New Developments in Hepatocellular Carcinoma

November 19, 2003

Medscape coverage of: 54th Annual Meeting of the American Association for

the Study of Liver Diseases

Disclosures

S. Befeler, MD

Introduction

Hepatocellular carcinoma (HCC) is usually diagnosed in the background of

chronic liver disease with cirrhosis, and has been estimated to result in up

to 1 million deaths per year worldwide.[1] Unlike many other cancers in the

United States, the incidence and mortality of HCC are growing. After

analyzing several national databases, El-Serag and Mason[2] reported a 41%

increase in mortality and a 70% increase in incidence of HCC when comparing

the period 1976-1980 with 1991-1995. Further analysis from the late 1990s

shows continuing increases in age-adjusted incidence rates. The most recent

estimates from the American Cancer Society predict that in 2003 there will

be 17,300 new cases of, and 14,400 deaths from, HCC in the United States.[3]

Hepatitis C-related cirrhosis is thought to be the main cause of the recent

increase in incidence and mortality due to HCC.[2] Approximately 2.7 million

individuals are actively infected with hepatitis C virus (HCV) in the United

States, and up to 186,000 of these persons could develop HCC over the next

20 years.[1]

After diagnosis of HCC, overall survival is often poor, with half of

patients succumbing to the disease in the first year. Survival is tightly

linked to the size of the tumor, the number of tumor foci, and the

underlying hepatic function. Liver transplantation provides the best

possible chance of long-term survival because it achieves the widest

possible resection margins -- it removes the entire liver which is at high

risk of de novo tumor and replaces the poorly functioning cirrhotic liver.

If Milan criteria (no evidence of extrahepatic tumor and unifocal tumor mass

< 5 cm in diameter or multifocal tumors < 4 in number, each < 3 cm in

diameter) are followed, survival after liver transplantation is as good as

other indications for transplantation.[4] Unfortunately, only a small

proportion of patients diagnosed with HCC in the United States are

candidates for curative treatments such as liver transplantation or hepatic

resection because of either tumor size or lack of hepatic reserve. Thus,

prevention of HCC, or at least early detection that enhances the chance for

curative treatment, may provide the best opportunities to reduce the

predicted increases in mortality. These strategies depend on a better

understanding of the epidemiology and pathogenesis of HCC.

New information presented at the 54th Annual Meeting of the American

Association for the Study of Liver Diseases may help achieve the goal of

improved survival in patients with HCC. This report focuses on the most

important data presented at this year's meeting, as related to epidemiology,

early detection markers, treatment, and prevention of HCC.

New Findings in the Epidemiology of HCC

One of the keys to effective early detection is an understanding of the

epidemiologic risk factors for HCC; this will permit the medical community

to focus its limited resources on those individuals at highest risk for

disease. Currently, the best understood risk factors for HCC include

cirrhosis related to hepatitis B and C. Marrero and colleagues[5] presented

a case-control study which demonstrated that heavy alcohol consumption, body

mass index (BMI) > 30, and tobacco smoking > 15 pack-years were significant

independent predictors of HCC, with odds ratios of 1.73, 2.8, and 4.3,

respectively. Conversely, a French group using a retrospective cohort

methodology found that smoking had no effect, but confirmed that obesity and

especially insulin resistance were strong predictors of HCC.[6] Marrero and

coworkers' study is limited by its small size and inclusion of a combined

" normal " and cirrhotic control group, and the French study is limited by

lack of quantification of tobacco consumption and insulin resistance. If

tobacco consumption and BMI are confirmed in larger population-based studies

as risk factors for HCC, this knowledge may be used to enhance the

effectiveness of surveillance and early detection.

The relationship of race to HCC was also examined. Population-based

databases reveal that rates of HCC in blacks are more than twice that in

whites.[3] Yu and colleagues[7] presented an analysis of hospital admissions

for HCC and showed that black patients with HCC were significantly younger

in age than white patients, but that there were no differences in rates of

curative treatment or survival. HCC may have a more important impact on the

lifespan of blacks with chronic liver disease. This argues for focusing more

resources on this segment of the population. Although concerning, further

analysis to correct for differences in the age distribution of blacks vs

whites in this setting is needed before changing surveillance policies.

Hepatitis B is the major risk factor for HCC in Alaskan Natives and Asians

in the United States. Some Asian studies suggest an association between

hepatitis B virus genotype B or C and HCC. In a case-controlled study,

Livingston and colleagues[8] showed a 9-fold increased risk of HCC for

hepatitis B in Native Alaskans with genotype F. The genotype F cases were

also much younger than nongenotype F cases. This study demonstrates the

importance of viral-host interactions in the development of HCC. Perhaps

genotyping of hepatitis B will become a tool for identifying HCC risk in

certain populations.

Serum Markers of HCC

In combination with epidemiologic risk factors, serum markers for the early

detection of HCC are clearly needed. Although, alpha-fetoprotein (AFP) level

is commonly used in surveillance for HCC in the United States, its utility

for screening as opposed to diagnosis is controversial.

Data presented from the 1136 patients in the lead-in phase of the HALT-C

(Hepatitis C Antiviral Longterm Therapy against Cirrhosis) study

demonstrated that 12% had AFP levels between 25 and 200 ng/mL.[9] Only 1

patient developed HCC in subsequent follow-up, suggesting that the positive

predictive value of an elevated AFP level was very poor in nonresponders to

HCC treatment. Furthermore, there were significant decreases in AFP level in

all patients on pegylated interferon therapy, except for the patient who

eventually developed HCC.

Additional data were presented on other tumor markers, such as DCP

(des-gamma-carboxy prothrombin) and L-3 fraction of AFP. Unfortunately,

these studies did not provide any clear conclusions regarding the utility of

these markers in the setting of HCC surveillance. A new marker, GP-73, is

potentially useful for HCC detection.[10] It is a Golgi membrane protein

present in increasing levels in the serum of patients with viral hepatitis,

cirrhosis, and HCC. Confirmation of its discriminate ability for early HCC

and development of a reliable enzyme-linked immunosorbent assay test are

essential to further validate use of GP-73 as a screening tool for HCC.

Liver Transplantation

Many studies evaluating the relationship between liver transplantation and

HCC were presented during these meeting proceedings. Although orthotopic

liver transplantation (OLT) has been recognized as the most effective means

of treating patients with HCC who meet Milan criteria, its clinical utility

has been limited by long waiting times for transplantation, with frequent

deaths while on the waitlist, which substantially decreases the

intention-to-treat survival of these patients.

In February 2002, allocation of organs for OLT in the United States changed

to the model for end-stage liver disease (MELD) system. The latter provided

significant advantages to patients with HCC. Freeman and colleagues[11]

presented data from the first 10 months under the MELD liver allocation

system. HCC became a major indication for OLT during this period,

representing 23% of all adult liver transplantations. Less than 7% of

potential candidates with HCC were removed from the waiting list for tumor

progression or other causes. Based on a review of 84% of the explant

pathology reports, at least 30% of patients with HCC exceeded Milan

criteria, with 20% having stage 4 disease. These findings are concerning

because exceeding Milan criteria, especially stage 4 disease, will lead to

high rates of tumor recurrence and patient mortality. On the other end of

the spectrum, more than 20% of those individuals who underwent

transplantation for HCC may not have had any evidence of HCC on further

evaluation. These outcomes indicate a significant effect of transplant

center " gaming. " The most recent changes in organ allocation policy

hopefully will limit this situation.

Yao and colleagues[12] presented data evaluating pretransplant

chemoembolization or ablation for HCC. They found equivalent 5-year

tumor-free survival (88.5% vs 93.8%, respectively) for proposed " expanded

tumor criteria " (unifocal tumor mass < 6.5 cm in diameter or multifocal

tumors, < 4 in number, each < 4.5 cm in diameter with total tumor diameter <

8 cm) compared with tumors meeting Milan criteria, but significantly worse

outcomes for those exceeding " expanded tumor criteria " (59.3% for stage IIIB

and 27.8% for stage IV). These data are limited because tumor size was based

on transplant explants rather than on preoperative radiologic evaluation.

This analysis combined with those of Freeman and colleagues[11] suggests

that posttransplant recurrence and resulting mortality will increase in the

coming years in the United States. Yao and his group[12] also found improved

tumor-free survival with neoadjuvant therapy, but overinterpretation of the

study is cautioned because it is unclear how many patients did not receive

OLT secondary to complications of treatment.

Cortes and colleagues[13] presented a study comparing outcomes in patients

who underwent OLT for HCC (primary liver transplantation) with those who

underwent OLT with a history of prior hepatic resection for HCC (secondary

liver transplantation). They found no differences in survival between the

patients who had prior resection and those who did not undergo liver

resection for HCC prior to transplantation, after a median follow-up of 32

months. Although this study suggests that resection prior to potential OLT

can be effective, it is severely limited by the fact that the number of

patients who did not reach transplantation as a result of the resection was

not presented.

Local Ablative Therapies

The popularity of potentially curative local therapy with radiofrequency

ablation (RFA), either as primary treatment or adjuvant treatment for HCC,

is growing. There is only limited information about complication rates,

especially needle implantation, in the published literature. Kasugai and

colleagues[14] presented the largest series on RFA to date (2614 patients)

and showed a clinically important complication rate of 7%, with only 0.5%

3-month mortality and only 3 cases of needle implantation.

Andriulli and colleagues[15] compared 452 patients with HCC meeting Milan

criteria who were treated with percutaneous ethanol injection (PEI) because

OLT was unavailable locally, vs 210 patients who received OLT for HCC. They

found significant differences in 5-year survival rates -- 61% vs 35%

favoring OLT. This finding occurred despite the fact that the patients who

received PEI had better initial hepatic function. This study demonstrates

the superiority of OLT in this setting, but these findings need to be

reanalyzed using intention-to-treat methodology to make a more convincing

argument.

Systemic Chemotherapy

Systemic chemotherapy is sometimes used as palliation for patients with HCC

who are not amenable to surgery or local therapies. Success is variable and

often limited by underlying cirrhosis. No agent is accepted as the standard

of care, and new, less toxic agents are actively being investigated.

Allgaier and colleagues[16] presented early results of a randomized,

placebo-controlled trial of long-acting octreotide* for patients with HCC

not amenable to treatment with surgery or local therapy. Unfortunately,

initial analysis showed no difference in survival. MacKenna and

colleagues[17] presented early data on a modified form of araC

(cytarabine),* a cell cycle inhibitor, in in vitro and animal models of HCC.

The modification technology leads to higher levels of drug in the liver and

the HCC while limiting systemic toxicity. The latter shows the potential for

designing chemotherapy agents to target hepatic tissues. Gish[18] reported

safety data from a clinical trial of nolatrexed dihydrochloride,* an

inhibitor of thymidylate synthase. This study is probably the only ongoing

registration trial in the United States for a chemotherapeutic agent against

HCC. The safety profile appeared reasonable, and clinical results are

eagerly awaited. Obi and colleagues[19] described a pilot study of hepatic

artery infusion of 5-fluorouracil* in combination with interferon*

subcutaneously for patients with HCC and portal vein invasion. A patient

with this disease profile would generally be sent to hospice care in the

United States, so the results must be viewed with caution. Remarkably, these

investigators saw a 53% response rate (22% with complete responses), leading

to an overall 1-year survival of 38%. If confirmed by an ongoing prospective

controlled trial, this strategy will represent the first treatment available

for this patient population.

Prevention

Because of the often limited options available for the treatment of HCC and

the poor overall survival, prevention is a very attractive strategy. The

only currently proven means of prevention are hepatitis B vaccination and

eradication of HCV with interferon before the onset of advanced fibrosis.

Liaw and colleagues[20] presented the first evidence that patients with

hepatitis B-associated cirrhosis treated with the nucleoside analogue

lamivudine had a significant reduction in the rate of HCC development, with

an odds ratio of 0.49. They also showed that there was a dramatic reduction

in progression to decompensated liver disease. Taken together, these results

are leading to an evolution in the treatment of hepatitis B-associated

cirrhosis and provide hope that future development of protease and/or

polymerase inhibitors for HCV will lead to a similar transformation in the

treatment of this more common disease.

Results of several studies describing the role of cyclooxygenase and

retinoids in the pathogenesis of HCC in in vitro and in vivo models were

also presented. Although the findings may provide the basis for clinical

trials of cyclooxygenase-2 inhibitors and retinoids in the chemoprevention

of HCC, enthusiasm needs to be tempered because of the potential toxicity

associated with these agents and the difficulty of designing trials in

chemoprevention.

Concluding Remarks

Liver transplantation is the major mode of curative treatment for HCC in the

United States. New developments indicate that it may be possible to modestly

expand the size of " acceptable tumors " (for treatment). The latter already

seems to be the case since adaptation of the MELD system for organ

allocation, but such implementation may have gone too far in this setting.

Local ablative and regional therapy remain as options for other patients and

appear to be reasonably safe, if not as effective, as OLT. Some new

chemotherapeutic agents are in development, but none have demonstrated

efficacy yet. Thus, prevention and early diagnosis of HCC remain

appealing --although difficult -- goals to achieve. Clues from epidemiology,

understanding hepatocarcinogenesis, and effective treatments for viral

hepatitis will all help lead the way to more effective strategies in this

setting.

*The United States Food and Drug Administration has not approved this

medication for this use.

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November 19, 2003