BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PS, performance score; RCT, randomized controlled trial. Josep M. Llovet, MD: Median survival in patients with intermediate-stage disease is approximately 17 months if left untreated but may be extended with chemoembolization.
HCC, hepatocellular carcinoma.
HCC, hepatocellular carcinoma.
BCLC, Barcelona Liver Clinic Cancer stage; CLIP, cancer of the liver Italian program; CUPI, Chinese University Prognostic Index; CTP, Child-Pugh-Turcotte; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; JIS, Japan Integrated Staging score; TNM, tumor-node-metastasis.
BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma. Josep M. Llovet, MD: Dr. Marrero led a comparative study of HCC staging systems in a cohort of American patients that identified the BCLC system as the best predictor of survival. In addition, the BCLC system is the only system that stratifies patients into treatment groups as well as provides prognostic stratification. For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx
PEI, percutaneous ethanol injection; RFA, radiofrequency ablation. Josep M. Llovet, MD: A third option is percutaneous local ablation. This procedure is suitable for patients who are not candidates for surgery or liver transplantation. Radiofrequency ablation is considered the first-line treatment option for these patients based on data from 4 randomized, controlled trials that found this approach to be significantly more effective than percutaneous ethanol injection regarding local control of disease. In addition, meta-analyses suggest there may be an overall survival benefit in favor of radiofrequency ablation.
TACE, transarterial chemoembolization. Josep M. Llovet, MD: Chemoembolization is not appropriate for all patients with intermediate-stage disease. For instance, extrahepatic spread, lack of portal blood flow, advanced disease, or clinical symptoms of end-stage cancer are contraindications for chemoembolization.
HCC, hepatocellular carcinoma. Jorge A. Marrero, MD, MS:Management of HCC requires a multidisciplinary approach. Treatment options involve surgery, medical oncology, diagnostic and interventional radiology, as well as hepatology. Josep M. Llovet, MD: Hepatocellular carcinoma is a complex and unique disease, involving cirrhosis and liver disease as well as cancer. Hepatic resection and liver transplantation requires specialist surgeons, and skilled pathologists are needed to confirm diagnosis. Use of local ablation therapies and chemoembolization depends on access to interventional radiologists, and finally, hepatologists and oncologists must be well versed in treatment strategy. The multidisciplinary team is central to the management of this disease.
HCC, hepatocellular carcinoma.
Hcc with sternal mets presentation
UNUSUAL PRESENTATION OF HCC DR. RAJKUMAR, R. III YR POST GRADUATE DR. KALAICHELVI D.M. H.O.D. & PROF DEPT. OF MEDICAL ONCOLOGY MADRAS MEDICAL COLLEGE CHENNAI
MR . X 60/ M REFERRED FROM SGE IC/O SWELLING OVER THE ANT. CHEST WALL – 6MONTHS .H/O PAIN FOR THE PAST- 2 WEEKS.NON ALCOHOLIC/ BEEDI SMOKER
10×7 CM MASS OVER THE ANT. CHEST WALLFIRM IN CONSISTENCYP/A- HEPATOMEGALY
INVESTIGATIONS• CBC- NORMAL• LFT- S. BILIRUBIN- 1.3 DIRECT- 0.9 ALK.POS- 80 T.PROT- 6.8 ALB- 3.7• RFT- NORMAL• HbSAG- NEGATIVE• ANTI HCV- NEGATIVE• HIV I & II- NEGATIVE• ALPHA-FETO PROTEIN- 1.62 IU/ml• USG ABDOMEN- HETEROECHOIC LESION RIGHT LOBE OF LIVER-11.5×10.5 CM –• IMPRESSION- HCC Rt. LOBE OF LIVER
HCC – METASTATIC• UNUSAL EXTRA HEPATIC METASTATIC SITE• NON CIRRHOTIC BACKGROUND• GOOD P.S. STATUS• BCLC STAGE C• SORAFENIB – 200 MG B.I.D.• PALLIATIVE R.T. - STERNUM
HCC: COMMON AND INCREASING• 694,000 deaths from liver cancer yearly worldwide• Age-adjusted US incidence has increased 2-fold from 1985-1998 – Expected to continue to increase until 2015- 2020• American Cancer Society statistics for liver cancer in 2010 – Estimated new cases: 24,120 – Estimated deaths: 18,910 – 5th leading cause of cancer deaths in males 1. GLOBOCAN 2008. 2. SEER stat fact sheets: liver and intrahepatic bile duct. 3. Llovet JM. J Gastroenterol. 2005;40:225-235. 4. American Cancer Society. Cancer facts & figures 2010.
M.M.C. DATA• 2010-2011• TOTAL NO. CASES- 88 ALCOHOLISM- 36% HEPATITIS B – 14.7% HEP B & ALCO -13.6% HEP C – 1.1%• MALE- 78.4%• FEMALE- 21.2%• BCLC D – 85.3%
HCC: RISK FACTORSThe most important risk factor is cirrhosis from any cause:1. Hepatitis B (integrates in DNA)2. Hepatitis C3. Alcohol4. Aflatoxin5. Other
HCC: Metastases• Rest of the liver• Portal vein• Lymph nodes• Lung• Bone• Brain
Natural History of Nonsurgical HCC Study Design: Control Arm of 2 RCTs• 102 untreated cirrhotic patients with unresectable HCC – Managed with symptomatic treatment• Median survival of 17 months (range: 1-60 months) – 1-yr survival was 54% – 2-yr survival was 40% – 3-yr survival was 28% Llovet JM, et al. Hepatology. 1999;29:62-67.
Malignant Transformation: Multistep HCC Epigenetic alterations Genetic alterations Dysplastic nodules Liver cirrhosis Hepatitis C Hepatitis B Potential Targets Ethanol Oxidative Viral Carcinogen NASH stress and oncogenes s inflammation Normal liver Growth Telomere Cancer factors shortening stem cells Loss of cell Antiapopto Angiogenes cycle sis is checkpoints1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.
CONTRAST WASHOUT IN HCC Arterial Phase Portal Venous Phase
STAGING SYSTEMS IN HCCStaging Hepatic Function Alpha- Performance Tumor StagingSystem fetoprotein ScoreOkuda Ascites, albumin, and No No Tumor > or < 50% of cross- bilirubin sectional area of liverTNM No No No Number of nodules, tumor size, presence of portal vein thrombosis, and presence of metastasisCLIP CTP < 400 or No Number of nodules, tumor > or ≥ 400 ng/mL < 50% area of liver, and portal vein thrombosisBCLC CTP No Yes Tumor size, number of nodules, and portal vein thrombosisCUPI Bilirubin, ascites, < 500 or Presence of TNM alkaline phosphatase ≥ 500 ng/mL symptomsJIS CTP No No TNMGRETCH JA, et Bilirubin, alkaline, Marrero al. Hepatology. 2005;41:707-716.35 or < Yes Portal vein thrombosis phosphatase ≥ 35 µg/L
Barcelona Clinic Liver Cancer Staging Classification Stage 0 Stage A-C Stage D PST 0, Child-Pugh A Okuda 1-2, PST 0-2, Child-Pugh A-B Okuda 3, PST > 2, Child-Pugh C Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal Single < 2 cm Single or 3 nodules Multinodular, PST 0 Portal invasion, stage (D) Carcinoma in situ < 3 cm, PST 0 N1, M1, PST 1-2 Single 3 nodules ≤ 3 cmPortal pressure/bilirubin Increased Associated diseases Normal No Yes Liver transplantation Systemic Resection PEI/RFA Chemoembolism (CLT/LDLT) treatment Curative treatments Randomized controlled trials Symptomatic 50% to 75% at 5 yrs 40% to 50% at 3 yrs vs 10% at 3 yrs treatment Llovet JM et al. Lancet. 2003;362:1907-1917.
COMPARISON OF HCC STAGING SYSTEMS• BCLC system uses key independent predictors of survival – Performance score, portal vein thrombosis, tumor diameter• Compared with other staging systems in cohort study – BCLC had best stratification of survival across all stages – BCLC was only system to have independent predictive value on survival• BCLC is the only staging system that stratifies patients into treatment groups Marrero JA, et al. Hepatology. 2005;41:707-716.
LIVER TRANSPLANTATION FOR HCC: MILAN CRITERIA (STAGE 1 AND 2)Single tumor, not > 5 cm Up to 3tumors, none>3Cm + Absence of macroscopic vascular invasion, absence of extrahepatic spread • 5-yr survival with transplantation: ~ 70% • 5-yr recurrent rates: < 15%Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.
Candidates for RFA/PEI• Includes individuals who are not candidates for surgery• Radiofrequency ablation generally preferred over percutaneous ethanol injection – Necrotic effect more predictable across tumor sizes – Meta-analyses suggest survival benefit with radiofrequency ablation vs percutaneous ethanol injection Bruix J, et al. AASLD HCC guidelines. July 2010.
CHEMOEMBOLIZATIONImage courtesy of www.hopkinscoloncancercenter.org.
Contraindications to TACE• Extrahepatic tumor spread• Lack of portal blood flow – Portal vein thrombosis, portosystemic anastomoses or hepatofugal flow• Advanced liver disease (Child-Pugh Class B or C)• Clinical symptoms of end-stage cancer Bruix J, et al. AASLD HCC guidelines. July 2010.
Phase III SHARP Study: Sorafenib vs Placebo in Advanced HCC Sorafenib 400 mg PO BID, continuous dosing (n = 299) Patients with advanced Stratified by macroscopic hepatocellular vascular invasion and/or carcinoma, extrahepatic spread; ECOG PS; ECOG PS ≤ 2, no geographical region previous systemic treatment Placebo (N = 602) 2 tablets PO BID, continuous dosing (n = 303)Primary endpoints: OS, time to symptomatic progressionSecondary endpoint: TTP (independent review) Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Sorafenib in Advanced HCC (SHARP): Survival Sorafenib median OS: 1.00 46.3 wks (10.7 mos) (95% CI: 40.9-57.9) Placebo median OS: 0.75 34.4 wks (7.9 mos)Survival Probability (95% CI: 29.4-39.4) 0.50 0.25 HR (S/P): 0.69 (95% CI: 0.55-0.87; P < .001) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mos Since RandomizationLlovet JM, et al. ASCO 2007. Abstract LBA1. Llovet JM, et al. N Engl J Med.2008;359:378-390.
Multidisciplinary HCC Management• HCC is the intersection of 2 diseases – Liver disease and cancer• Skilled pathologists needed for diagnosis• Specialists required to deliver treatment options – Surgeons for resection or transplantation – Radiologists for ablation and chemoembolization• Hepatologists and oncologists follow treatment strategy and labs• Midlevel providers bring support, particularly for oral therapy
Conclusions• HCC occurs in cirrhotic patients and complicates diagnosis and treatment• The Barcelona Clinic Liver Cancer staging system accounts for key prognostic factors: hepatic function, performance score, and tumor burden• Chemoembolization is the best option in nonresectable patients without vascular involvement• Sorafenib is the best option for advanced tumors• Novel therapies are needed