By Sunni Hosemann
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver.
This discussion addresses HCC that is confined to the liver (has not
metastasized to distant sites). Although traditional TNM staging is
used to guide treatment decisions for many cancers, it is less useful
for guiding HCC treatment because it does not take into account the
liver disease that often accompanies liver cancer—an important
determinant of therapy.
The current 5-year overall survival rate for patients with very
early-stage liver cancer who undergo surgical resection or liver
transplantation is 50%–70%. However, these treatment options are
available to very few patients because most liver cancers are not
discovered until they are more advanced or occur in patients who are
not candidates for liver transplantation or for whom a matching organ
cannot be found. Thus, the 5-year overall survival rate for patients
with liver cancers of any stage is about 15%.
According to Ahmed Kaseb, M.B.B.S., an assistant professor in the
Department of Gastrointestinal Medical Oncology at The University of
Texas MD Anderson Cancer Center, it is useful to consider liver cancer
not as a disease but as a syndrome wherein the cancer itself is one
component and underlying disease in the liver is the other. “Two
patients with the same stage liver cancer but differing health in the
rest of the organ would likely need different treatments,” he said.
“Treatment must be personalized to both conditions.”
As many as 90% of patients diagnosed with HCC have underlying
cirrhosis, and the risk factors for developing cirrhosis and HCC are
the same—infection with hepatitis B or C virus and chronic alcohol use
are the most prevalent. Liver disease caused by environmental exposure
or autoimmune or hereditary conditions is less common. Nonalcoholic
steatohepatitis—fatty infiltration of the liver associated with
obesity, metabolic syndrome, and diabetes—is an increasingly important
factor in the development of HCC and affects patients who are younger
than the traditional population of patients with liver disease, said
Steven Curley, M.D., a professor in the Department of Surgical
Oncology. Patients who have more than one of the known risk
factors—chronic viral hepatitis and alcohol use, for example—are at
heightened risk of developing HCC.
“Patients with chronic hepatitis B or C infections are at risk for the
development of HCC and should be followed closely,” Dr. Curley said.
“Ultrasonography and serum α-fetoprotein monitoring are cost-effective
methods for that purpose.”
HCC may present as a solitary tumor or as multiple, sometimes diffuse,
liver lesions. HCC tends to spread within the liver first and then to
distant sites. Without treatment, HCC results in liver failure and
death, often within weeks or a very few months.
Surgery: resection or transplantation
According to Dr. Curley, surgery—either resection or liver
transplantation—is the preferred primary treatment option and is
potentially curative for patients whose disease is confined to the
liver and consists of a single tumor or a few small, well-defined
Cancer that involves lymph nodes or has spread to distant sites
precludes surgery. “Unfortunately, fewer than 10% of our patients are
surgical candidates,” Dr. Curley said.
Another consideration in establishing candidacy for any surgery is
whether the patient is able to tolerate the proposed operation.
Performance status compromised by the cancer itself or comorbidities
stemming from advanced cirrhosis, such as portal vein hypertension or
esophageal varices, often render patients ineligible for surgery. For
serious surgical procedures like liver resection, some patients who
might not do well in other settings can be successfully operated on in
high-volume centers where extensive supportive care is available.
Other considerations are whether the size and location of the tumor(s)
permit the cancer to be completely resected and whether the remaining
liver (future liver remnant) will be adequate. Patients without
cirrhosis require at least 20% of the liver to remain after resection;
those with early-stage cirrhosis require 40% or more; and patients with
advanced cirrhosis usually are not candidates for resection. If the
cancer can be completely resected and the future liver remnant is
adequate, resection is the recommended treatment.
Resection alone results in prolonged survival and, in select patients,
a cure; however, resection is associated with a high rate of
recurrence—presumably due to occult disease.
Liver transplantation offers the best possibility of a cure for HCC
because it addresses the cancer itself as well as the underlying
cirrhosis that most often accompanies HCC. However, the criteria for
transplant eligibility are narrow, and patients who meet them can face
a long wait for a donor organ to become available.
Transplant eligibility is determined by the Milan criteria, proposed by
Mazzaferro et al. in 1996 for the purpose of selecting patients who
would most benefit from receiving transplant organs. Meeting these
criteria are patients with single tumors no larger than 5 cm in
diameter or three or fewer tumors no larger than 3 cm in diameter and
with no evidence of vascular invasion or extrahepatic disease.
There are ongoing efforts to refine the Milan criteria to account for
the length of time a patient has been waiting for an organ and for
potential death during the wait. Other attempts to widen the criteria,
particularly for tumor size, remain controversial. Meanwhile, the
United Network for Organ Sharing reports that more than 16,000 patients
in the United States are currently waiting for a liver to become
available for transplantation.
Because most patients with HCC are not good candidates for surgical
resection or transplantation, liver-directed therapies for HCC have
become increasingly important. These procedures are carried out by
interventional radiologists under image guidance (computed tomography,
magnetic resonance imaging, or fluoroscopy) and include several
techniques that can be customized to treat tumors that would otherwise
be untreatable or would be treated with a less focused modality such as
According to Sanjay Gupta, M.D., an interventional radiologist and a
professor in the Department of Diagnostic Radiology, liver-directed
therapies for HCC fall into two broad categories: ablation and
embolization. Ablation is a needle-based application to tumor tissue of
a chemical (ethanol) or thermal energy (heat or freezing) to
effectively destroy the tumor. Radiofrequency, laser, or microwave
energy sources may be used for thermal ablation. Embolization is the
selective occlusion of blood vessels to prevent blood from reaching the
Embolization techniques take advantage of the liver’s unique blood
supply, wherein the portal vein supplies the organ with 75% of its
blood and the hepatic artery supplies the remaining 25%. Liver tumors
are typically fed by the hepatic artery, so embolizing branches of this
vessel can effectively deny tumor tissue its blood supply. This is
accomplished by injecting microspheres into the hepatic artery through
Bland embolization uses microspheres alone, but chemotherapy drugs can
be added to deliver a high drug dose directly to the tumor without the
side effects that systemic therapy would have. Although chemotherapy
drugs were formerly injected via the catheter as solutions, a more
recent development is the use of drug-eluting beads—microspheres that
can sequester the drug (most commonly doxorubicin) and release it in a
controlled and sustained way. This prolongs drug contact with cancer
cells and leads to tumor necrosis while reducing potential damage to
hepatic tissue. Similarly, microspheres impregnated with yttrium 90 may
be introduced via the catheter to deliver a higher dose of radiation to
tumor tissue with less exposure to normal tissue than would be possible
using an external radiation source.
According to Dr. Gupta, these techniques are customized to individual
patients, and a combination of techniques may be used. Generally,
ablative techniques are used for small tumors (3–5 cm) or where there
are few lesions (five or fewer lesions ≤ 3 cm). “This is best used
where there is a chance of killing the entire tumor and creating
tumor-free margins,” Dr. Gupta said. He added that studies have shown
thermal ablation to be superior to chemical ablation with ethanol in
treating small, well-defined lesions. However, if a tumor is near
another organ or a major blood vessel that could be damaged by the
application of heat or cold, then chemical ablation is safer. The
presence of an adjacent blood vessel can also reduce the local
temperature as the blood flow carries away the heat caused by thermal
ablation, resulting in inadequate thermal exposure for a portion of the
tumor tissue. In such situations, Dr. Gupta often ablates half the
tumor thermally and the other half chemically. For tumors larger than 5
cm or for multiple tumors larger than 4 cm, there is less possibility
of complete tumor eradication. In such cases, Dr. Gupta prefers using
chemoembolization to debulk the tumors. For lesions that are less
defined—that is, more diffuse—radioembolization is considered.
“All of these techniques can be used as stand-alone treatments or as a
bridge to other treatment,” Dr. Gupta said. In some patients, for
example, tumors that have been debulked using thermal or chemical
ablation can then be resected. In other patients, the techniques can be
used to downstage the disease to render a patient eligible for a
transplant. For patients who are awaiting a liver transplant, ablation
or embolization can be used to keep the disease at bay until an organ
is available. “The wait for a transplant organ can be quite long, and
uncontrolled disease progression during that time can mean that a
patient becomes ineligible and is thus denied potentially curative
treatment,” Dr. Gupta said.
“It is notable that these procedures can themselves result in long-term
survival if done properly,” Dr. Curley said. He noted that this is
particularly true for patients with small, early-stage tumors located
deep in the right lobe of the liver.
Portal vein embolization is another interventional strategy that can be
employed for patients who are not candidates for surgical resection
because of an inadequate future liver remnant. This procedure can be
used to block blood flow and cause atrophy on one side of the liver,
which causes hypertrophy on the other side, thus taking advantage of
the liver’s unique regenerative capability and increasing the amount of
functional liver tissue that would remain after resection.
External-beam radiation therapy
External-beam radiation therapy is an option for patients in whom
liver-directed therapies are not possible because of performance status
or comorbidities. When external-beam radiation is used,
three-dimensional conformal, stereotactic, or proton therapy is
preferred to target tumor tissue and minimize the radiation dose to
surrounding liver tissue.
Traditional chemotherapies have proven ineffective against liver
cancers and until recently were used only in palliative care, according
to Dr. Kaseb. The 2007 advent of the oral multikinase inhibitor
sorafenib added a much-needed treatment for HCC. Sorafenib is an option
for patients with advanced disease that is not amenable or not
responsive to other approaches, such as patients with infiltrative or
At MD Anderson, sorafenib is being given to patients with unresectable
HCC in combination with yttrium 90 radioembolization, a treatment that
requires close collaboration between medical oncologists and
interventional radiologists. Also, the combination of bevacizumab and
erlotinib is being studied in a clinical trial for patients whose HCC
progressed during treatment with sorafenib.
Dr. Kaseb said that local and systemic therapies are particularly
important for patients whose comorbidities preclude surgery. “The goal
is to extend life and improve quality of life for these patients,” he
said. “These therapies focus on tumor control and can delay progression
to liver failure, which is a more imminent cause of death from this
disease than distant metastases.”
On the horizon
Systemic therapy for HCC is an area of ongoing research. “At MD
Anderson, we are studying neoadjuvant chemotherapies aimed at
downsizing disease to fit criteria for resection or transplant,” Dr.
Kaseb said. This includes more aggressive therapies for patients who
have single metastases that are resectable or treatable.
According to Dr. Kaseb, the trend will be toward increasingly
personalized treatment for this complex and serious disease. For
example, researchers hope to identify biomarkers that will help
stratify HCC patients for treatment based on their functional hepatic
Because it often occurs in a cirrhotic liver and because of its
numerous possible treatments, HCC is a condition that usually requires
the coordination of a number of specialists, potentially including
medical, surgical, and radiation oncologists, hepatologists, diagnostic
and interventional radiologists, and transplant surgeons. “This is a
complex two-in-one disease, and referral to a multidisciplinary center
is desirable,” Dr. Kaseb said. “But we are happy to hear from community
physicians who would like to consult us about their patients as well,
and we encourage them to contact us.”
Cancer Society. Liver Cancer.
El-Serag HB, Mason AC. Rising incidence of hepatocellular cancer in the United States. N Engl J Med 1999;340:745–750.
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.
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology, Hepatobiliary Cancers, V2.2012 [registration required].
The University of Texas MD Anderson Cancer Center. Practice Algorithms:
Hepatocellular Carcinoma, V3.2012 [PDF].
United Network for Organ Sharing.
World Health Organization. Fact Sheet No. 297, February 2012.
The University of Texas MD Anderson Cancer Center
Steven A. Curley, M.D.
Professor, Surgical Oncology
Sanjay Gupta, M.D.
||Ahmed Kaseb, M.B.B.S.
For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
articles in OncoLog, January 2013 issue:
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