HCC and HCV Nancy Reau Associate Professor of Medicine

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1 HCC and HCV Nancy Reau Associate Professor of Medicine University of Chicago An Overview of Hepatocellular Carcinoma From a Hepatitis C Perspective Increased Burden of Hepatocellular Carcinoma Surveillance and ddiagnosisi Staging and treatment algorithm HCV and HCC 2 1

2 Hepatocellular Carcinoma (HCC): Common and Increasing 694,000 deaths from liver cancer yearly worldwide 1 US incidence has increased 2-fold from ,3 American Cancer Society 5 th leading cause of cancer deaths in males in Incidence of HCV-related HCC continues to rise 5 Increase in numbers of persons who have had HCV for decades Presence of comorbid factors Longer survival of persons with advanced liver disease 1. GLOBOCAN SEER stat fact sheets: liver and intrahepatic bile duct. 3. Llovet JM. J Gastroenterol. 2005;40: American Cancer Society. Cancer facts & figures NIH. NIH Consensus State Sci Statements, 2002; 19(3): HCV and HCC 3 HCV is the Dominant Risk Factor for HCC in the United States El-Serag HB. N Engl J Med 2011 HCV and HCC 4 2

3 Multistep Malignant Transformation to HCC 1. Tornillo L, et al. Lab Invest. 2002;82: Verslype C, et al. AASLD Abstract 24. HCC 2 Epigenetic alterations Genetic alterations Dysplastic nodules 1 Liver cirrhosis Hepatitis C Hepatitis B Ethanol NASH Normal liver Oxidative stress and inflammation Growth factors Loss of cell cycle checkpoints Potential Therapeutic Targets Viral oncogenes Telomere shortening Anti-apoptosis Carcinogens Cancer stem cells Angiogenesis HCV and HCC 5 Projected Incidence of HCV Related Liver Cancer and Death Also Expected to Peak in Coming Decades 1 DCC=decompensated cirrhosis; HCC=hepatocellular carcinoma Between 1995 and 2010, 41% of the 126,862 new primary registrants for liver transplants carried a diagnosis of HCV infection 2 1. Rein DB, et al. Dig Liver Dis. 2011;43(1): Biggins SW, et al. Liver Transpl. 2012;18(12): HCV and HCC 6 3

4 Liver cancer projected to 3 rd leading cause of cancer-related death by 2030 The American Association for Cancer Research has published a report in its journal Cancer Research, published online on May 19, 2014 entitled Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver and Pancreas Cancers in the United States. The abstract to the article reports that: Breast, prostate, t and lung cancers will remain the top cancer diagnoses thyroid cancer will replace colorectal cancer as the fourth leading cancer diagnosis by 2030, Lung cancer is projected to remain the top cancer killer Pancreas and liver cancers are projected to surpass breast, prostate, and colorectal cancers to become the second and third leading causes of cancer-related death by Cancer Res; 1 9. _2014 AACR. HCV and HCC 7 SVR Decreases but Does Not Eliminate Risk for Liver Related Complications Van der Meer, et al. JAMA 2012:308: HCV and HCC 8 4

5 AASLD Surveillance Guidelines Surveillance recommended in at-risk groups Specific hepatitis B carriers Non hepatitis B cirrhosis HCC surveillance should be performed with ultrasound Patients should be screened at 6-mo intervals Increased surveillance interval in patients at higher risk not needed Bruix J, et al. AASLD HCC guidelines. July HCV and HCC 9 Groups in Whom the Rik of HCC is Increased, but in Whom Efficacy of Surveillance Has Not Been Demonstrated Population Group Threshold Incidence for Efficacy of Surveillance (%/year) Incidence of HCC (%/year) Hepatitis B Carriers <40 (males or 50 (females) 0.2 <0.2 Hepatitis C and stage <1.5 fibrosis Noncirrhotic NAFLD 1.5 <1.5 Sherman M. Semin Liver Dis. 2010;30(1):3-16 HCV and HCC 10 5

6 Diagnosis: HCC Arterial phase Equilibrium Dynamic imaging: Arterial uptake followed by washout of contrast in the venousdelayed phases HCV and HCC HEPATOLOGY, Vol. 53, No. 3,

7 AASLD: Barcelona Clinic Liver Cancer (BCLC) Staging System BCLC is the only staging system that stratifies patients into treatment groups based on all 3 parameters Tumor stage - tumor size, number of nodules, PVT Liver function CTP Patient s health status ECOG PS BCLC system uses key independent predictors of survival Performance score, portal vein thrombosis, tumor diameter Marrero JA, et al. Hepatology. 2005;41: HCV and HCC 13 BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A PS 0-2, Child-Pugh A-B PS > 2, Child-Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Single Portal pressure/bilirubin Increased 3 nodules 3 cm Associated diseases Unresectable HCC Normal No Yes Resection Liver transplantation RFA/PEI Curative treatments (30%); 5-yr survival: 40%-70% TACE Sorafenib RCTs (50%); 3-yr survival: 10%-40% Symptomatic (20%); survival < 3 mos Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10): HCV and HCC 14 7

8 Resection Treatment of BCLC Very Early Stage 0 or Early Stage A - 1 HCC without portal hypertension or increased bilirubin Recurrence following resection Approximately 50% at 3 yrs Approximately 70% at 5 yrs Adjuvant Therapy in the Resection Setting Llovet JM, et al. Hepatology. 1999;30: Llovet JM, et al. J Natl Cancer Inst. 2008;100: HCV and HCC 15 Liver Transplantation BCCLC Stage 0 with increased portal hypertension and bilirubin or Stage A Absence of macroscopic vascular invasion or extrahepatic spread Milan Criteria Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm - 5-yr survival with transplantation: ~ 70% - 5-yr recurrent rates: < 15% Mazzaferro V, et al. N Engl J Med. 1996;334: Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433. HCV and HCC 16 8

9 Radiofrequency Ablation or Percutaneous Ethanol Injection Treatment of BCLC Stage 0 or A - With macroscopic vascular invasion or extrahepatic spread Candidates for RFA or PEI: - Include individuals who are not candidates for surgery Radiofrequency ablation generally preferred - 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 HCV and HCC 17 BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A PS 0-2, Child-Pugh A-B PS > 2, Child-Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Single Portal pressure/bilirubin Increased 3 nodules 3 cm Associated diseases Unresectable HCC Normal No Yes Resection Liver transplantation RFA/PEI Curative treatments (30%); 5-yr survival: 40%-70% TACE Sorafenib RCTs (50%); 3-yr survival: 10%-40% Symptomatic (20%); survival < 3 mos Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10): HCV and HCC 18 9

10 Transarterial Chemoembolization (TACE) Treatment of BCLC Intermediate Stage B - Multinodular, PS = 0 - Drug-eluting g bead chemoembolization (DEB) delivers chemotherapy doxorubicin - DEB produced lower systemic levels of doxorubicin and therefore fewer adverse effects - Conventional transarterial chemoembolization Embolizing the artery with gel foam packets 1. Lammer J, et al. Cardiovasc Intervent Radiol. 2010;33: HCV and HCC 19 Transarterial Chemoembolization (TACE) 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: HCV and HCC 20 10

11 Sorafenib - Treatment of BCLC Advanced Stage C Phase III SHARP Trial: Sorafenib vs Placebo in Advanced HCC Stratification by macroscopic vascular invasion and/or extrahepatic spread, ECOG PS, geographical region Patients with advanced, measurable HCC, ECOG PS 0-2 (N = 602) Sorafenib 400 mg BID PO (n = 299) Placebo (n = 303) Primary endpoints: OS, time to symptomatic progression Secondary endpoints: progression (radiologic, clinical), adverse events Llovet JM, et al. N Engl J Med. 2008;359: HCV and HCC 21 Sorafenib OS (ITT) ability Survival Prob Pts at Risk, n Sorafenib Placebo HR (S/P): 0.69 (95% CI: ; P =.00058) Sorafenib (n = 299) Median: 10.7 mos (95% CI: ) Placebo (n = 303) Median: 7.9 mos (95% CI: ) Wks Sorafenib significantly improved survival vs placebo, from a median time of 7.9 to 10.7 months Llovet JM, et al. N Engl J Med. 2008;359: HCV and HCC 22 11

12 Sorafenib Conclusions From Phase III SHARP Trial Sorafenib is first systemic therapy to prolong survival in HCC patients Survival: HR: 0.69; 31% decrease in risk of death Time to radiologic progression: 5.5 mos with sorafenib vs 2.8 mos with placebo (P <.001) Llovet JM, et al. N Engl J Med. 2008;359: HCV and HCC 23 Sorafenib Therapy Pinter 2009 Oncologist 14(1)

13 Y90 90Yttrium radioembolization (Y90) allow accurate tumor targeting while sparing surrounding parenchyma Above 3 cm efficacy of RFA is diminished Radiation segmentectomy is defined as Y90 infusion limited to 2 hepatic segments (Couinaud) (A) Contrast-enhanced arterial phase MRI demonstrating a surface segment 4 HCC adjacent to the gallbladder, falciform ligament, and liver capsule. (B) Angiography of segment 4 lesion where radiation segmentectomy was performed with 300 Gy. (C) Complete mrecist tumor necrosis at 16-month follow-up. No viable tumor was found at explant. HCV and HCC 25 Effect of Previous Interferon-based Therapy on Recurrence after Curative Treatment of Hepatitis C Virus-related Hepatocellular Carcinoma Int J Med Sci. 2014; 11(7): HCV and HCC 26 13

14 Summary The diagnosis and burden of HCC is increasing BCLC staging system is recommended by AASLD guidelines BCLC system provides framework for selection of treatmentt t Very Early Stage 0 - Resection Early Stage A - Transplantation or RFA / PEI Intermediate Stage B TACE Advanced Stage C - Sorafenib Terminal Stage D Symptomatic & Supportive Care HCV and HCC 28 14