OncoLog

 

From OncoLog, January 2013, Vol. 58, No. 1

Compass: Hepatocellular Carcinoma

By Sunni Hosemann

Introduction

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.

Treatment options

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 tumors.

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.

Liver-directed therapies

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 external-beam radiation.

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 tumor.

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 a catheter.

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.

Systemic therapy

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 ill-defined lesions.

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 reserve.

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.”

REFERENCES

American 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.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Steven A. Curley, M.D.
Professor, Surgical Oncology

Sanjay Gupta, M.D.
Professor, Diagnostic Radiology

Ahmed Kaseb, M.B.B.S.
Professor, Gastrointestinal Medical Oncology

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

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