Hepatocellular Carcinoma Report 
 
Report prepared by Adrian M. Di Bisceglie M.D., John Richart M.D., Kirke Bieneman M.D. and Janet (Betsy) Tuttle-Newhall M.D.

 

Introduction

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death world wide.  In the United States, it is the cancer that is rising at the greatest rate.  Although HCC has long been considered to have a poor prognosis, recent innovations have been shown to considerably improve patient outcomes.

Faculty at Saint Louis University have had a long standing interest in HCC and the presence of the Liver Center has attracted patients with chronic liver disease and cirrhosis.  Many of these patients have or will develop HCC and they are subsequently managed by physicians in the Saint Louis University Cancer Center.

 

Background

a.         Epidemiology

HCC is the most common form of primary cancer of the liver.  In terms of numbers, HCC is the sixth most common cancer world wide (estimated 711,000 cases annually); however, because of its poor prognosis (survival rates 3 – 5% in cancer registries for the United States and developing countries), it is the third most common cause of cancer death (1,2).  The most significant risk factor for the development of HCC is infection with hepatitis B or C virus, causing 56% of all cases, and 92% of these occur in low- and middle- resource countries (2).

In the United States, more than 3 million people are chronically infected with hepatitis C virus.  Risk factors for contracting this virus are contaminated blood product transfusion and injected drug use.  Many of these chronically infected were exposed as young adults beginning in the 1960s.  Age adjusted HCC incidence rates in this country have tripled between 1975 and 2005.  From 2000 – 2005, marked increases in incidence rates have occurred among Hispanic, black and white middle aged men (3).  It is estimated that there will be 24,120 new cases (17,430 male, 6,690 female) and 18,910 deaths (12,720 male, 6,190 female) in the United States this year (4).  Approximately 75% of patients with HCC present with advanced, unresectable disease and some element of liver dysfunction (5). 

One of the challenges in managing patients with HCC is that it usually occurs in patients with underlying liver disease, typically cirrhosis.  On a worldwide basis, it is estimated that approximately 54% of cases are associated with chronic hepatitis B viral (HBV) infection, approximately 31% with chronic hepatitis C viral (HCV) infection and the remainder with a variety of other liver diseases including cirrhosis due to alcohol or metabolic liver diseases.  The presence of cirrhosis limits the ability to carry out surgical resection.  Furthermore, patients may often die of complications of cirrhosis and end stage liver disease rather than HCC.

b.         Diagnosis and Staging

Clinical staging systems are used to describe the extant of cancer in any given patient.  The stage of a cancer predicts treatment outcomes.  It is needed to counsel the patient and to guide treatment decisions ranging from potentially curative therapies to palliative (comfort) measures.  It also is important in selecting patients for participation in clinical trials.

The American Joint Committee on Cancer (AJCC) is a staging system that uses tumor size and spread to stratify patients with respect to predicted survival.  Four stages for HCC are assigned, with stage I being the least advanced and stage IV, cancer that has spread from the liver to other locations in the body, being the most advanced.  Median survivals for stage I HCC ranges from 50 – 90 months; for stage II HCC, they are 40 – 50 months and stage III 10 – 20 months.  The reported 5-year survival rates of stage I, II and III HCC are 55%, 37% and 16% respectively.  Survival beyond 3 years is rare for stage IV HCC with a median survival of approximately 9 months (5).

The diagnosis of liver cancer can be very challenging.  Symptoms do not generally occur until the HCC is far advanced.  For patients with known liver disease, screening imaging, ultrasound and CT scan, and blood tests are obtained regularly in order to identify cancer at a very early, potentially curable, stage.  However, cirrhosis of the liver poses a difficult challenge for interpretation of standard imaging techniques.  And even when abnormalities are seen, a biopsy can be a very dangerous as patients with liver disease are at an increased risk of major bleeding from the procedure.  Multiphasic CT scanning and dynamic MRI of the liver can diagnose HCC.  These are very sensitive and specific tests, but are they require a team of skilled radiologists and technicians.  Accuracy is crucial to guide appropriate treatment.  Figure 1 is a representative image obtained on a 3 Tesla MRI (about twice as powerful as a standard MRI) available at Saint Louis University Hospital.  The patient was thought to have early stage HCC based on CT scanning and was referred for liver transplant.  Because widespread disease was evident, transplant was deemed to be contraindicated and the patient received alternative treatments for his advanced disease.

Figure 1:  Magnetic resonance imaging for hepatocellular carcinoma using the new 3T MRI at Saint Louis University Hospital.

 

c.         Treatment of HCC

Accurate diagnosis, staging and multidisciplinary evaluation is essential to establish a treatment plan for an individual patient.  Potentially curative therapies exist for appropriately selected patients.  These include surgical and ablative approaches.  Surgery can range from minimally invasive procedures to liver transplantation.  Ablation involves guiding a needle into the tumor itself and either injecting alcohol to kill the cancer cells or destroying them with heat generated by radiofrequency waves. 

 Most patients with HCC are not candidates for curative treatment because of advanced disease at the time of diagnosis.  For these individuals, treatment goals are to prolong survival while maximizing quality of life.  Many are able to undergo localized cancer therapy such as blocking the blood supply to the cancer in a procedure called embolization.  This can be performed using microscopic beads loaded with chemotherapy or radiation emitting particles.  Chemotherapy is used to treat advanced disease and is sometimes used in combination with other surgical, ablative or embolization approaches.  The most common form of chemotherapy used in liver cancer (sorafenib) is a pill taken everyday, but other agents given in the veins are occasionally used.  Sometimes, individuals with advanced HCC respond well enough to treatment that they become candidates for curative procedures, a process called “downstaging” (see Table 2).

Table 1:  Characteristics of 202 patients with HCC treated at Saint Louis University Hospital between 2007 to 2010.

 

Patient Characteristics

 

No

 

(%, range)

 

Gender

Male

164

81%

 

Female

38

19%

Race

Caucasian

160

79%

 

African American

36

18%

 

Other

6

3%

Age

Mean (yrs)

58

19-84

AJCC stage

I

86

42.6%

 

II

58

28.7%

 

III

32

15.9%

 

IV

13

6.4%

 

Unknown

13

6.4%

Treatments*

RFA

43

21.2%

 

Transarterial chemoembolization

84

41.5%

 

Resection

13

6.4%

 

Transplantation

42

20.7%

 

Systemic chemotherapy

50

24.7%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

*Patients may have been treated with more than one modality

 

The Saint Louis University Multidisciplinary Liver Cancer Program

The purpose of the Liver Cancer Program at Saint Louis University is to provide our patients with the best cancer care available anywhere and to partner with researchers to find effective new treatments for cancer.  It is composed of a team of highly trained doctors and researchers who are experts in the diagnosis, treatment and management of HCC.  It includes hepatologists, surgeons, pathologists, medical oncologists, diagnostic and interventional radiologists as well as specialized nurses and social workers.  The team meets regularly to review cases, outline treatment plans and to follow outcomes.

Saint Louis University Cancer Center is a research institution.  We investigate new ways to better diagnose, treat and predict outcomes of HCC.  Patients diagnosed with HCC are asked to donate blood for molecular research.  We offer clinical trials of novel therapeutic agents not only for patients with newly diagnosed cancer but even those who have cancer that has progressed after treatment with all currently available treatments.

 

Outcomes of Patients with HCC at Saint Louis University

For this report, we surveyed treatments received by patients diagnosed with HCC between January 2007 and June 2010.  Outcomes were assessed through December 2010 (see Table 1).  Some of our best results are obtained with combination of local ablation and liver transplantation, as shown in table 2 and figure 2 below.

Table 2: Patients with hepatocellular carcinoma being treated with local ablative treatments (RFA and/or TACE) at Saint Louis University Hospital, 2007-2010 (Table 2a shows those who subsequently underwent transplantation while Table 2b shows those who did not).

Table 2a: Local ablation plus transplantation

 

 

No.

(%, range)

 

 

34

 

Gender

Male

27

79%

 

Female

7

21%

Race

Caucasian

28

82%

 

African American

5

15%

 

Other

1

3%

Age

Mean (yrs)

56

(46-74)

AJCC stage

I

18

53%

 

II

13

38%

 

III

3

9%

 

IV

0

0%

 

Unknown

0

0%

Outcomes

1 yr survival

 

100%

 

3 yr survival

 

100%

Table 2b: Local ablation alone

 

 

 

No.

(%, range)

 

 

79

 

Gender

Male

61

77%

 

Female

18

23%

Race

Caucasian

63

80%

 

African American

12

15%

 

Other

4

5%

Age

Mean (yrs)

69

(42-84)

AJCC stage

I

40

51%

 

II

26

33%

 

III

8

10%

 

IV

0

0%

 

Unknown

5

6%

Outcomes

1 yr survival

 

98%

 

3 yr survival

 

89%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2:  Overall survival of patients with HCC undergoing local ablative treatments (trans-arterial chemoembolization and/or radiofrequency ablation) without liver transplantation.

 

 Wherever possible, we aim for liver transplantation as being the best definitive form of therapy as it removes both the tumor itself and the underlying diseased liver from which new tumors can arise.  Table 3 and Figure 3 below summarizes the outcomes of patients undergoing liver transplantation for HCC.

 

Table 3:  Patients undergoing liver transplantation for hepatocellular carcinoma at Saint Louis University Hospital, 2007-2010.

 

 

No.

(%, range)

Gender

Male

40

80%

 

Female

10

20%

Race

Caucasian

43

86%

 

African American

6

12%

 

Other

1

2%

Age

Mean (yrs)

58

(46-74)

AJCC stage

I

26

52%

 

II

20

40%

 

III

4

8%

 

IV

0

0%

 

Unknown

 

 

Survival*

1 year graft

31/33

94%

 

1 year patient

32/33

97%

 

2 year graft

15/17

88%

 

2 year patient

16/17

94%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

*In this analysis, survival is assessed from the time of transplantation rather than from the time of diagnosis.

 

 

Figure 3:  Overall survival of patients with HCC undergoing liver transplantation at Saint Louis University Hospital, 2007 -2010.

 

 

Bibliography

  1. Parkin DM, Bray B, Ferlay J and Pisani P.  Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
  2. Fontham ETH.  Infectious diseases and global cancer control. CA Cancer J Clin 2009;59:5-7.
  3. Altekruse SF, McGlynn K A and Reichman ME.  Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485-1491.
  4. Jemal A, Siegel R, Xu J and Ward E.  Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
  5. Vauthey J, Lauwers GY, Esnaola NF, et al.  Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002;20:1527-1536

Research and publications related to hepatocellular carcinoma by Saint Louis University faculty and members of the Saint Louis University Cancer Center

1.                  Tumors and cysts of the liver.  Di Bisceglie AM, Befeler AS.  In, Feldman M, Friedman LS, Brandt LJ, eds.  Sleisinger and Fordtran’s Gastrointestinal and Liver Disease.  Ninth Edition.  Saunders Elsevier.  Philadelphia 2010.  pp. 1569-1592.

2.                  Hepatitis B and hepatocellular carcinoma.  Di Bisceglie AM.  Hepatology 2009;49:S56-S60.

3.                  Design and endpoints of clinical trials in hepatocellular carcinoma.  Llovet, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwakar J, Gores GJ for the Panel of Experts in HCC-Design Clinical Trials.  J Natl Cancer Inst 2008;100:698-711.

4.                  Cancer of the liver.  Bartlett DL, Di Bisceglie AM, Dawson LA.  in, DeVita, Hellman and Rosenberg’s Cancer:  Principles and Practice of Oncology.  Wolters Kluwer/Lippincott Williams and Wilkins.  Philadelphia.  2008.  pp.  1129-1156.

5.                  Diagnostic and therapeutic approach to hepatocellular carcinoma in the USA.  Di Bisceglie AM, Befeler AS.  Hepatology Research 2007;37(suppl 2):S251-S253.

6.                  Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma.  Comunale MA, Rodemich-Betesh L, Hafner J, Wang M, Norton P, Di Bisceglie AM et al. PLoS ONE 2010;5: e12419. doi:10.1371/journal.pone.0012419

7.                  Outcome of Sustained Virological Responders with Histologically Advanced Chronic Hepatitis C.  Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL, Lee WM, Di Bisceglie AM, Bonkovsky HL, Dienstag JL, Morishima C, Lindsay KL, Lok AS, and the HALT-C Trial Group. Hepatology 2010;52:833-44.

8.                  Des-g-carboxy Prothrombin and a-fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma.  Lok AS, Sterling R, Everhart J, Wright E, Hoefs J, Di Bisceglie AM, Morgan T, Kim H-Y, Lee W, Bonkovsky H, Dienstag J.  Gastroenterology 2010;138:493-502.

9.                  Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma. Wang M, Long R, Comunale MA, Junaidi O, Marrero J, Di Bisceglie AM, Block T, Mehta A.  Cancer Epidemiol Biomarkers Prev 2009;18:1914-1921 (Epub 2009 May 19).

10.              Mutations in the Hepatitis C Virus Core Gene Are Associated with Advanced Liver Disease and Hepatocellular Carcinoma.  Fishman S, Di Bisceglie AM, Branch A and others.  Clin Cancer Res Clin Cancer Res 2009:15;3205-3213.

11.              Lack of Association between Genotypes and Subtypes of HCV and Occurrence of Hepatocellular Carcinoma in Egypt.  Ryu S, Fan X, Xu Y, Elbaz T, Zekri A-RN, Abdelaziz AO, Di Bisceglie AM.  J Med Virol 2009;81:844-847.

12.              Clinical, Virologic, Histologic, and Biochemical Outcomes after Successful HCV Therapy: a 5 year follow-up of 150 patients.  George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Hepatology 2009;49:729-738.

13.              Incidence Of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease. Lok AS, Seeff LB, Morgan TR, Di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman and the HALT-C Trial Group.  Gastroenterology 2009;136:138-148.

14.              Hepatocyte senescence in end-stage chronic liver disease:  a study of cyclin-dependent kinase inhibitor p21 in liver biopsies as a marker for progression to hepatocellular carcinoma.  Brunt EM, Walsh SN, Hayashi PH, LaBundy J, Di Bisceglie AM.  Liver International 2007;27:662-671.

15.              Organ Donation and Utilization in the United States: 1998–2007, J. E. Tuttle-Newhall, S. M. Krishnan, M. F. Levy, V. McBride, J. P. Orlowski, R. S. Sung. American Journal of Transplantation. Special Issue: The 2008 SRTR Report on the State of Transplantation 2009;9:879-893.

16.              Kanda T, Steele R, Ray R, Ray RB. Hepatitis C virus core protein augments androgen-receptor mediated signaling. J. Virol. 82: 11066-11072, 2008.

17.              Kanda T, Steele R, Ray R, Ray RB. inhibition of intrahepatic IFN-γ production by hepatitis C virus non-structural protein 5a in transgenic mice.  J Virol. 83:8463-9, 2009.

18.              Banerjee A, Saito K, Meyer K, Banerjee S, Ait-Goughoulte M, Ray RB, Ray R. Hepatitis C virus core protein and cellular protein HAX-1 promote 5-fluorouracil-mediated hepatocyte growth inhibition. J Virol. 83:9663-71, 2009.

 

Federally funded research grants related to liver cancer held by members of the Saint Louis University Cancer Center

Ranjit Ray

Principal Investigator RO1 DK080812                      2009-2014

National Institute of Diabetes and Digestive and Kidney Diseases                                                                               

Mechanisms of Liver Disease Progression by Hepatitis C virus

The major goal of this project is to study the molecular mechanisms of insulin resistance and cirrhosis during hepatitis C virus infection.

 

Adrian M. Di Bisceglie

Principal Investigator “1 U01 DK082871-01             2008-2015 

National Institute of Diabetes and Digestive and Kidney Diseases

Midwest Hepatitis B Consortium

The goals of this project are to establish and participate in a national netwrok studying epidemiology and treatment of hepatitis B

 

Principal Investigator NO1-DK-9-2324                     1999-2010

National Institute of Diabetes and Digestive and Kidney Diseases

Hepatitis C Clinical Trial Clinical Centers: Prevention of Cirrhosis, Hepatic Decompensation and Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

 

Co-investigator N01-DK-9-2328                                2010-2011

National Cancer Institute/National Institute of Diabetes and Digestive and Kidney Diseases K, subcontract from NERI

Utility of the SCCA-IgM Biomarker for HCV-Related HCC

 

Co-Investigator 2U01 CA084951-06                                     2004-2009

National Cancer Institute

Early Detection Research Network – effect of medical treatment upon biomarker level study 

 

Ratna B. Ray.

Principal Investigator R56 AI 45144                          2005-2008

Role of hepatitis C virus NS5A protein in pathogenesis 

National Institute of Allergy and Infectious Diseases

This project studies the role of the hepatitis C viral NS5A protein in the pathogenesis of liver disease and hepatocellular carcinoma associated with HCV infection

 

 

Principal Investigator R01 CA 52799                                    1996-2008

Characterization of c-myc Promoter Binding Protein 

National Cancer Institute

This project studies the role of c-myc binding protein in the development of cancer, including hepatocellular carcinoma

 

John Tavis

Principal Investigator R01 CA126807                       2008-2012

HCV genetic variation and hepatocellular carcinoma

National Cancer Institute

The major goal of this project is to determine how natural sequence variation in the full-length HCV genome affects its oncogenic potential through a combination of genetic and functional analyses.

 

Principal Investigator  R21 CA125321                      2007-2009

Variation in NTP use by the HCV polymerase and response to therapy

National Cancer Institute        

The major goal of this project was to determine how natural variation in the HCV RNA polymerase affects its use of ribavirin triphosphate. 

Industry sponsored clinical trials of new therapies for HCC carried out at the Saint Louis University Cancer Center 2007-2010

IRB

Number

Study Sponsor

Principal Investigator

Study Title

Status

13768

Bayer HealthCare AG  

 

Alex Befeler

A Phase III randomized, placebo-controlled study of sorafenib in patients with advanced hepatocellular carcinoma

closed

14612

BMS

 

Adrian Di Bisceglie

A Phase II  Open-Label Study of Brivanib (BMS-582664), Administered Orally at a Dose of 800 mg Daily in Subjects with  Unresectable, Locally Advanced or Metastatic Hepatocellular Carcinoma Who Have Received Either No Prior Systemic Therapy or One Prior Regimen of Angiogenesis Inhibitor Therapy

closed

14642

MDS Pharma Services

 

Alex Befeler

A Randomized, Controlled Trial of TheraSphere versus Best Supportive Care for the Treatment of Advanced Hepatocellular Carcinoma

closed

16036

Bayer

 

Alex Befeler

Study Title: A Phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial chemoembolization (TACE) performed with DC bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC).

closed

16517

Abbott

 

Adrian Di Bisceglie

An Open-label, Randomized Phase 3 Study of the Efficacy and Tolerability of Linifanib (ABT-869) versus Sorafenib in Subjects with Advanced Hepatocellular Carcinoma (HCC)

Abbott M10-963

Open to enrollment