for CCA

43. Selecting Patients With PSC and CCA for OLTx Must be an acceptable candidate for transplant No intrahepatic or extrahepatic metastases Diagnosis of CCA based on: - Positive bushing or transcatheter biopsy or - CA 19-9 > 100 with a suspicious mass or stricture on imaging studies or cholangiography or - Abnormal cells by FISH with suspicious stricture Pre-OLTx treatment with chemoradiation Staging laparotomy to exclude metastatic disease

44. OLTx for CCA in Patients With PSC Complete treatment with chemoradiation and have no metastases on staging laparotomy MELD score 22 -> increased every 3 months if criteria for transplant still met Acceptable outcomes Mayo Clinic experience - 82%, 63% and 55% survival at 1, 3, and 5 years Multicenter experience - 68% and 53% survival at 2 and 5 years

45. Treatment of Locally Advanced CCA not Amenable to OLTx Chemoradiotherapy Photodynamic therapy Systemic chemotherapy Percutaneous or endoscopic biliary stents for those with obstructive jaundice Prophylactic antibiotics in those with history of bacterial cholangitis

46. Radiation Therapies for CCA External Beam Radiation (EBRT) * High dose radiation therapies * - Transcatheter brachytherapy +/- EBRT - 3-Dimmensional conformal RT - Intensity modulated RT Stereotactic radiotherapy * Radiation treatments typically combined with chemotherapy with 5-FU or Capecitabine

47. Treatment of Advanced CCA Good performance status - Gemcitabine + Cisplatin or Oxaliplatin (1 st line) - Gemcitabine + Capecitabine - Capecitabine + Oxaliplatin - Ertonilab + Bevacizumab Borderline performance status - Gemcitabine or Capecitabine or 5-FU +Leucovorin Poor performance status - no chemotherapy Stents for obstruction and antibiotics for cholangitis

48. Management of CCA in PSC CCA Diagnosed Advanced tumorLocalized tumor Chemoradiotherapy Photodynamic therapy and/or Chemotherapy Refer for OLTx Chemoradiotherapy Staging Laparotomy Metastatic tumor Yes No List for OLTx

49. Cancer Screening and Surveillance for PSC

50. Specific Cancer Risks in PSC Colon cancer Gallbladder cancer Hepatocellular carcinoma (HCC) in those with underlying cirrhosis Cholangiocarcinoma (CCA)

51. Colon Cancer Screening in PSC For those without IBD colonoscopy every 5 years For those with IBD colonoscopy every 1-2 years For those with IBD and a liver transplant colonoscopy annually

52. Gallbladder Cancer Screening in PSC Yearly Ultrasound Remove gallbladder for any size mass identified

53. HCC Cancer Screening in PSC Recommended only in those with cirrhosis Screening same as for other causes of cirrhosis AASLD Guidelines for HCC Screening: Ultrasound every 6 months Ultrasound with AFP tumor marker every 6 months increases detection but with more false positives and higher costs

54. CCA Cancer Screening in PSC Unproven if screening improves outcomes No clear consensus or best approach Evaluate for CCA for any unexplained deterioration in health or liver tests (LFT’s) Consider annual or semi-annual ultrasound and/or MRCP Consider annual or semi-annual CA19-9 tumor marker