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Hepatocellular Carcinoma in Veterans: Multidisciplinary Approaches to a Growing Clinical Challenge

Hepatocellular Carcinoma in Veterans: Multidisciplinary Approaches to a Growing Clinical Challenge. This program is supported by educational grants from. About These Slides.

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Hepatocellular Carcinoma in Veterans: Multidisciplinary Approaches to a Growing Clinical Challenge

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  1. Hepatocellular Carcinoma in Veterans: Multidisciplinary Approaches to a Growing Clinical Challenge This program is supported by educational grants from

  2. About These Slides • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Program Chairs Jorge A. Marrero, MD, MSProfessor of Medicine Chief of Hepatology Medical Director, Liver Transplantation UT Southwestern Medical Center Dallas, Texas Alan P. Venook, MDProfessor of Clinical Medicine Division of Medical Oncology University of California, San Francisco San Francisco, California

  4. Faculty Adrian M. Di Bisceglie, MD, FACPProfessor of Internal Medicine Chairman Department of Internal Medicine Saint Louis University School of Medicine Chief, Hepatology Division of Gastroenterology and Hepatology Saint Louis University Hospital St Louis, Missouri Hashem B. El-Serag, MD, MPHChief, Gastroenterology and HepatologyChief, Clinical Epidemiology and OutcomesDepartment of MedicineBaylor College of MedicineHouston, Texas Douglas Heuman, MD, FACP, FACG, AGAProfessor of Medicine Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine Chief of Hepatology and Liver Transplantation Department of Medicine/Gastroenterology Section Hunter Holmes McGuire Department of Veterans Affairs Medical Center Richmond, Virginia

  5. Faculty David Kaplan, MD, MSc Assistant Professor of Medicine Division of GastroenterologyUniversity of Pennsylvania Perelman School of MedicineDirector of HepatologyGastroenterology SectionPhiladelphia VA Medical CenterPhiladelphia, Pennsylvania Paul Martin, MDProfessor of Medicine Chief, Division of Hepatology Center for Liver Disease University of Miami School of Medicine Miami, Florida James A. Posey, III, MDAssociate Professor Hematology/Oncology The University of Alabama at Birmingham Birmingham, Alabama

  6. Faculty Stacey Stein, MD Assistant Professor of Medicine Yale University School of MedicineSection of Medical Oncology New Haven, Connecticut Tamar Taddei, MDAssociate Professor of Medicine Division of Digestive DiseasesDepartment of MedicineYale UniversityDirector, Liver Cancer ProgramsSmilow Cancer HospitalYale-New Haven HospitalVA ConnecticutWest Haven, Connecticut Melanie B. Thomas, MD, MSAssociate Professor Division of Hematology/Oncology Hollings Cancer Center, Medical University- South Carolina Charleston, South Carolina Andrew X. Zhu, MD, PhD, FACPDirector, Liver Cancer Research Massachusetts General Hospital Cancer Center Boston, Massachusetts

  7. Faculty Disclosures Adrian M. Di Bisceglie, MD, FACP, has disclosed that he has received funds for research support from Abbott, Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Idenix, Janssen, Roche/Genentech, Transgene, and Vertex and has received consulting fees from Bayer, Janssen, Novartis, Roche/Genentech, Salix, and Vertex. Hashem B. El-Serag, MD, MPH, has disclosed that he has received consulting fees from Gilead Sciences and funds for research support from Aptalis. Douglas Heuman, MD, FACP, FACG, AGAF, has disclosed that he has received consulting fees from Grifols and funds for research support from Astellas, Bayer, Bristol-Myers Squibb, Celgene, Centocor, Exelixis, Ikaria, Grifols, Millennium, Osiris, Otsuka, Salix, Scynexis, and UCB. David Kaplan, MD, MSc, has disclosed that he has received funds for research support from Merck. Jorge A. Marrero, MD, MS, has disclosed that he has received consulting fees from Bayer and Onyx. Paul Martin, MD, has disclosed that he has received consulting fees from Abbott, Gilead Sciences, Janssen, and Vertex and funds for research support from Abbott and Vertex.

  8. Faculty Disclosures James A. Posey, III, MD, has no financial relationship(s) with commercial interests to disclose. Stacey Stein, MD, has disclosed that she hasreceived consulting fees from Onyx-Bayer. Tamar Taddei, MD, has disclosed that she has received funds for research support from Bayer Health. Melanie B. Thomas, MD, MS, has disclosed that she has received consulting fees from Celgene and Genentech and fees for non-CME/CE services received directly from a commercial interest of their agents (eg, speaker bureaus) from Onyx-Bayer. Alan P. Venook, MD, has disclosed that he has received funds for research support from Bayer, Genentech, Genomic Health, and Onyx. Andrew X. Zhu, MD, PhD, FACP, has disclosed that he has received funds for research support from Bayer and Eli Lilly and Company and consulting fees from Daiichi-Sankyo, Eisai, Exelixis, and sanofi-aventis.

  9. Overview • Reasons behind the rapid increase in HCC in the US • Importance of early detection and the guidelines for surveillance in patients at risk • Factors that affect prognosis and treatment options for HCC, including anatomic stage, biological grade, and cirrhosis severity • Curative and palliative treatments • Multidisciplinary collaboration to design the best treatment strategy for the individual patient

  10. Epidemiology

  11. Trends in Mortality for HCC vs Other Cancers • At a time when most cancer mortality is decreasing, deaths from HCC in the US are increasing • Deaths from HCC are increasing faster than deaths from any other form of cancer US Cancer Mortality Trends in Men, 1990-2005 Better Worse Hodgkin’s lymphoma Stomach Prostate Colorectal Oropharynx Larynx Lung Gallbladder Non-Hodgkin’s lymphoma Small intestine Brain Leukemia Myeloma Sarcomas Bladder Kidney Pancreas Melanoma Esophagus Liver All malignant cancers -60 -40 -20 0 20 40 60 Percent Change Jemal A, et al. CA Cancer J Clin. 2009;59:225-249.

  12. Adjusted Incidence of HCC 1975-2009 • Between 1975 and 2009, the adjusted incidence of HCC tripled in the US • The trend is continuing 9.0 8.0 7.0 6.0 5.0 Rate per 100,000 4.0 3.0 2.0 1.0 0 1975 1980 1985 1990 1995 2000 2005 2009 Yr of Diagnosis National Cancer Institute. SEER fast stats.

  13. 2013 Estimated US Cancer Deaths • Liver cancer in 2013 estimated as: • The #5 cancer killer in men (up from #7 in 2005) • The #9 cancer killer in women (not among top 10 in 2005) Men 306,920 Lung& bronchus 28% Prostate 10% Colon & rectum 9% Pancreas 6% Liver & intraheptic bile duct 5% Leukemia 4% Esophagus 4% Urinary bladder 4% Non-Hodgkin’s lymphoma 3% Kidney & renal pelvis 3% All other sites 24% Women 273,430 26% Lung & bronchus 14% Breast 9% Colon & rectum 7% Pancreas 5% Ovary 4% Leukemia 3% Non-Hodgkin’s lymphoma 3% Uterine corpus 2% Liver & intrahepatic bile duct 2% Brain/other nervous system 25% All other sites Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

  14. Who Gets HCC? • People with liver cirrhosis of any cause • People with chronic hepatitis B or hepatitis C • Risk increases with • Male gender • Age • Diabetes

  15. Why Is Liver Cancer Increasing? • Liver cancer is increasing because cirrhosis is increasing • Cirrhosis is increasing because • There are a lot of baby boomers • They have a high prevalence of hepatitis C • They are getting older • They are getting fatter

  16. HCV Among Baby Boomers in the VA • Most HCV infected veterans • Were born in the baby boom • Served in Vietnam war era • Were infected in their 20s • Average duration of infection is now 30-40 yrs • Veterans in this cohort account for ~ 1/3 of all veterans in care and as many as 1 in 8 is seropositive for HCV 2000 Vietnam 1500 Korea & WWII Gulf 1000 Frequency Iraq 500 0 20 40 60 80 100 Age Age distribution of veterans in care, DVAMC Richmond, fiscal 2007. Dominitz JA, et al. Hepatology. 2005;41:88-96.

  17. Trends in HCC Etiology • ~50% increase in HCV-related HCC between 1991-2008 Others: 21% Others: 38% Others: 46% HBV: 4% NAFLD: 11% HBV:10% Alcohol alone: 19% HBV: 4% NAFLD:7% Alcohol alone: 25% Alcohol and HCV: 17% Alcohol and HCV: 7% Alcohol alone: 45% HCV alone: 28% HCV alone: 18% 1976-1990 1991-2000 2001-2008 Yang JD, et al. Mayo Clin Proc. 2012;87:9-16.

  18. Davison J, et al. Public Health Matters. 2009;4:2-4. Cirrhosis and HCC in Veterans: A Perfect Storm 3369 2007 55,093 2761 2006 51,436 Over an 8-yr period (2000-2007) , the number of veterans in care in the VA system with diagnosed cirrhosis increased 2.5-fold, whereas the number of cases of HCC in care increased 5-fold 2320 2005 47,914 1953 2004 44,049 1635 2003 39,878 1316 2002 34,693 1013 2001 28,352 677 2000 19,905 Patients with HCC 0 15,000 30,000 45,000 60,000 Patients (n) Patients with cirrhosis

  19. Detection and Surveillance

  20. HCC Carries a High Mortality Compared With Other Common Cancers • 5-yr survival from diagnosis of liver cancer overall is 15% • The only common cancer with worse overall prognosis is pancreatic cancer (6%) Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

  21. Why Is HCC So Lethal? • Cirrhosis is often not diagnosed • Evolves silently, often in multiple foci • Progresses to invade vessels • Spreads via both blood and lymph • Rarely produces symptoms until advanced stage • Most are diagnosed late

  22. Survival by HCC Tumor Stage: VCU/McGuire VA Experience, 1997-2005 • Survival of HCC is strongly related to stage at diagnosis • Earlier detection of HCC could improve outcome 1.0 0.8 I 0.6 II Survival 0.4 III 0.2 IV 0 0 1 2 3 4 5 Yrs Stravitz RT, et al. Am J Med. 2008;121:119-126.

  23. Surveillance Imaging for HCC • Ultrasound is the usual modality for HCC surveillance and detection • Advantages: cheap, safe, supported by data • Drawbacks: operator dependent, limited sensitivity, difficult in obese patients • Masses detected by ultrasound typically require further characterization with other modalities (CT, MRI) Sonogram shows a small hypoechoic mass Wilson SR, et al. Radiology. 2010;257:24-39.

  24. Ultrasound Surveillance in Early HCC: Systematic Review • AFP improves detection to 70% • Every 6 mos significantly better than 12 mos Study Sensitivity (95% CI) % Weight Pateron 1994 0.58 (0.37-0.84) 6.45 Kobayashi 1985 0.40 (0.31-0.78) 5.10 Arrigoni 1988 0.69 (0.49-0.89) 9.60 Oka 1990 0.68 (0.54-0.81) 11.56 Cottone 1994 0.87 (0.77-0.96) 12.81 Zoli 1996 0.91 (0.84-0.98) 13.41 Tradati 1998 0.33 (-0.11 to 0.78) 4.30 Henrion 2000 0.67 (0.38-0.96) 7.16 Bolondi 2001 0.82 (0.73-0.91) 13.03 Tong 2001 0.58 (0.41-0.75) 10.47 Santa 2003 0.25 (0.62-0.82) 4.93 Subtotal 0.63 (0.52-0.82) 87.27 0 1.0 (I2 = 76.7%; P < .0001) Singal A, et al. Aliment Pharmacol Ther. 2009;30:37-47.

  25. HCC Surveillance: Guideline Recommendations • Who: • Patients at risk due to cirrhosis or chronic hepatitis B • How: • VA and NCCN: recommend AFP and liver ultrasound every 6-12 months • AASLD and EASL: recommend liver ultrasound every 6 months • NCI and USPHS Task Force do not recommend surveillance for HCC • Rationale: • Benefit is has not been proven in cirrhosis • Cost, risk • Prospective randomized study of surveillance is needed

  26. Diagnosis and Staging

  27. HCC Diagnosis: Dynamic Imaging • HCCs are hypervascular • Tumor blood supply: • 100% hepatic artery • Liver parenchymal blood supply: • 30% hepatic artery • 70% portal vein • Dynamic imaging (MRI, CT) follows tumor density with time after IV contrast bolus • Requires both arterial enhancement and washout During early arterial phase on CT, an HCC appears brighter than surrounding liver In later portal venous phase, the HCC appears darker than surrounding liver (washout)

  28. Diagnosis of HCC: To Biopsy or Not? • Yes • Positive biopsy provides • Diagnostic certainty if imaging is inconsistent with HCC • Prognostic information • Avoids inappropriate treatment and misleading “cure” • May be required for experimental treatments • May permit personalized therapy based on tumor gene expression • No • Not always feasible • Not needed if high diagnostic certainty based on imaging • Risk • Hemorrhage • Tumor seeding • False negatives (up to 1/3 of biopsies) may delay treatment Heuman DM, et al. Eur J Intern Med. 2012;23:37-39.

  29. Staging of HCC: The ABCs • Prognosis of HCC and treatment options are determined by • Anatomical extent of tumor (stage) • Biological aggressiveness (grade) • Cirrhosis severity and functional status • Staging tests typically include multiphase CT/MRI of abdomen, chest CT, and bone scan

  30. Anatomic Staging: TNM Goodman J, et al. Arch Surg. 2005;140:459-464.

  31. AASLD Diagnostic Criteria for HCC Mass on surveillance US or high AFP in a cirrhotic liver < 1 cm 1-2 cm > 2 cm Repeat USevery 3-4 mos 1 dynamic imaging study 1 dynamic imaging technique Typical vascular pattern Atypical vascular pattern with both techniques Atypical vascular pattern Typical vascular pattern on dynamic imaging Biopsy Stable > 18-24 mos Enlarging Diagnostic of HCC Nondiagnostic of HCC Other diagnosis Return to surveillance every 6-12 mos Repeat biopsy or imaging follow-up Proceed according to lesion size Change in size/profile Repeat imaging and/or biopsy + - Treat as HCC Adapted from Bruix J, et al. Hepatology. 2011;53:1020-1022.

  32. Child-Pugh Classification of Severity of Liver Disease Pugh RN, et al. Br J Surg. 1973;60:646-649. Lucey MR, et al. Liver Transpl Surg. 1997;3:628-637.

  33. BCLC Staging and Treatment Strategy HCC Okuda 3, PS > 2,Child-Pugh C PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminalstage (D) Very early stage (0) Single < 2 cm Carcinoma in situ Single 3 nodules ≤ 3 cm Portal pressure/bilirubin Associated Increased diseases Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival < 3 mos Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% Llovet JM, et al. Journal of the National Cancer Institute. 2008;100:698-711.

  34. Biologically Aggressive HCC • Features • Microvascular invasion • Satellite nodules • Diffuse infiltrating growth • Poorly differentiated • Mixed cholangio-carcinoma • Bad molecular signature • FDG-PET scan positive • High AFP and AFP-L3% • Rapid growth • Associated with • Early metastasis • High risk of recurrence after resection or liver transplantation • Failure of local control with RFA/TACE • Poor prognosis • There is no consensus on how to incorporate biology into tumor staging

  35. Importance of Cirrhosis Severity and Functional Status Log-Rank P Value A vs B: < .0001 B vs C: .04 C vs D: .01 • BCLC staging system combines anatomic extent of disease with severity of liver failure (CTP class) and functional status • Patients with poor functional status or decompensated cirrhosis are stage D regardless of anatomical stage • BCLC stage D has poorest survival and few treatment options 100 80 A 60 Survival Probability B 40 C D 20 0 10 20 30 40 50 60 70 Pts at Risk, n Stage A 64 51 25 8 Stage B 60 22 11 4 Stage C 76 10 3 1 Stage D 39 7 1 0 Mos 0 Marrero JA, et al. Hepatology. 2005;41:707-716.

  36. Treatment

  37. Treatment Options for HCC • Curative (stage I-II) • Thermal ablation (radiofrequency, microwave) • Resection (partial hepatectomy) • Liver transplantation (total hepatectomy) • Palliative (stage III-IV) • Transarterial therapies • Targeted therapy (sorafenib)

  38. Solitary Liver Cancers < 5 cm May Be Cured by Resection or Ablation • Normal bilirubin concentration, and the absence of clinically significant portal hypertension measured by hepatic vein catheterization (hepatic vein pressure gradient <10 mmHg) are predictors of excellent outcomes after surgery Bruix J, Serman M. Hepatology. 2005;42:1208-1236.

  39. Radiofrequency Ablation B

  40. RFA Candidacy • Unresectable, liver-dominant • Best: < 3 lesions < 3 cm • Location: not subcapsular, not subdiaphragmatic, not near major vessels • Visible by US/non-contrast CT • Can lipiodol label in rare cases • Adequate clotting function

  41. RF Ablation - Complications • Pain • Fever • Abnormal LAEs • Vasovagal/Hypotension • Pleural Effusion (0.6%) • Pneumothorax • Hemorrhage (0.5%) • Ascites • Cholangitis • Abscess • Hepatic Infarct • Biliary Stricture • Tumor Seeding • Skin burns

  42. RFA for Very Early–Stage HCC 1. Lencioni R, et al. Radiology. 2005;234:961-967. 2. Tateishi R, et al. Cancer. 2005;103:1201-1209. 3. Choi D, et al. Eur Radiol. 2007;17:684-692.

  43. Microwave Ablation • Kills tumor by heating tissue with microwaves • Approach, application similar to RFA • Advantages • Easier targeting • Less “heat sink” effect of adjacent vessels • Less painful Simon CJ, et al. Radiographics. 2005;25(suppl 1):S69-S83.

  44. Randomized Trial of RFA vs Resection: No Survival Difference • N = 168 • HCC < 4 cm and up to 2 nodules • 85% positive for viral hepatitis (77% with HBV) 1.0 OS 0.8 0.6 Probability of Survival 0.4 Resection group Radiofrequency ablation group Censored 0.2 0 6 12 18 24 30 36 0 Mos Pts at Risk, n RES group 84 75 70 66 63 55 52 RFA group 84 73 67 64 58 50 46 Feng K, et al. J Hepatol. 2012;57:794-802.

  45. Resection or Thermal Ablation for HCC: Pros and Cons • Potentially curative • Best results with solitary small tumors • Some lesions may be untreatable due to location • Some patients may be untreatable due to severity of liver disease • Significant procedural morbidity • Does not cure cirrhosis • Does not eliminate risk of new HCCs

  46. Total Hepatectomy With Liver Transplantation for Early-Stage HCC • Transplantation • Cures cancer • Eliminates cirrhosis • Feasibility demonstrated in a landmark study by Mazzaferro in 1996 • Inclusion criteria (N = 48) • Unresectable HCC • Staging criteria • Single lesion < 5 cm or • < 3 lesions, each < 3 cm • Following liver transplantation, • Actuarial survival at 4 yrs: 75% • Recurrence-free survival at 4 yrs: 83% 100 80 60 OS (%) 40 6 12 18 24 30 36 42 48 0 20 Pts at Risk, n Mos After Transplantation 48 45 40 32 27 21 17 9 5 0 Mazzaferro V, et al N Engl J Med. 1996;334:693-699.

  47. Effect of MELD Exceptions on Transplantation for HCC HCC, no exception HCC, MELD exception • Since 2002 • Transplantation for HCC within Milan criteria has been given high priority (MELD exceptions) • LT for HCC increased 6-fold: now > 20% of all LT’s performed 30 25 20 15 Liver Transplantation Recipients With HCC (%) 10 5 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Pre-MELD Era MELD Era Ioannou GN, et al. Gastroenterology. 2008;134:1342-1351.

  48. Transplantation for HCC: Expanding the Limits via “Downstaging” • Extended stage criteria (3A) • 1 lesion >5 cm and ≤ 8 cm or • < 3 lesions, largest ≤ 5 cm or • < 5 lesions, largest ≤ 3 cm • Total sum ≤ 8 cm • No vascular invasion • Required for downstaging • Tumor ablation • 3-mo follow-up showing lack of further progression • Downstaged HCC then listed and transplanted under MELD exception • In 61 patients exceeding Milan criteria • 71% successfully downstaged • 57% underwent LT • 4-year survival post LT = 92% • No posttransplant recurrence • Predictors of failure • AFP > 1000 Yao FY, et al. Hepatology. 2008;48:819-827.

  49. Limits of Liver Transplantation for HCC • Arithmetic: Only 1 in 10 patients with end-stage liver disease or HCC can receive liver transplantation because of the scarcity of donor livers • Transplantation can only be offered if there is good chance of long-term survival benefit • Considerations include • Expected poor survival with alternative treatments • Medical and surgical risk (comorbidities) • Compliance and sobriety • Social support

  50. Palliation of HCC: Transarterial Chemoembolization • Treatment strategy combines • Selective arteriography (precise targeting) • Chemotherapeutic drugs (produce necrosis) • Adsorbent (release chemo drugs gradually) • Embolization (produce ischemia, prevent washout) • Numerous technical variations

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