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  1. 1. Hepatocellular Carcinoma Renown Univ Nevada Reno Dept of Medicine: Teaching Conf May 2009
  2. 2. Disclosures: that are relevant to this presentation <ul><li>I have consulting and speaker arrangements with </li></ul><ul><ul><li>Bayer </li></ul></ul><ul><ul><li>Onyx </li></ul></ul><ul><li>I have research contract relationships with </li></ul><ul><ul><li>BMS </li></ul></ul><ul><ul><li>Bayer/Onyx </li></ul></ul><ul><li>I do not own stock or have any investment positions in any company relative to this presentation </li></ul>
  3. 3. HCC: Epidemiology <ul><li>HCC is the most common primary liver malignancy </li></ul><ul><li>Worldwide incidence >600,000 cases per year </li></ul><ul><ul><li>Liver cancer is the most rapidly increasing cancer in the U.S. </li></ul></ul><ul><ul><ul><li>19,160 new cases and 16,780 deaths in 2007 </li></ul></ul></ul><ul><li>More common in men than women (4:1) </li></ul><ul><li>For resection, rate of recurrence can be as high as 50% at 2 years </li></ul><ul><ul><li>Only 12% are eligible for resection or for transplant </li></ul></ul><ul><ul><li>80%-90% of HCC cases occur in cirrhotic livers </li></ul></ul>International Agency for Cancer Research. Globocan 2002. Available at: http://www-dep.iarc.fr. Accessed February 19, 2008; Parkin DM et al. Int J Cancer . 2001;94;153-156; American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA; American Cancer Society, 2007. McGlynn KA et al. Int J Cancer . 2001;94:290-296; McGlynn KA et al. Cancer Epidemiol Biomarkers Prev . 2006;15:1198-1203; Jemal A et al. CA Cancer J Clin . 2006;56:106-130; El-Serag HB. Gastroenterology . 2004;127:S27-S34.
  4. 4. Burden of HCC in the United States <ul><li>Annual prevalence, incidence, and survival with HCC estimated from SEER database </li></ul><ul><li>Costs distribution of costs estimated from 392 HCC patients </li></ul><ul><li>Annual estimated cost of HCC in the United States: $454.5 million </li></ul><ul><ul><li>Per-patient cost: $32,907 </li></ul></ul><ul><li>Healthcare costs accounted for 89.2% of cost </li></ul><ul><li>Lost productivity accounted for 10.8% of cost </li></ul>Lang K, et al. J Hepatol. 2008. In press.
  5. 5. Goodman Z.
  6. 6. Goodman Z.
  7. 7. HCC incidence tripled over the last three decades Altekruse, JCO 2009
  8. 8. Proportion of HCC by Patient Race Among Hospitalizations for HBV (1998) White Black Hispanic Asian Other Unknown HCC (%) Kim WR, et al. AASLD 2002. Abstract 223. 25 14 7 51 0 4 0 20 40 60 80 100
  9. 9. Racial Differences in Survival of Patients with HCC Caucasian Black Asian Hispanic 0 Years Survival (%) 20 40 60 80 100 Davila J, El-Serag HB. Clin Gastro Hepatol; 2006 0 1 2 3
  10. 10. HCC Prognosis <ul><li>Survival has been improving over last 15 years </li></ul><ul><ul><li>Improved survival after resection </li></ul></ul><ul><ul><li>More diagnosis at earlier stage (screening!) </li></ul></ul><ul><ul><li>More local therapy available </li></ul></ul>Altekruse, JCO 2009
  11. 11. Overview <ul><li>Screening and Surveillance for HCC: who is at risk and how/when to screen and complete follow up surveillance </li></ul><ul><li>Biomarkers </li></ul><ul><li>Imaging </li></ul><ul><li>Pathology </li></ul><ul><li>Liver Transplant </li></ul><ul><li>Regional Therapy for HCC </li></ul><ul><ul><li>Medical Management of Patients Undergoing Regional Therapy for Hepatocellular Carcinoma </li></ul></ul><ul><li>Current Trends in the Treatment of Patients With Advanced HCC </li></ul><ul><li>Systemic Therapy and Supportive Care in Patients With Advanced Hepatocellular Carcinoma </li></ul>
  12. 12. Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach Radiation Oncology Pathology Oncology Radiology Hepatobiliary Surgery Hepatology
  13. 13. Risk Factors for HCC in US Patients Obesity Polesel J, et al. Ann Oncol. 2008;[Epub ahead of print]. BFRSS Database. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed October 21, 2008. Emerging Risk Factor: Obesity (BMI ≥ 30) No Data < 10% 10-14% 15-19% 20-24% 25-29% ≥ 30%
  14. 15. Background <ul><li>In the United States and Europe, the majority of HCC develops in the setting of underlying liver cirrhosis </li></ul><ul><li>Treatment strategies for HCC should avoid worsening liver function to such an extent that would offset their possible benefit </li></ul><ul><li>Staging systems for treatment allocation, therefore, must concurrently consider tumor extension and severity of the underlying liver function impairment </li></ul><ul><li>There is n o universally accepted staging system for HCC </li></ul><ul><li>The BCLC staging system for HCC is the most widely used in Western countries, particularly for treatment allocation </li></ul>
  15. 17. Malignant Transformation Multistep 1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24. Potential Targets Oxidative stress and inflammation Viral oncogenes Carcinogens Growth factors Telomere shortening Cancer stem cells Loss of cell cycle checkpoints Antiapoptosis Angiogenesis Normal liver Liver cirrhosis Hepatitis C Hepatitis B Ethanol NASH Epigenetic alterations Genetic alterations HCC [2] Dysplastic nodules [1]
  16. 19. <ul><li>Event a 3 rd line treatment such as lamivudine can decrease HCC risk </li></ul>
  17. 20. <ul><li>After El Serag EASL 2007 </li></ul>
  18. 21. Screening and surveillance for HCC is the standard of care <ul><li>SOC </li></ul><ul><li>Screening: first test </li></ul><ul><li>Surveillance: all subsequent testing – typically on a regular schedule </li></ul>
  19. 22. AASLD Practice Guidelines on Screening & Surveillance for HCC <ul><li>AASLD recommends surveillance using AFP + US every 6-12 months for at-risk patient groups: </li></ul><ul><ul><li>Hepatitis B carriers </li></ul></ul><ul><ul><ul><li>Asian males >40 years </li></ul></ul></ul><ul><ul><ul><li>Asian females >50 years </li></ul></ul></ul><ul><ul><ul><li>All cirrhotic hepatitis B carriers </li></ul></ul></ul><ul><ul><ul><li>Family history of HCC </li></ul></ul></ul><ul><ul><ul><li>Africans >20 years </li></ul></ul></ul><ul><ul><ul><li>Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past levels of inflammatory activity </li></ul></ul></ul><ul><ul><li>Cirrhosis due to hepatitis C, alcohol, or other causes </li></ul></ul>Bruix & Sherman. AASLD Practice Guideline: Management of Hepatocellular Carcinoma, Hepatology 2005; 42(5): 1208.
  20. 23. HCC Screening by Ultrasound <ul><li>Performance characteristics of ultrasound as a screening test </li></ul>Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. Performance Characteristic, % Cohort 1 Years 1-5 Cohort 1 Years 6-8 Cohort 2 Years 1-3 Sensitivity 79 87 80 Specificity 94 87 91 PPV 15 13 14 NPV 98 100 100
  21. 24. Surveillance for HCC Reduces Mortality: A Randomized Controlled Trial Zhang BH, et al. J Cancer Res Clin Oncol 2004 0 Time (Years) 1 2 3 4 5 0 .8 .6 .2 .4 Screening Survival Probability (%) Control
  22. 25. Screening/surveillance Current Strategies: US and AFP <ul><li>US q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S. </li></ul><ul><li>Rationale for 6-month screening/surveillance interval </li></ul><ul><ul><li>Doubling time: median = 6 mo (range, 1-19 mo) </li></ul></ul><ul><ul><li>Growth from 1 to 3 cm: 4 mo for most aggressive, 18 mo for moderately aggressive, 5 yr for indolent HCC </li></ul></ul><ul><li>Median detectable subclinical period for HCC = 3.2 yr </li></ul>
  23. 26. Making the diagnosis of HCC <ul><li>Biopsy is very rarely indicated </li></ul><ul><ul><li>Risk of tracking tumor cells </li></ul></ul><ul><ul><li>High false negative rate </li></ul></ul><ul><li>Diagnosis is by imaging criteria </li></ul>
  24. 27. DIAGNOSTIC CRITERIA FOR HCC EASL CONFERENCES ON HCC, BARCELONA 2005 AASLD PRACTICE GUIDELINE, HEPATOLOGY 2005 <ul><li>Cyto-histological criteria </li></ul><ul><li>Non-invasive criteria (cirrhotic patients) </li></ul><ul><li>1. One imaging technique * </li></ul><ul><li>Focal lesion > 2 cm with arterial hypervascularization </li></ul><ul><li>and venous wash-out </li></ul><ul><li>2. Two coincident imaging techniques * </li></ul><ul><li>Focal lesion 1-2 cm with arterial hypervascularization </li></ul><ul><li>and venous wash-out </li></ul>* Three techniques considered: contrast US, CT, and dynamic MRI
  25. 28. AP PVP Arterial Phase hypervascular necrotic Portal Venous Phase “ washout” to less than liver HCC
  26. 29. How do we use AFP ? <ul><li>AFP is a useful biomarker of a patients increased RISK for HCC in the future </li></ul><ul><li>AFP is not a screening or surveillance tool for HCC </li></ul>
  27. 30. Performance Characteristics of AFP to diagnose HCC Based on Cutoff Level Colli A, et al. Am J Gastro 2005 Cutoff 10-11 17-21 50 > 100 Studies 4 7 4 5 (#) %
  28. 31. Sensitivity/Specificity of DCP and AFP as a Function of Disease Stage <ul><li>Effect of tumor size on the diagnosis of HCC by DCP, AFP </li></ul>Nakamura S, et al. Am J Gastroenterol. 2006;101:2038-2043. AMERICAN JOURNAL OF GASTROENTEROLOGY by Nakamura S, et al. Copyright 2006 by Blackwell Publishing - Journals. Reproduced with permission of Blackwell Publishing - Journals in the format Copy via Copyright Clearance Center. DCP Tumor Size Tumor Size AFP 1-Specificity Sensitivity 0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 3 cm 3-5 cm 5 cm 1-Specificity Sensitivity 0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 3 cm 3-5 cm 5 cm
  29. 32. AFP L3% rises before AFP in typical course of HCC occurrence case 21 months HCC diagnosis Tumor size: 3-5 cm Before HCC diagnosis Tumor size: ≤ 2 cm Sterling, Am J Gastro
  30. 33. Current Biomarkers and Risk of Portal Vein Invasion <ul><li>AFP-L3 ≥ 15% </li></ul><ul><ul><li>RR: 2.459 (95% CI: 1.005-6.017; P = .0487) </li></ul></ul><ul><li>DCP ≥ 100 mAU/mL </li></ul><ul><ul><li>RR: 3.019 (95% CI: 1.077-8.464; P = .0357) </li></ul></ul><ul><li>Number of HCC tumors ≥ 2 </li></ul><ul><ul><li>RR: 4.912 (95% CI: 1.619-14.905; P = .0049) </li></ul></ul>Hagiwara S, et al. J Gastroenterol. 2006;41:1214-1219.
  31. 34. Current Biomarkers and Risk of Microvascular Invasion <ul><li>Independent predictors of microvascular invasion </li></ul><ul><ul><li>Tumor size (< 2, 2-4, > 4 cm) </li></ul></ul><ul><ul><ul><li>Odds ratio: 3.4 (95% CI: 1.5-4.1) </li></ul></ul></ul><ul><ul><li>Preoperative DCP levels (< 100, 100-500, > 500 mAU/mL) </li></ul></ul><ul><ul><ul><li>Odds ratio: 2.2 (95% CI: 1.1-2.4) </li></ul></ul></ul><ul><ul><li>Tumor grade (3-grade system) </li></ul></ul><ul><ul><ul><li>Odds ratio: 2.2 (95% CI: 1.1-3.7) </li></ul></ul></ul>Shirabe K, et al. J Surg Oncol. 2007;95:235-240.
  32. 35. Incidence of Portal Venous Invasion of HCC in relation to the Serum DCP level   at diagnosis DCP(-): 183 patients with DCP < 100 mAU/mL Koike Y, et al. Cancer 2001 Feb 1;91(3):561-9 DCP(+): 37 patients with DCP > 100 mAU/mL DCP predicts clinical course
  33. 36. HCC: overall survival
  34. 37. HCC is treatable <ul><li>HCC is curable ! </li></ul><ul><ul><li>In selected patients </li></ul></ul><ul><ul><ul><li>Justifying screening and surveillance </li></ul></ul></ul>
  35. 38. Management of HCC <ul><li>Liver transplantation </li></ul><ul><li>Resection </li></ul><ul><li>Tumor ablation </li></ul><ul><ul><li>Radiofrequency thermal ablation </li></ul></ul><ul><ul><li>Alcohol injection </li></ul></ul><ul><ul><li>Chemoembolization </li></ul></ul><ul><li>Targeted molecular therapy </li></ul><ul><li>Chemotherapy </li></ul><ul><ul><li>Regional/systemic </li></ul></ul>Potentially curative
  36. 39. Staging Strategy and Treatment for Patients With HCC Liver transplant PEI/RF Curative treatments TACE HCC Single Increased Associated diseases Normal No Yes No Yes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST 0 Portal invasion, N1, M1 Sorafenib Portal pressure/bilirubin 3 nodules ≤ 3 cm Intermediate stage PST > 2, Child-Pugh C Very early stage Single < 2 cm Early stage Single or 3 nodules ≤ 3 cm, PST 0 Advanced stage Portal invasion, N1, M1, PST 1-2 PST 0, Child-Pugh A Resection Symptomatic (unless LT) Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Bruix J, et al. Hepatology. 2005;42:1208-1236.
  37. 40. Treatment for HCC Often Suboptimal <ul><li>Proportion of patients receiving potentially curative therapy </li></ul><ul><ul><li>34.0% of patients with single lesions </li></ul></ul><ul><ul><li>34.0% of patients with lesions < 3 cm </li></ul></ul><ul><ul><li>19.3% of patients with lesions > 10 cm </li></ul></ul><ul><ul><li>4.9% of patients with metastatic disease </li></ul></ul><ul><li>11.5% of patients ideal for transplantation received it </li></ul><ul><li>14.3% of patients ideal for surgical resection received it </li></ul>El-Serag HB, et al. J Hepatol. 2006;44:158-166.
  38. 41. 0.004 1.46-7.19 3.24 Atlanta 0.010 1.29-6.29 2.85 New Mexico 0.007 1.28-4.74 2.47 Los Angeles 0.047 1.01-4.55 2.15 Iowa 0.287 0.73-3.00 1.47 San Francisco 0.565 0.60-2.59 1.24 Seattle 0.072 0.94-4.36 2.02 Hawaii 0.119 0.86-3.61 1.77 Detroit 0.024 1.12-5.18 2.41 Connecticut 0.008 1.41-9.42 3.65 Utah Reference - 1.00 San Jose Geographic Variations in Receipt of Potentially Curative Therapy in the Elderly Adjusting for time period, age, sex, comorbidity, liver disease severity, tumor size, risk factors for HCC
  39. 42. Influence of Cirrhosis on Operative Mortality for HCC
  40. 43. Surgical Resection: only for patients without portal hypertension
  41. 44. Hepatic resection Colombo, Antiviral Research, 2003
  42. 45. Treatment of HCC in US non-Federal Hospitals in 2000 <ul><li>Surgical Resection: 4.9% </li></ul><ul><li>Liver Transplant: 1.8% </li></ul><ul><li>Local Ablation: 3.5% </li></ul><ul><li>Embolization: 5.5% </li></ul><ul><li>Chemotherapy: 11% </li></ul>Kim WR et al. Gastroenterology 2005
  43. 46. Survival Follow up Duration (Years) Transplant Resection Ablation TACE 1 0.8 0.6 0.4 0.2 0 Outcomes of HCC Treatment in the Elderly El-Serag HB et al J Hepatology 2006 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
  44. 47. Ablation <ul><li>RFA or TACE is/are the current standard(s) </li></ul><ul><li>PEI is for developing countries with limited resources </li></ul><ul><li>Microwave is faster to full tumor ablation but resources are expensive </li></ul><ul><li>Cryosurgery is no longer used due to length of time of procedure and complications of “ice ball” </li></ul>
  45. 49. -Survival Rates of Patients with small HCC treated with RFA 45 50 98 38 61 20 47 48 83 55 71 0 94 34 Prospective 2003 Cervantes 77 548 Prospective 2000 Siperstein 87 53 Prospective 2000 Guglielmi et al 19 87 41 Prospective 2000 Rossi et al 100 102 RCT 2000 Lencioni et al 18 97 206 Prospective 1997 Lencioni et al Recurrence Rate % 1y 3 y 5 y Survival Rate % 1 yr 3 yr 5 y # of Pts Type of study Year Trial
  46. 50. Treatment: Chemoembolization <ul><li>Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery </li></ul><ul><li>Tumor receives most of its blood supply from the hepatic artery </li></ul><ul><li>Injection into the hepatic artery spares most of the normal liver </li></ul><ul><li>Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor </li></ul>Tumor Liver Portal vein Hepatic artery Catheter placement for chemoembolization
  47. 51. TACE vs Surgical Resection: A Case-Control Prospective Study N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm <ul><li>Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0 </li></ul><ul><ul><li>BUT for tumors > 3 cm and/or CLIP stage 1-2, 5-year survival identical for both groups (27%) </li></ul></ul><ul><ul><li>Median OS ( P = .1529) </li></ul></ul><ul><ul><ul><li>Resection: 65.1 months </li></ul></ul></ul><ul><ul><ul><li>TACE: 50.4 months </li></ul></ul></ul>Lee HS, et al. J Clin Oncol. 2002;20:4459-4465. Technique Survival, % Year 1 Year 2 Year 3 Year 5 TACE 96 80 56 30 Surgical resection 90 80 70 52
  48. 52. Chemoembolization: Efficacy Before Transplantation <ul><li>Major issue: dropout rate (~ 20%) </li></ul><ul><ul><li>Lower in US since adoption of MELD criteria </li></ul></ul><ul><li>Role of TACE </li></ul><ul><ul><li>Control tumor and prevent progression </li></ul></ul><ul><ul><li>Should be considered if waiting time > 6 months </li></ul></ul><ul><li>Complications from TACE: rare (no increased rate of hepatic artery complications) </li></ul>Richard HM 3rd, et al. Radiology. 2000;214:775-779. Graziadei IW, et al. Liver Transpl. 2003;9:557-563. Alba E, et al. Am J Roentgenol. 2008;190:1341-1348.
  49. 53. Primary Treatment Modality Used in Korea TACE 48.2% RFA 1.5% Surgery 11.2% Chemotherapy 7.5% Radiotherapy 2.1% Conservative treatment 29.5% N = 1078 Joong-Won Park, MD, National Cancer Center. Adapted with permission.
  50. 54. Chemoembolization: Randomized Trials (Nearly Identical Techniques) Llovet et al [2] : N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal) Lo et al [1] : N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal) 1. Lo CM, et al. Hepatology. 2002;35:1164-1171. 2. Llovet JM, et al. Lancet. 2002;359:1734-1739. Technique Survival, % Year 1 Year 2 Year 3 TACE 57 31 26 Supportive care 32 11 3 Technique Survival, % Year 1 Year 2 TACE 82 63 Supportive care 63 27
  51. 55. New Therapies Under Investigation <ul><li>Targeted and Chemotherapy </li></ul><ul><li>Sorafenib* (Nexavar) </li></ul><ul><li>Erlotinib (Tarceva) </li></ul><ul><li>Sirolimus (Rapamune) </li></ul><ul><li>Capecitabine (Xeloda) </li></ul><ul><li>Floxuridine (FUDR) </li></ul><ul><li>Bevacizumab (Avastin) </li></ul><ul><li>Sargramostim (Leukine) </li></ul><ul><li>Oxaliplatin (Eloxatin) </li></ul><ul><li>Imatinib (Gleevac) </li></ul><ul><li>Local Therapy </li></ul><ul><li>Radiation Therapy </li></ul><ul><ul><li>90 Yttrium microspheres (Therasphere/SIRsphere) </li></ul></ul><ul><ul><li>Stereotactic RadioSurgery (Cyberknife) </li></ul></ul><ul><li>Doxorubicin Eluting Beads (DC Bead) </li></ul><ul><li>Photoactive chemicals (Litx) </li></ul>* Sorafenib approved November 2007
  52. 56. <ul><li>Absolute contraindications </li></ul><ul><ul><li>Child-Pugh class C disease </li></ul></ul><ul><ul><li>Poor performance status (ECOG PS > 2) </li></ul></ul><ul><li>Relative contraindication </li></ul><ul><ul><li>Extrahepatic disease (benefit unclear) </li></ul></ul><ul><li>Former contraindication </li></ul><ul><ul><li>PVT </li></ul></ul><ul><ul><ul><li>Minimize embolization and be more selective </li></ul></ul></ul>Chemoembolization: Ineligibility Criteria
  53. 57. Chemoembolization: Predictors of Survival <ul><li>Lo et al [1] </li></ul><ul><ul><li>Absence of presenting symptoms (ECOG PS < 2) </li></ul></ul><ul><ul><li>Absence of portal vein obstruction </li></ul></ul><ul><ul><li>Tumor size (≤ vs > 5 cm) </li></ul></ul><ul><ul><li>Okuda stage (I vs II) </li></ul></ul><ul><li>Llovet et al [2] </li></ul><ul><ul><li>Absence of constitutional syndrome (ECOG PS < 2) </li></ul></ul><ul><ul><li>Low serum bilirubin </li></ul></ul><ul><ul><li>Treatment response (modified WHO criteria, > 6 months) </li></ul></ul>1. Lo CM, et al. Hepatology. 2002;35:1164-1171. 2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
  54. 58. <ul><li>Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors </li></ul><ul><li>Yttrium-90 microspheres </li></ul><ul><ul><li>Average diameter: 20-30 µm  </li></ul></ul><ul><ul><li>100% pure beta emitter (0.9367 MeV) </li></ul></ul><ul><ul><li>Physical half-life: 64.2 hours </li></ul></ul><ul><ul><li>Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm) </li></ul></ul>Intra-arterial Radioembolization With Yttrium-90: Rationale and History Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.
  55. 59. Clinical Response to Yttrium-90 Microspheres 1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681. 2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110. 3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205. 4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639. Outcome Dancey et al [1] (N = 20) Carr et al [2] (N = 65) Geschwind et al [3] (N = 80) Salem et al [4] (N = 43) Response rate, % 39 47 Median survival 378 days (> 104 Gy) <ul><li>Okuda stage I </li></ul>649 days 628 days 24.4 mos <ul><li>Okuda stage II </li></ul>302 days 384 days 12.5 mos
  56. 60. Drug Eluting Beads <ul><li>LC Bead is a Drug Delivery Embolisation System capable of loading and the controlled release of high doses of chemotherapeutic agents </li></ul><ul><ul><li>Doses per ml and per treatment: </li></ul></ul><ul><ul><ul><li>Doxorubicin maximum dose of 37.5mg/ml and 150mg/treatment with 4ml </li></ul></ul></ul><ul><li>Novel N-fil technology sulphonate modified hydrogel polymer </li></ul><ul><li>Blue tinted to aid visualisation </li></ul><ul><li>Delivered as vials containing 2ml Beads in 6ml saline </li></ul><ul><li>LC Bead is available in 3 sizes. </li></ul><ul><ul><li>100-300um </li></ul></ul><ul><ul><li>300-500um </li></ul></ul><ul><ul><li>500-700um </li></ul></ul>
  57. 61. Mechanism of Loading the LC Bead with Doxorubicin <ul><li>The LC Bead has a negative charge where as doxorubicin has a positive charge… </li></ul><ul><li>The doxorubicin is loaded and eluted by an ‘reversible ionic exchange mechanism’ . </li></ul>Hydrated Beads Hydration shell associated with PVA and ionic groups Bulk (non-bound) water Interaction of doxorubicin with SO3 groups displaces water from the hydration shells Loaded Beads
  58. 62. Reducing Systemic Exposure <ul><li>This is the relative drug distribution for standard arterial chemotherapy vs. conventional TACE vs. precision TACE </li></ul>Relative Drug Distributions
  59. 63. Conventional TACE vs DCBs-TACE Overall 6-Month Tumour Response Rates p = 0.11 Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response Lammer et al, CIRSE 2008
  60. 64. Complications SAE Comparison : Conventional TACE vs PRECISION TACE 75% Reduction in SAE’s at the same institution
  61. 65. 90 Yttrium vs. TACE <ul><li>90 Yttrium does not occlude the vessels at the arteriolar level </li></ul><ul><ul><li>Option for repeat embolic treatment </li></ul></ul><ul><ul><li>Less ischemic damage </li></ul></ul><ul><li>Response rates seem to be similar (no head-to-head comparisons) </li></ul><ul><li>Equivalent side effect profile </li></ul><ul><li>90 Yttrium can be used in portal vein thrombosis and in more extensive disease </li></ul>
  62. 66. <ul><li>TACE accepted as treatment of choice for unresectable (nonablatable?) HCC </li></ul><ul><li>Prolonged survival established through randomized trials and prospective studies </li></ul><ul><li>Best vs good performance status, Child-Pugh class A-B </li></ul><ul><li>Role for yttrium-90 microspheres </li></ul><ul><li>Growing role for doxorubicin-loaded beads, pending outcome of clinical trials </li></ul>Conclusions
  63. 67. Staging Strategy and Treatment for Patients With HCC Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and 2% to 5% of recurrent HCC Liver transplant PEI/RF TACE HCC Single Increased Associated diseases Normal No Yes No Yes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST 0 Portal invasion, N1, M1 Sorafenib Portal pressure/bilirubin 3 nodules ≤ 3 cm Intermediate stage PST > 2, Child-Pugh C Very early stage Single < 2 cm Early stage Single or 3 nodules ≤ 3 cm, PST 0 Advanced stage Portal invasion, N1, M1, PST 1-2 PST 0, Child-Pugh A Resection Symptomatic (unless LT) Nonsurgical treatments: applicable overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of recurrent HCC
  64. 68. Liver Transplantation <ul><li>The only treatment with a major chance of cure for HCC </li></ul>
  65. 69. Survival Follow up Duration (Years) Transplant Resection Ablation TACE 1 0.8 0.6 0.4 0.2 0 Outcomes of HCC Treatment in the Elderly El-Serag HB et al J Hepatology 2006 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
  66. 70. Liver Transplant for HCC in cirrhosis Milan Criteria (Stage I+II) + Absence of Macroscopic Vascular Invasion Absence of Extrahepatic Spread Single, not > 5cm Up to 3, none > 3cm Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.
  67. 71. Survival Curves for Transplant vs. Other Treatment for Hepatocellular Carcinoma 0.2 0.4 0.6 1 0 12 24 36 48 60 Time (months) Survival Transplant N=239 Other Treatment N=917 0.8
  68. 72. Automatic MELD Upgrades for patients with unresectable HCC Surgery with resection is the current standard of care for patient without cirrhosis <ul><li>22 points at diagnosis </li></ul><ul><li>25 points 3 months </li></ul><ul><li>28 - 6 months </li></ul><ul><li>29 - 9 months </li></ul><ul><li>31 – 12 months </li></ul>
  69. 73. Liver Transplantation For HCC in patients with cirrhosis Four -Year Survival 40% 75% 76% % Surviving Mazzaferro N Engl J Med 1996 0 10 20 30 40 50 60 70 80 Unselected 1991 Milan Criteria Other Dx
  70. 74. Intermediate/Advanced HCC: Future Directions <ul><li>499 trials registered at clinicaltrials.gov for HCC as of August 21, 2008, including </li></ul><ul><ul><ul><li>Improving efficacy of RF and TACE (drug-eluting beads) </li></ul></ul></ul><ul><ul><ul><li>Exploring alternative treatments for intermediate HCC (yttrium-90) </li></ul></ul></ul><ul><ul><ul><li>Molecularly targeted agents in combination regimens (advanced HCC) </li></ul></ul></ul><ul><ul><ul><li>Molecularly targeted agents in combination with current modalities (early/intermediate HCC) </li></ul></ul></ul><ul><ul><ul><li>Improving tumor targeting of chemotherapeutic agents </li></ul></ul></ul><ul><ul><ul><li>New molecular targets and new molecularly targeted agents </li></ul></ul></ul>
  71. 75. Staging Strategy and Treatment for Patients With HCC Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and 2% to 5% of recurrent HCC Liver transplant PEI/RF TACE HCC Single Increased Associated diseases Normal No Yes No Yes Terminal stage PST 0-2, Child-Pugh A-B Multinodular, PST 0 Portal invasion, N1, M1 Sorafenib Portal pressure/bilirubin 3 nodules ≤ 3 cm Intermediate stage PST > 2, Child-Pugh C Very early stage Single < 2 cm Early stage Single or 3 nodules ≤ 3 cm, PST 0 Advanced stage Portal invasion, N1, M1, PST 1-2 PST 0, Child-Pugh A Resection Symptomatic (unless LT) Nonsurgical treatments: applicable overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of recurrent HCC
  72. 76. Evidence of Benefit in Treatment of HCC (cont’d) Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Treatment Benefit Evidence Systemic therapies Sorafenib Increased survival Randomized trial, meta-analysis, double blinded Tamoxifen No benefit Randomized trial, meta-analysis, double blinded Chemotherapy No benefit Randomized trial, meta-analysis, nonblinded IFN No benefit Randomized trial, meta-analysis, nonblinded
  73. 77. Key Pathways in Hepatocarcinogenesis: Possible Targets for Novel Therapies <ul><li>Growth factor-stimulated receptor tyrosine kinase signaling </li></ul><ul><li>Wnt/beta-catenin pathway </li></ul><ul><li>p13Kinase/AKT/mTOR </li></ul><ul><li>JAK/STAT signaling </li></ul><ul><li>Angiogenic signaling pathways </li></ul><ul><li>p53 and cell cycle regulatory pathways </li></ul><ul><li>Ubiquitin-proteasome pathway </li></ul><ul><li>Epigenetic promoter methylation and histone acetylation pathways </li></ul><ul><li>Ras-Raf-MEK-MAPK pathway </li></ul>Roberts LR, et al. Semin Liver Dis. 2005;25:212-225.
  74. 78. OS in the SHARP and Asia-Pacific Trials Months from Randomization Survival Probability Sorafenib (n=299) Median: 10.7 months 95% CI: 9.4-13.3 Placebo (n=303) Median: 7.9 months 95% CI: 6.8-9.1 HR (S/P): 0.69 95% CI: 0.55-0.87 P =0.00058 0.25 0.50 0.75 1.00 0 0 4 8 12 16 20 SHARP 1 Sorafenib (n=150) Median: 6.5 months 95% CI: 5.6-7.6 Placebo (n=76) Median: 4.2 months 95% CI: 3.7-5.5 HR (S/P): 0.68 95% CI: 0.50-0.93 P =0.014 0.25 0.50 0.75 1.00 0 0 4 8 12 16 20 Asia-Pacific 2 Months from Randomization Survival Probability 1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390. 2. Cheng AL, et al. Lancet Oncol . 2009;10:25-34.
  75. 79. The SHARP Trial: Drug-Related AEs Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. © 2008, Massachusetts Medical Society. All rights reserved. AEs, % Sorafenib (N = 297) Placebo (N = 302) P Value Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Grade Grade 3 or 4 Overall incidence 80 52 Constitutional symptoms Fatigue 22 3 1 16 3 < 1 .07 1.00 Weight Loss 9 2 0 1 0 0 < .001 .03 Dermatologic events Alopecia 14 0 0 2 0 0 < .001 NA Dry skin 8 0 0 4 0 0 .04 NA Hand-foot skin reaction 21 8 0 3 < 1 0 < .001 < .001 Pruritus 8 0 0 7 < 1 0 .65 1.00 Rash or desquamation 16 1 0 11 0 0 .12 .12 Other 5 1 0 1 0 0 < .001 .12
  76. 80. Hand-Foot Syndrome Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.
  77. 81. Strategies for Managing AEs <ul><li>Hand-foot syndrome </li></ul><ul><ul><li>Creams and lotions </li></ul></ul><ul><ul><li>Avoid tight footwear </li></ul></ul><ul><ul><li>May require dose reduction </li></ul></ul><ul><li>Diarrhea </li></ul><ul><ul><li>Antidiarrheal agents if severe </li></ul></ul><ul><li>Fatigue </li></ul><ul><ul><li>Consider modafinil or methylphenidate if severe </li></ul></ul><ul><li>Hypertension </li></ul><ul><ul><li>Start or adjust antihypertensives </li></ul></ul>
  78. 82. Possible Future Studies in HCC <ul><li>New targeted molecular agents </li></ul><ul><li>Small molecules in combination </li></ul><ul><ul><li>With each other </li></ul></ul><ul><ul><li>With local ablation </li></ul></ul><ul><ul><li>With conventional chemotherapy </li></ul></ul>
  79. 83. Summary <ul><li>Hepatocellular Carcinoma </li></ul><ul><ul><li>Prevention is possible by vaccine </li></ul></ul><ul><ul><li>Risk driven by cirrhosis </li></ul></ul><ul><ul><ul><li>Viral load in HBV </li></ul></ul></ul><ul><ul><li>Treatment of underlying disease decreases risk </li></ul></ul><ul><ul><li>Surveillance for HCC is SOC in selected patients </li></ul></ul><ul><ul><li>HCC is curable in some patients </li></ul></ul><ul><ul><li>Team approach is current standard to manage HCC </li></ul></ul>
  80. 84. Management of Hepatocellular Carcinoma Requires a Multidisciplinary Approach Radiation Oncology Pathology Oncology Radiology Hepatobiliary Surgery Hepatology

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