hepatocellular carcinoma in 2019: a new era in diagnosis ...• hepatocellular carcinoma (hcc) is...

Hepatocellular Carcinoma in 2019: A New Era in Diagnosis and

Management

Advances in Liver Disease 2019: A Year in Review

December 7, 2019

Richard Kalman, MD

[email protected]

55 yo M with decompensated HCV cirrhosis diagnosed with 2.8 cm HCC in 2009 - Disappointed by an underachieving

Eagles team with a veteran coach and talented quarterback on the hot seat

- Failed Interferon therapy - Listed for transplant and rises to

top of the transplant list - Develops progressive HCC - Receives palliative Sorafenib

stopped after 2 weeks

55 yo M with decompensated HCV cirrhosis diagnosed with 2.8 cm HCC in 2019- Disappointed by an underachieving


- Cured with 12 weeks Harvoni- Listed for transplant and never rises

high enough on the list for transplant

- Develops progressive HCC - Receives palliative Sorafenib

stopped after 2 weeks followed by immunotherapy with durable response

Outline

• Surveillance

• HCC Risk Assessment

• Protective Factors

• UNOS Transplant Updates

• Updates in HCC therapy

Richard Kalman [email protected]

Introduction

• Hepatocellular carcinoma (HCC) is the 5th

most common cancer worldwide and 3rd

most common cause of cancer related mortality

• Half million new cases worldwide annually

• US 2018 Estimates

– 42,220 cases

– 30,200 deaths Jemal A et al. J Natl Cancer Inst. 2013;105:175–201Siegel R et al. Cancer J Clin. 2012;62:10–29El-Serag, H. NEJM. 2011;365:1118-27http://www.cancer.gov/cancertopics/types/liver

Too Little, Too Late

Llovet JM et al. Hepatology. 1999;29:62-7Njej B et al. Hepatology. 2015;61:191-199http://www.cancer.gov/cancertopics/types/liver

5 year survival rate ~70%

Early stage Disease Advanced Disease

Median survival < 1 year

• Only 46% of cases are diagnosed early

• 15-30% patients eligible for curative therapy

• 10-20% 5-year survival overall

HCC Surveillance

2011 HCC Guidelines 2018 HCC Guidelines

Bruix J et al. Hepatology. 2011;53:1020-22Heimbach JK e tal. Hepatology. 2018.;67:358-380

The AFP Controversy

• Not all tumors secrete AFP

• In tumors that secrete AFP, the concentration is related to the size of the tumor

• AFP is not specific for HCC

–May increase with inflammation and severity of disease

• AFP of 20 ng/mL only 60% sensitive and PPV 41.5%

Sherman Met al. Semin Liver Dis. 2010;309:3-16

Combined Methylated DNA and Protein Markers: An Accurate Blood-based Test for Detection of HCC

• Aim to identify panel of blood based biomarkers with improved sensitivity for early HCC

• 135 HCC cases, 305 age and liver etiology matched controls – 77% male, 88% cirrhotic

– 57.8% within Milan

• 10 methylated DNA markers (MDM) and multiple proteins

• Ultimately used 4 MDMs (DAB2IP, EMX1, HOXA1, TSPYL5) and 2 proteins (AFP, AFP L-3) with specificity set at 90%

Chalasani NP et al. AASLD 2019, Boston, MA. #109

Chalasani NP et al. AASLD 2019, Boston, MA. #109

Combined Methylated DNA and Protein Markers: An Accurate Blood-based Test for Detection of HCC

Biomarker Panel

Early Stage* Sensitivity (95%CI)

All Stage Sensitivity (95% CI)

Specificity (95% CI)

AUC (95%CI)

Exact (4MDM+2 protein)

71% (60-81%)

80% (72-86%)

90% (86-93%)

0.912 (89-94%)

AFP (20) 21% (13 –32%)

43% (35-52) 98% (95-99%)

0.706 (66-76%)

AFP (100) 6.6% (2-15%)

27% (20-36%)

100% (99-100%)

0.637 (58-69%)

AFP (5) + AFP-L3(4%)

37% (26-49%)

55% (43-63%)

94% (90-96%)

0.795 (75-84%)

* Early Stage = BCLC 0 and A

Financial Burden is Common in U.S. Patients With Cirrhosis and Associated with Lower HCC

Surveillance Receipt

• Telephone based survey of 1021 patients with cirrhosis

• April – December 2018 at safety net health system and VA

• Defined surveillance as any imaging within 1 year

• High knowledge about HCC risk and surveillance (median score 83.3% overall)– 22.7% did not know curable options existed

Singal AG et al. AASLD 2019, Boston, MA. #201




0%

10%

20%

30%

40%

50%

60%

Delays in care Borrow money oracquire debt

Unable to cover co-pays

Worry about payingmedical bills

Financial Distress is Common in Cirrhotic Patients

Parkland UTSW Houston VA




0%

5%

10%

15%

20%

25%

30%

35%

40%

Cost of testing Difficulty scheduling Uncertainty where toget US

Transportationdifficulties

Patient reported barriers to HCC surveillance

Parkland UTSW Houston VA




Consistent, 28.5

None, 26.4

Inconsistent, 45.1

Receipt of HCC surveillance in prior year

Variables Odds Ratio (95% CI)

Age < 50 (vs 61-90) 1.56 (95% CI 1.03-2.36)

Widowed (vs married) 0.59 (95% CI 0.37 – 0.93)

CPT B (vs A) 1.76 (95% CI 1.29 -2.40)

Hepatology 5.60 (95% CI 4.01-7.84)

Lack of insurance 0.53 (95% CI 0.33 – 0.86)

Financial burden resulting in medical care delays

0.73 (95% CI 0.54 -0.98)

Correlates of HCC Surveillance in year prior to survey

Outline

• Surveillance






HCV Induced Epigenetic Changes

• HCV infection cleared • Fibrosis may improve • Epigenetic changes persists

– H3K27ac changes – Continued genet expression – SPHK1, SOX9

• Cancer risk persists

Hamdane N et al. Gastroenterol. 2019;156:2313-2329

HCC Surveillance Post DAA

Who? When? How?

F4 +/- F3 fibrosis As long as they are eligible for curative

treatment

US +/- AFP

Risk varies with individual –> Personalized Approach

HCC Risk Post DAA Therapy

• Single center

• n = 565

– cirrhosis on biopsy or 11.9 kpa on Fibroscan

• 28 de novo HCCs

– Predictors – Men, Diabetes, Fibrosis

Degasperi E et al. Clin Gastroenterol Hepatol. 2019;17:1183-1191

HR (95% CI) p value

Male 6.17 (1.44-26.47) .01

Diabetes 2.52 (1.06-5.87) .03

LSM, kpa 1.03 (1.01-1.06) .01

Fib-4 1.08 (1.01-1.14) .01

Models to Predict HCC after SVR

• 45,810 VA patients – 23% cirrhosis, 74% SVR

• 1412 developed HCC

• Dramatic variation in risk

Ioannou GN et al. J Hepatol. 2018;69:1088-1098

No Cirrhosis

Cirrhosis

HCC Risk Model

• www.hccrisk.com

http://www.hccrisk.com/

HCC Risk Model

• www.hccrisk.com

Age 66 59 55

Albumin 3.6 3.1 3.8

AST 45 44 25

ALT 35 35 35

Plt 55 110 145

3 yr HCC risk 21.9% 8.9% 2.2%

HIGH RISK MEDIUM RISK LOW RISK

Intensive Surveillance

Low Surveillance

http://www.hccrisk.com/

FibroScan and HCC Risk

Masuzaki R et al. Hepatology. 2009;49:1954-61Adler MA et al. HPB. 2016;18:678-83Rinaldi L et al. Dig Dis Sc. 2019;64:3013-19

Prospective HCV study 45 fold higher risk > 25 kpa

432 patients, 50% HCVAll > 20 kpa4.8 fold higher risk > 40 kpa

Multicenter, prosp. 258 pts with HCV and cirrhosis Fibroscan > 13.5 kpaLSM > 27.8 kpaAUROC 0.691

NAFLD and HCC

• VA cohort of NAFLD patients

• n = 271,906, 22,794 cirrhosis, 253 HCC

• Risk of progression lowest with only 1 or no metabolic traits

• Stepwise increase in risk with each trait

Kanwal F et al. Hepatology. 2019 epub Nov 1

00.5

11.5

22.5

33.5

44.5

Dyslipidema Dyslipidemia andDiabetes

Dyslpidemia,Diabetes andHypertension

Adjusted Hazard Ratio for Developing HCC

Outline

• Surveillance






Reducing HCC Risk

Modify Risk Factors Prevention Future treatments

Treat Viral Hepatitis Coffee Reverse fibrosis

Reduce Alcohol use Diet Change epigenetics

Lose weight Exercise

Treat Hypertension Metformin

Reduce A1c Statins

Protective Factors

• Diet

– Adherence to Mediterranean diet associated with lower HCC risk

– Fish , vegetables, and omega 3 fatty acids

– High vegetable > fruit diet

Turati F et al. J Hepatol. 2014;60:606-11Yang Y et al. Gastroenterol. 2014;147:1031-42

Protective Factors

• Coffee

– Associated with reduced liver enzymes and decreased severity of liver disease progression

– Meta-analysis 12 studies, n=3,414

Bravi F et al. Eur J Cancer Prev. 2017;26:368-77

Healthy Lifestyle and Risk of HCC and Liver-Related Mortality in U.S. Adults

• Evaluated overall lifestyle in Nurse’s Health Study and Health Professionals Follow-up Study – 2,388,811 person years

• Exclude baseline viral hepatitis, cirrhosis or cancer

• Reviewed 5 modifiable lifestyle exposures – BMI – 18-25

– Physical activity – MET hours per week

– Smoking – none or < 5 pack years

– Diet – defined by Alternative Healthy Eating Index (AHEI)

– Alcohol – ≤ 1 per day F, and ≤ 2 per day M

• Population Attributable Risk (PAR) to estimate preventable HCC cases through healthy lifestyle

Simon TG et al. AASLD 2019, Boston, MA. #16



Lifestyle factor

% cohort Adjusted HR (95% CI)

PAR % (95% CI)

Not currently smoking

87.5 0.73 (0.59-0.98)

8 (1-15)

Healthy diet (upper 40% AHEI)

40.0 0.83(0.67-0.96)

10 (2-17)

≤1 ETOH F ≤ 2 ETOH M

69.3 0.79 (0.63-0.94)

14 (8-27)

BMI < 25 47.5 0.64 (0.40-0.85)

25 (12-38)

Exercise > 7.5 MET-hours/wk

77.5 0.65 (0.41-0.92)

22 (11-35)



Number Healthy Factors

HCC cases per 100,000 PY

0 8 (p for trend 0.0004)

1 7

2 4

3 3

≥4 2

Definition Health Lifestyle

% of cohort

Adjusted HR (95% CI)

PAR% (95% CI)

≥4 healthy factors

11.1 0.12 (0.05-0.42)

82 (47-99)


27.2 0.54 (0.38-0.72)

74 (26-92)


60.7 0.70 (0.46-0.90)

45 (19-61)

Protective Factors • Statins

– Inhibits pro-oncogenic mevalonate pathway– Meta-analysis – adjusted OR 0.63, 95% CI 0.52-0.76– Stronger association in Asian populations

• Metformin – Activates adenosine monophosphate – activated protein

kinase (AMPK) → inhibits mammalian target of rapamycin – Meta-analysis – OR 0.50, 95% CI 0.34-0.73

• Sulfonylureas (OR 1.62) and Insulin (OR 2.61) increased risk

• Beta blockers – Antioxidant and anti-inflammatory properties– Small, retrospective studies suggest an effect (HR 0.25, 95%

CI 0.06-0.45) Singh S et al. Gastroenterology. 2013;144:323-332Singh S et al. Am J Gastroenterol. 2013;108:881-891 Nkontchou G et al. Cancer Prev Res. 2012;5:1007-14

Statin Use and HCC

• Prospective Swedish cohort study

• n=16,668 with viral hepatitis

Simon TG et al. Ann Int Med. 2019;171:318-27

Outline

• Surveillance






Liver Transplantation for HCC

• Initial outcomes for HCC and OLT were poor

– Initial 5 year survival 30-40%

• Landmark work by Mazzaferro was revolutionary

– 48 patient prospective cohort study

– Patients in Milan criteria had excellent outcomes

– 4 year recurrence free survival 83%

Penn I et al. Surgery. 1991 110:726-734Iwatsuki S et al. Ann Surg. 1991 214:221-228

Mazzaferro V et al. N Eng J Med. 1996 334:693-699

Recurrence Rate = 8%

Milan UCSF

Single lesion < 6.5 cm

or

Up to 3 lesions each < 4.5 cm

and

Sum of diameters < 8 cm

Single lesion < 5 cm

or

Up to 3 lesions each < 3cm

No Extrahepatic disease

No Vascular invasion

• 4 y survival = 75%

• Recurrence = 17%

• 5 y survival = 75%

• Recurrence = 11%

Expanding Transplant Criteria Beyond Milan

UCSF Downstaging protocol

Yao F et al. Hepatology. 2015;61:1968-77

• Single lesion < 8 cm

• 2-3 lesions each < 5 cm and sum < 8 cm

• 4-5 lesions each < 3 cm and sum < 8 cm

• After treatment patient within Milan criteria AND minimum observation x 3 months

U.S. Multicenter Analysis of 2529 HCC Patients Undergoing Liver Transplantation: 10-Year Outcome Assessing the Role of

Downstaging to Within Milan Criteria

• Aim to evaluate 10 year outcomes

• 5 large US centers from 2001-2015

– UCLA, Sinai, UCSF, NYP, Wash U

• Compared MC (2086), Downstaged (330), Beyond MC (110)

• Overall 10 year

– Survival 58.3%

– Recurrence 16.7%

Tabrizian P et al. AASLD 2019, Boston, MA. #15

U.S. Multicenter Analysis of 2529 HCC Patients Undergoing Liver Transplantation: 10-Year Outcome Assessing the Role of

Downstaging to Within Milan Criteria

Tabrizian P et al. AASLD 2019, Boston, MA. #15

Predictors of downstaging failure

OR (95% CI) p value

> 3 tumors at diagnosis OR 2.30 (1.17-4.51) 0.015

Initial diameter > 7 cm OR 2.70 (1.30-5.77) 0.011

No AFP response to LRT OR 2.49 (1.24-4.49) 0.009

Predictors of poor recurrence free survival

HR (95% CI) p value

Max viable tumor > 5 cm

HR 2.49 (1.51-4.09) < 0.001

Pre-LT NLR > 5 HR 2.20 (1.39-3.47) < 0.001

Pre-LT AFP > 20 HR 1.59 (1.09-2.31) 0.015

HCC Transplant Exception Guidelines

1996 In Milan = Child C

2002 T1 = 24 T2 = 29

2003 T1 = 20 T2 = 24

2004 T1 = 0 T2 = 24

2005 T1 = 0 T2 = 22

2015 6 mo delayT2 = 28

Elevator caps at 34

20196 mo delayT2 = MMAT -3(MELD 27)

No elevator Every 3 months MELD increases until transplant

Outline

• Surveillance






Current Landscape for Advanced HCC

First Line

Second Line

Sorafenib

2007


First Line

Second Line

Sorafenib

2008


First Line

Second Line

Sorafenib

2009


First Line

Second Line

Sorafenib

2010


First Line

Second Line

Sorafenib

2016


First Line

Second Line

Sorafenib

2017

Regorafenib Nivolumab


First Line

Second Line

Sorafenib Lenvatinib

Regorafenib Nivolumab

Pembrolizumab

2018AtezolizumabBevacizumab


First Line

Second Line

Sorafenib Lenvatinib AtezolizumabBevacizumab

Regorafenib Nivolumab+/- Ipilimumab

Ramucirumab

Cabozantinib Pembrolizumab

2019

HCC Therapy

ImmunotherapyPD-1, PDL-1, CLA4

VEGF InhibitorsTyrosine Kinase

Inhibitors

- Inhibits many protein kinases (VEGFR, PDGFR, RAF)

- Sorafenib, Lenvatinib, Cabozatonib, Regorafenib

- Antibodies against VEGF reduce angiogenesis

- Bevacizumab, Ramucirumab

- Allows immune system to recognize tumor cells

- Nivolumab, Atezolizumab, Pembrolizumab, Ipilimumab

Buchbinder EI et al. Am J Clin Onc 2016;39:98-106

Nivolumab

• CheckMate 459

• Randomized phase 3 study vs Sorafenib for first line therapy

• Did not reach endpoint for overall survival – HR=0.85 [95% CI: 0.72-

1.02]; p=0.0752

• ? clear trend towards improvement in OS

Yao T, ESMO 2019

CheckMate 040:Efficacy, Hepatic Safety, and Biomarkers of Nivolumab and Ipilimumab Combination Therapy in

Patients with Advanced HCC

• Sorafenib exposed patients treated with one of 3 randomized regimens until toxicity or disease progression (n=148) – Nivo 1 mg/kg + Ipi 3 mg/kg Q3 weeks x4 doses

• Followed by Nivo 240 mg Q2 weeks

– Nivo 3 mg/kg + Ipi 1 mg/kg Q3 weeks x 4 doses• Followed by Nivo 240 mg Q2 weeks

– Nivo 3 mg/kg + Ipi 1 mg/kg Q6 weeks

• CPT A, ECOG 0-1, uninfected if viral hepatitis • 91% BCLC C

– 34% vascular invasion and 91% extrahepatic spread – 44% AFP > 400

Sangro B et al. AASLD 2019, Boston, MA. #200

CheckMate 040:Efficacy, Hepatic Safety, and Biomarkers of Nivolumab and Ipilimumab Combination Therapy in

Patients with Advanced HCC

• Similar Objective response rate (ORR)

– 32%, 31%, 31%

– Grp A complete response rate 8%

• OS 22.8 mo, 12.5 mo, 12.7 mo

• Abnormal liver tests 39%, 37%, 21%

– Hepatitis tended to start within first 5-8 weeks and then subsided rapidly (a total of 10 patients had to d/c)

• Phase 3 underway comparing to Sorafenib or Lenvatinib (Checkmate 9DW)

Sangro B et al. AASLD2019, Boston, MA. #200

Atezolizumab/Bevacizumab

• Combination PD-L1 inhibitor and VEGF inhibitor • FDA approved July 2018 based on phase 1b trial • Phase 3 –treatment naïve patients vs sorafenib• n=501 , 2:1 randomization • Atezo 1200 mg IV + Bev 15 mg/kg IV Q3 weeks• Median follow up only 8.6 months - could not estimate

OS for treatment group (NE) • OS HR 0.58 (95%CI 0.42-0.79) • Median PFS 6.8 mo vs 4.2 mo

– HR 0.59 (95% CI 0.47-0.76)

• Overall Response rate 27% vs 12% (p < 0.0001)

Cheng AL et al. ESMO Asia 2019, Singapore

55 yo M with decompensated HCV cirrhosis diagnosed with 2.8 cm HCC in 2009 - Disappointed by an underachieving


- Failed Interferon therapy - Listed for transplant and rises to

top of the transplant list - Develops progressive HCC - Receives palliative Sorafenib

stopped after 2 weeks

55 yo M with decompensated HCV cirrhosis diagnosed with 2.8 cm HCC in 2019- Disappointed by an underachieving


- Cured with 12 weeks Harvoni- Listed for transplant and never rises

high enough on the list for transplant

- Develops progressive HCC - Receives palliative Sorafenib

stopped after 2 weeks followed by immunotherapy with durable response

Take Home Points

• HCC surveillance with US +/- AFP remains standard of care (for now)

• Risk for HCC varies widely in post DAA population and NASH patients

• Medications and lifestyle modifications can reduce HCC risk

• Downstaging allows tumors as large as 8 cm • Transplant allocation changes reduce likelihood of

HCC patients being transplanted• More systemic therapies than ever before

– 3 first line , 6 second line and 2 combo

THANK YOU

Harms of Surveillance

• Cost

• Psychological harm

• Risk of unnecessary biopsy

• Over-diagnosis

– Asymptomatic tumors that would not effect patient lifespan

1,000 Cirrhotics, CPT A, > 50, x 5 years

Taylor EJ et al. Hepatology 2017;66:1546-1555

Number needed to harm = 7

Number needed to treat = 77

Over-diagnosis

Hepatocellular Carcinoma Risk Factors

Major Risk Factors Minor Risk Factors

Hepatitis B Hemochromatosis

Hepatitis C Alpha 1 antitrypsin deficiency

Alcoholic Liver Disease Autoimmune Hepatitis

NASH/NAFLD Porphyria

Wilson’s disease

El-Serag H. Hepatocellular Carcinoma. NEJM.2011;365:1118-27

Growth Rates of Untreated HCC in Patients with Cirrhosis

• Aim to quantify growth rates

• Retrospective multicenter cohort of cirrhotic patients diagnosed with HCC 2008-2017– Meet imaging criteria for HCC

– > 2 contrast enhanced images > 30 days apart before tx

– Measured single largest tumor if multifocal

– Classified • Indolent: TDT > 365 days

• Intermediate: TDT 90-365

• Rapid: TDT < 90 days

– Validated results from 2 centers in US and UK

Rich NE et al. AASLD2019, Boston, MA. #842

Growth Rates of Untreated HCC in Patients with Cirrhosis

• 3,180 HCC patients – Only 242 met inclusion

• 73.6% within Milan • Overall TDT 229 days (IQR 89-627)• Median specific growth rate 0.3% per day• Inverse relationship between TDT and size

(p =0.04)– 1-2 cm: 6.1 mo– 2-5 cm: 7.2 mo– > 5 cm: 13.6 mo

• 12% had pathology – No difference between differentiation stage and TDT

• MV analysis – indolent associated with larger HCC diameter (OR 1.15 95% CI 1.03-1.30) and inversely associated with AFP > 20 (OR 0.60 95% CI 0.37-0.98)

• T1 HCC subset (2 cm) indolent associated with non-viral hepatitis (OR 3.41 95% CI 1.08-10.80)

Rich NE et al. AASLD 2019, Boston, MA. #842

DAA therapy for HCV Infection is Associated with Increased Survival in Patients with History of HCC

• Multicenter retrospective cohort study

– 2013-2017 at 31 health systems US and Canada

• 797 patients with HCV related HCC

– Achieved complete response with HCC treatment

• Resection, ablation, TACE/TARE, SBRT

• Excluded extrahepatic HCC, DAA prior to dx, uknownHCC response and recurrent HCC within 30 days of radiographic response

– 51.9% untreated and 48.1% treated

Sinal AG et al. AASLD2019, Boston, MA. #199


• Multicenter retrospective cohort study

– 2013-2017 at 31 health systems US and Canada

• 797 patients with HCV related HCC


DAA treated (383)

Untreated (414)

P value

Within Milan

313 (82.6) 332 (80.8) 0.51

Resection 81 (21.2) 33 (8.0) < 0.001

RFA 138 (36.0) 130 (31.4) < 0.001

TACE 136 (35.5) 222 (53.8) < 0.001

TACE/SBRT/Other

28 (7.3) 28 (6.8) < 0.001

CPT A 235 (61.4) 199 (48.1) < 0.001

HCC Transplant Exception Guidelines

• Standard Candidates – Single tumor < 5 cm – 3 tumors each < 3 cm – AFP < 500 after LRT if > 1000 – No tumor thrombus or metastasis

• Downstaging Candidates – Single tumor < 8 cm – 3 tumors < 5 cm each and TTD < 8 cm – 5 tumors < 3 cm each and TTD < 8 cm – Within standard criteria after treatment and stable x 3

months


• 43 deaths during 941 person years in DA group vs 103 deaths during 527 person years in untreated


HR 0.54 (95% CI 0.33 – 0.90)

Regorafenib vs Nivolumab for HCC Patients Who Experienced Sorafenib Failure: Propensity Score Analysis

• Consecutive patients who received second line regorafenib or nivolumab between July 2015-October 2018 at Seoul University Hospital

• Retrospective propensity matched analysis • Primary end point was overall survival • 151 HCC

– 103 regorafenib – 48 Nivolumab

• Median survival 6.4 mo (95% CI 2.4-10.4) for regorafenib vs 5.9 mo for nivolumab (95% CI 3.7-8.1) was not statistically significant – Adjusted HR 0.81 (95% CI 0.48 -1.36, p =0.42)

• When controlling for baseline Alk Phos, AST, AFP, PIVKA, CPT and portal hypertension – aHR 0.48 (95% CI 0.25-0.91, p = 0.03)

Lee CH et al. AASLD 2019, Boston, MA. #331

Pembrolizumab (2nd line)

• KEYNOTE-240

• Treated with sorafenib

• Did not reach survival end point

– 18% had long lasting objective response

Finn R ASCO 2019

hepatocellular carcinoma in 2019: a new era in diagnosis ...• hepatocellular carcinoma (hcc) is...

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