STOP Hepatocellular Carcinoma...• Immunotherapy: Checkmate-040 • 14% Response Rate • 4.3mo...

STOP Hepatocellular Carcinoma

Laura Tenner MD, Amit G. Singal MD MS, Mamta Jain MD, Barbara Turner MD, Barbara Riske MS

ReACH Center and Dept of Medicine UT Health Science Center San Antonio

Dept of Medicine UT Southwestern Medical Center Dallas

Overview

• Hepatocellular Carcinoma (HCC) epidemiology • Focus on Texas

• Risk factors for developing HCC• Focus on HCV

• Value of screening and prevention• Treatment options

• Focus on opportunities if early stage

Epidemiology of HCC

HCC WorldwideSixth most prevalent cancer; 2nd leading cause of cancer-related

deaths; mortality rate close to incidence rate

Liver Cancer and HCC in U.S.

• Estimated new cases and deaths from liver and intrahepatic bile duct cancer nationally

• New cases: 35,660• Deaths: 24,550

• HCC is the most common type of primary liver cancer

http://www.cancer.gov/types/liver/hp/adult-liver-treatment-pdqAmerican Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015.Available online Exit Disclaimer. Last accessed July 1, 2015.

http://www.cancer.gov/types/liver/hp/adult-liver-treatment-pdqhttp://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdfhttp://www.cancer.gov/global/web/policies/exit

Incident of HCC in the US, 2000-2012

U.S. (SEER) Incidence of Liver and Bile Duct Cancer 1992-2015

https://seer.cancer.gov/statfacts/html/livibd.html

U.S. Incidence Rates by Age 2011-15


U.S. Incidence Rates by Sex 2011-15

http://seer.cancer.gov/statfacts/html/livibd.html

U.S. Death from Liver/Bile Duct Cancer 2011-15


U.S. Incidence and Deaths for HCC/Bile Duct Cancer


5 Year Survival Liver/Bile Duct Cancer


U.S. Survival by Stage of Disease 2008-14


-2 -1.5 -1 -0.5 0 0.5 1 1.5 2

National Cancer Institute Website. Available at: http://seer.cancer.gov/csr/1975_2003/sections.html..

All Other Cancers (Average)

Liver

Thyroid

Esophagus

Lung & Bronchus (Female)

Testis

Corpus & Uterus, NOS

Trends in US Cancer Mortality Rates

Annual Percent Change (1994-2003)*

Liver Cancer – Fastest Growing Cancer-related Death Rate in the US

http://seer.cancer.gov/csr/1975_2003/sections.htmlChart8

Liver & IBD

Thyroid

Esophagus

Lung and Bronchus (Female)

Testis

Corpus & Uterus, NOS

All Other Cancers (Average)

1.8

0.8

0.4

0.4

0.1

0.1

-1.6

Sheet1

Liver & IBD1.8

Thyroid0.8

Esophagus0.4

Lung and Bronchus (Female)0.4

Testis0.1

Corpus & Uterus, NOS0.1

All Other Cancers (Average)-1.6

Liver & IBD1.8

All Cancers-1.1

Liver & IBD2.6

All Cancers-0.4

Sheet1

Sheet2

Sheet3

National Trends2011-2015

Overall cancer death rates decreased during 1999-2015 by:o An average of 1.8 percent per year

for men.o An average of 1.4 percent per year

for women.o Liver and Bile duct cancer death

rates increased in both men and women

https://seer.cancer.gov/report_to_nation/statistics.html

HCC in Texas

Mortality from Liver Cancer in US 2014

Mokdad AH, Dwyer-Lindgren L, Fitzmaurice C, et al. Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980-2014. JAMA. 2017;317(4):388–406. doi:10.1001/jama.2016.20324

Texas HCC Incidence Doubled in the Past 15 Years

HCC in Texas• Texas HCC mean incidence

9.3/100,000 persons: 2ndhighest in U.S.

• National mean incidence is 7.9/100,000

• 2,000 new cases in Texas this year

• Incidence in Dallas county is 11.7/100,000

• Incidence in South Texas as high as 19.1/100,000

http://www.thetcr.org/article/view/1864/html

Risk Factors for HCC

Risk Factors for HCC

• Cirrhosis from any etiology• Viral hepatitis (Hepatitis B and/or C)• Nonalcoholic fatty liver disease (Obesity and Diabetes)• Heavy alcohol use• Hereditary hemochromatosis• Environmental toxins

• Aflatoxin, contaminated drinking water, betel nut chewing

Others: 38%

HBV:10%

NAFLD:7%

Alcohol alone: 45%

1976-1990

Others: 46%

HBV: 4%

Alcohol alone: 25%

Alcohol and HCV: 7%

HCV alone: 18%

1991-2000

Others: 21%

HBV: 4%

NAFLD: 11%

Alcohol alone: 19%

Alcohol and HCV: 17%

HCV alone: 28%

2001-2008

Trends in HCC Etiology~50% increase in HCV-related HCC between 1991-2008

Yang JD, et al. Mayo Clin Proc. 2012;87:9-16.

El-Serag HB, Rudolph KL Gastroenterology 2007: 132:2557-76

Prevalence in general

population

Risk estimate of HCC

Current prevalence in HCC cases

Population attributable

fraction

HBV 0.5-1% 20-25 10-15% 5-10%

HCV 1-2% 20-25 30-60% 20-25%

Alcoholic liver disease

10-15% 2-3 20-30% 20-30%

Metabolic syndrome

30-40% 1.5-2.5 20-50% 30-40%

HCC Risk Factors

El-Serag HB, Rudolph KL Gastroenterology 2007: 132:2557-76

HCV infection and HCC

HCV 4x as prevalent as HIV and HBV in U.S.

Chak E, et al. Liver Int. 2011;31(8):1090-1101.

HIV

Tota

l No.

Infe

cted

(milli

ons)

Diagnosed

Undiagnosed 3 to 5 Millionup to 75% unaware of Infection

1.1 Million21% unaware of

infection~800,000 to 1.4 Million

65% unaware of infection

HBV HCV

4

3

2

1

0

Time from HCV infection until serious complications

http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all

Chronic HCV in Texas

In 2000, nearly 400,000 Texans (1.79%) were estimated to be chronically HCV-infected

There is a 17 fold higher risk of developing HCC in HCV-infected individuals

Yalamanchili K. Proc (Bayl Univ Med Cent). 2005 Jan; 18(1): 3–6.

US Preventive Services Task Force (USPSTF) Guidelines - 2012

One time screening of all baby boomers (born 1945 through 1965) for HCV infection (USPSTF Rating: Class I, Level B)

• Reflects evidence that newer highly effective anti-HCV drugs can cure HCV infection and, in many cases, prevent serious complications of disease

Photo source: Centers for Disease Control and Prevention

2 of 3 Americans infected with HCV from 1945-1965

Reflects high incidence in past

5x higher prevalence than other birth cohorts (3.4 vs. 0.5%)

81% of HCV infected adults and 73% of HCV mortality

Smith et al MMWR 2012; 61(RR04): 1-18Rein et al Ann Int. Med 2012; 156(4): 263-70

Other Risk Factors for HCC

Diabetes and HCC: Meta-analysis

Chen J et al Eur J Cancer Prev. 2015 Mar;24(2):89-99.

Obesity (BMI >35) Increases Risk of Death from Liver Cancer (Men in a Prospective U.S. Cohort)

Calle EE et al. N Engl J Med, 2003;348:1625–38

Obesity-related non-alcoholic liver disease and HCV

The combination of NAFLD and HCV worsens fibrosis progression and increases risk of developing HCC even further

Obesity Prevalence 2014

High obesity prevalence in Texas and other southern states likely increases risk of HCC even further

http://www.cdc.gov/obesity/data/prevalence-maps.html

Alcohol and HCC

Persson EC et al. Alcohol consumption, folate intake, hepatocellularcarcinoma, and liver disease mortality. Cancer Epidemiol Biomarkers Prev. 2013;22(3):415-21.

NIH-American Association of Retired Persons Diet and Health Study 1996-2006 (N=494,743)

HCC Prognosis and Treatment

Why Is HCC So Deadly?

Cirrhosis is often not diagnosed

Rarely produces symptoms until

advanced stage

Most are diagnosed late

often multifocal

invades blood vessels

spreads lymphatically and

hematogenously

Stage Prevalence 5 –yr Survival

Localized 42% 30.5%

Regional 28% 10.7%

Distant 18% 3.1%

Treatment for HCC Can Be Effective if Early Stage

AASLD Guidelines Bruix et al. Hepatology 2011

Sorafenib: Overall SurvivabilitySorafenib median

overall survival of 6.5 months compared with 4.2 months in the placebo armHR 0.68, p=0.014

Cheng, Ann-Lii, et al. "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial." The lancet oncology 10.1 (2009): 25-34.

Sorafenib: Symptom Free Progression

There was no meaningful significant difference for Time To Symptom Progression (TTSP)

Sorafenib 3.5 moPlacebo 3.4 mo

Cheng, Ann-Lii, et al. "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial." The lancet oncology 10.1 (2009): 25-34.

New Treatments for HCC

• Immunotherapy: Checkmate-040• 14% Response Rate• 4.3mo Median duration of Stable disease• No Overall Survival data

• Regorafenib: Resource• 10.6mo versus 7.8mo (HR 0.63)

Bruix et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389(10064): p56-66. Jan 2017

HCC Screening

Guidelines

• 2010 American Association for the Study of Liver Diseases (AASLD) guideline

• Liver ultrasound every 6 months

Patients for Whom Surveillance Is Recommended

• Cirrhosis from any etiology (represents > 80% of HCC patients in the US)

• Hepatitis C• Alcohol-related cirrhosis• Non-alcoholic steatohepatitis• Hepatitis B• Other causes: Hemochromatosis, primary biliary cirrhosis, alpha-1

antitrypsin, etc

Bruix J, et al. Hepatology 2010 Simonetti RS, et al. Dig Dis Sci. 1991

HCC Surveillance Associated with Improved Survival in Patients with Cirrhosis

Author Lead Time Survival Rates Significance

El-Serag 2011 70 daysMedian survival

298 vs. 130 days

OR 0.81

(95%CI 0.70 – 0.94)

Tong 2010 118 days3-year survival

62.5% vs. 36.6%p=0.007

Wong 2008 236 days2-year survival

49.4% vs. 28.6%p=0.035

Tanaka 2006 238 daysMedian survival

6.3 vs. 5.3 yearsp=0.016

Trevisani 2002 98 - 239 daysMedian survival

30 vs. 20 monthsp

Impact of Screening on Stage of HCC at Time of Diagnosis

Impact of Screening on Survival

Low Surveillance Rates for HCC

Singal AG et al. Utilization ofhepatocellular carcinoma surveillance among American patients: a systematicreview. J Gen Intern Med. 2012 Jul;27(7):861-7

HCC Prevention

Ways to Reduce Risk

for HCC

• Avoid alcohol or drink in moderation

• Get immunized for Hepatitis B virus

• Weight loss and exercise

Advise Patients to:

• We now have a CURE!• Sofosbuvir/Simeprevir• Sofosbuvir/Ledipasvir• Paritaprevir/r, Ombitasvir,

Dasabuvir

What do we do about HCV?

Reducing HCV burden remains the highest yield target to reduce HCC incidence in TX.

Ashahina et al., Hepatology 2010

Curing HCV Reduces the Risk of HCCNon-SVR

SVRNon-SVR

SVR

For patients with cirrhosis, continue screening even after cured

Guidelines: High Risk Groups to Screen for HCV

Unexplained chronic liver disease or high ALT Injection-drug use (even once) or intranasal drug abuseEver in jailLong-term hemodialysis (ever)Transfusions or organ transplants: before July 1992 or clotting factor

given before 1987, HCV+ transfusionTattoo in an unregulated settingChildren born to HCV-infected womenHealthcare/public safety workers exposed to HCV+ bloodHIV infectionBorn in a high risk country

Baby Boomers (Born 1945–1965) Account for 76.5% of HCV in the US1

Estimated Prevalence by Age Group2

Birth Year Group

0

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

1990+1980s1970s1960s1950s1940s1930s1920s

Risk-Based Screening is NOT Enough

http://www.cdc.gov/features/HepatitisCTesting/

USPSTF and CDC New Recommendation

• In addition to screening individuals with high risk behavior for HCV, a one time HCV screening is recommended for all persons born between 1945 and 1965 (baby boomers).

http://catchinghealth.bangordailynews.com/2014/01/20/im-not-your-mother-but/why-baby-boomers-should-be-tested-for-hepatitis-c/

Fighting HCC in Texas!

Early detection and treatment of HCV can decrease the incidence of cirrhosis and HCC

New USPTSF and CDC guidelines recommend universal screening of baby boomers born 1945-1965 for HCV

Texas has high prevalence of risk factors for HCC including HCV, infection, and obesity

Texas has the 2nd highest prevalence of HCC

Liver cancer: fastest growing death rate of cancers in U.S.

AcknowledgementsTexasHepCA

Thank you for your attention!

STOP Hepatocellular Carcinoma OverviewEpidemiology of HCCHCC WorldwideLiver Cancer and HCC in U.S. Incident of HCC in the US, 2000-2012U.S. (SEER) Incidence of Liver and Bile Duct Cancer 1992-2015 U.S. Incidence Rates by Age 2011-15U.S. Incidence Rates by Sex 2011-15U.S. Death from Liver/Bile Duct Cancer 2011-15U.S. Incidence and Deaths for HCC/Bile Duct Cancer5 Year Survival Liver/Bile Duct CancerU.S. Survival by Stage of Disease 2008-14Liver Cancer – Fastest Growing Cancer-related Death Rate in the USNational Trends�2011-2015HCC in Texas Mortality from Liver Cancer in US 2014Texas HCC Incidence Doubled in the Past 15 YearsHCC in TexasRisk Factors for HCCRisk Factors for HCCTrends in HCC EtiologySlide Number 23HCC Risk FactorsHCV infection and HCCHCV 4x as prevalent as HIV and HBV in U.S.Time from HCV infection until serious complicationsChronic HCV in TexasUS Preventive Services Task Force (USPSTF) Guidelines - 2012 2 of 3 Americans infected with �HCV from 1945-1965Other Risk Factors for HCC�Diabetes and HCC: Meta-analysisObesity (BMI >35) Increases Risk of Death from Liver Cancer (Men in a Prospective U.S. Cohort)Obesity-related non-alcoholic liver disease and HCVObesity Prevalence 2014Alcohol and HCCHCC Prognosis and TreatmentWhy Is HCC So Deadly?Treatment for HCC Can Be Effective if Early Stage Treatment for HCC Can Be Effective if Early Stage Sorafenib: Overall SurvivabilitySorafenib: Symptom Free ProgressionNew Treatments for HCCHCC ScreeningGuidelinesPatients for Whom Surveillance Is RecommendedHCC Surveillance Associated with Improved Survival in Patients with Cirrhosis Impact of Screening on Stage of HCC at Time of DiagnosisImpact of Screening on SurvivalLow Surveillance Rates for HCCHCC PreventionWays to Reduce Risk for HCCReducing HCV burden remains the highest yield target to reduce HCC incidence in TX.Slide Number 54Guidelines: �High Risk Groups to Screen for HCVBaby Boomers (Born 1945–1965) Account for 76.5% of HCV in the US1Risk-Based Screening is NOT EnoughUSPSTF and CDC New RecommendationFighting HCC in Texas!SummaryAcknowledgementsThank you for your attention!

STOP Hepatocellular Carcinoma...• Immunotherapy: Checkmate-040 • 14% Response Rate • 4.3mo...

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