Jean-Nicolas Vauthey, MD
Until recently, liver cancers were thought to be
incurable. Limited surgical techniques were available and only selected
patients underwent resection. Most patients received systemic chemotherapy
with little hope for meaningful palliation, prolonged survival, or cure.
Recently, a better understanding of the hepatic anatomy, improved surgical
techniques and a variety of regional treatments based on the unique dual
blood supply of the liver have led to better palliation and hope for a
cure in patients with primary and metastatic liver cancers.
Most primary liver cancers are hepatocellular carcinoma,
which is one of the most common cancers worldwide. In the United
States, there are 6,000 to 9,000 new cases of hepatocellular carcinoma
each year, an incidence similar to Hodgkin’s disease. The natural history
of hepatocellular carcinoma is a rapid, progressive course with a median
survival of eight to 20 weeks after the diagnosis is established. Until
recently, experience with hepatocellular carcinoma in the West was limited.
In Japan, hepatocellular carcinoma is the third leading cause of death
from cancer. In the East, hepatocellular carcinoma is strongly associated
with viral hepatitis and cirrhosis, and the long-term prognosis is poor.
In the West, hepatocellular carcinoma is rare and less commonly associated
with cirrhosis. A few studies suggest a slightly better prognosis.
The carcinogenesis of hepatocellular carcinoma is
unfolding. Mutations/deletions of the tumor suppressor gene p53, which
is critical in the induction of apoptosis, have been reported from a number
of geographic regions. A number of "hot spots" have been identified. In
a recent study at the University of Florida, restoration of the wild-type
p53 gene into a hepatocellular carcinoma cell line was shown to induce
apoptosis, thus supporting the theory that p53 plays a key role in
hepatocellular carcinogenesis.
Treatment Options
The management of hepatocellular carcinoma depends on
the intrahepatic and extrahepatic extent of the disease and the function
of the underlying liver. For malignant liver neoplasms, in the absence
of extrahepatic disease, resection with negative pathological margins is
the mainstay of treatment. Major typical or atypical anatomical resections
can now be carried out with low morbidity and minimal mortality. Extended
resections -- up to 75% of liver -- can be safely performed in patients
if liver function is not compromised by underlying liver disease (eg, cirrhosis,
steatosis), hypotension, infection, or ischemic injury. In the Division
of Surgical Oncology of the Department of Surgery at the University of
Florida, 80 hepatic resections were performed over the past three years
with only one operative death. The majority of patients had major resections
defined as the resection of one lobe or more. The median length of stay
was nine days. The morbidity was 18%, and only 10% of patients received
transfusions.
Numerous treatment options are available for patients
with hepatocellular carcinoma ranging from percutaneous alcohol injections
in small tumors to arterial embolization or chemoembolization in advanced
hepatocellular carcinoma. The role of transplantation is controversial.
A three-year disease-free survival of 83% was recently reported after transplantation
for uninodular and binodular tumors of less than 3 cm. In a recent study
reporting on resection for hepatocellular carcinoma, the overall five-year
survival for patients with small tumors (0 to 5 cm) was 75% vs 36% for
patients with tumors greater than 5 cm. In the same study, the overall
five-year survival of 41% compared well with the 15% five-year survival
previously reported after transplantation for hepatocellular carcinoma
regardless of size. Although most recurrences developed within five years,
late recurrences and/or new hepatocellular carcinoma continued to occur
up to 10 years following transplantation, thus illustrating the need for
long-term follow-up in these patients. Today, resection remains the mainstay
of treatment for most patients with hepatocellular carcinomas arising in
noncirrhotic liver or Child-Pugh A patients with stable cirrhosis. Vascular
invasion, defined as lymphatic or hepatic and/or portal vein permeation
by malignant cells, is the most important predictor of survival following
resection. Survival for patients without vascular invasion is 54% at five
and 10 years. Thus, a detailed histologic documentation independently predicts
the groups at risk for recurrence.
Cryoablation has recently been used as an alternative
to resection. Probes of various sizes are inserted in liver lesions under
ultrasound guidance. Liquid nitrogen is circulated in the probes, and the
tumor is destroyed by the freezing process. An iceball with a frozen margin
of 1 cm around the tumor is obtained. Based on experimental data, two freeze-thaw
cycles are necessary to achieve complete tumor destruction. Definitive
data regarding five-year survival for cryoablation of hepatocellular carcinoma
are lacking, and mortality and morbidity are variously reported. In a series
reporting an average of four cryoablated lesions per patient, the mortality
and morbidity from cryoablation were higher than those reported by most
recent series of liver resections. At the University of Florida, we have
used cryotherapy primarily as an adjunct to resection in approximately
10% of patients with primary or metastatic liver cancers because resection
can be safely performed in the vast majority of patients, even for lesions
close to major veins.
New Approaches
New techniques of hepatic artery embolization are currently
under investigation at the University of Florida for the treatment of primary
unresectable liver cancer. The rationale for this approach is based on
the fact that malignant tumors derive their blood supply from the hepatic
artery and not the portal vein and the fact that the tumor may be selectively
treated by arterial therapy. New techniques of selective and superselective
catheterization of the hepatic artery and its branches have evolved over
the past decade allowing lobar, sectoral, or segmental hepatic artery embolization.
Recently, ethiodized oil (Lipiodol) has been combined with chemotherapeutic
agents traditionally used with embolization. This allows the retention
of chemotherapy as a suspension, which diffuses slowly through small tumor
vessels. In the past, embolization was performed using agents such as coils
or nonabsorbable microspheres. This led to permanent hepatic artery occlusion
and the rapid development of arterial collaterals feeding the tumor. Current
techniques allow the hepatic artery to recanalize within days of treatment,
thus permitting repeated cycles of embolization. This new technique appears
to lessen the early development of collateral vessels.
Since January 1994, 34 selected patients have been
treated with hepatic artery embolization at the University of Florida.
This series includes 13 hepatocellular carcinoma, 11 neuroendocrine tumors,
and 10 other unresectable tumors. The median length of hospital stay was
2.2 days. Complications have been minor and have consisted mainly of the
postembolization syndrome (transient fever, nausea and vomiting, and abdominal
pain). A radiological and functional response has been noted in 63% of
patients, while a major response, defined as a reduction of 50%
or more in the size of the tumor nodules, occurred in one third of patients.
Most major responses were observed in neuroendocrine tumors including three
patients with complete functional and radiological response and significant
improvement in symptoms in all others. Future studies will investigate
this promising form of therapy as part of a multicenter study.
References
1. Vauthey JN, Klimstra D, Franceschi D, et al. Factors affecting long-term
outcome after hepatic resection for hepatocellular carcinoma. Am J Surg.
1995;169:28-34.
2. Vauthey JN, Marsh RW, Davis GL. Treatment of unresectable hepatocellular
carcinoma. N Engl J Med. 1995;333:877.
3. Vauthey JN. Liver imaging. A surgeon’s perspective. Radiol Clin
North Am. 1998;36:445-457.
4. Vauthey JN, Baer HU, Guastella T, et al. Comparison of outcome between
extended and nonextended liver resections for neoplasms. Surgery.
1993;114:968-975.
5. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for
the treatment of small hepatocellular carcinomas in patients with cirrhosis.
N Engl J Med. 1996;334:693-699.
6. Ringe B, Pichlmayr R, Wittekind C, et al. Surgical treatment of hepatocellular
carcinoma: experience with liver resection and transplantation in 198 patients.
World J Surg. 1991;15:270-285.
7. Bhardwaj G, Reiser M, Ohno T, et al. Hepatocellular carcinoma and
the p53 gene: University of Florida. Gastrointest Cancer Lett. 1997;4:1.