Hepatocellular carcinoma: Options for diagnosing and managing a deadly disease
ABSTRACTHepatocellular carcinoma (HCC) is an important cause of death in patients with liver disease, and its incidence appears to be rising in the United States. Because early diagnosis improves the chances of survival, it is important to identify patients who would benefit from surveillance. Once HCC is suspected on surveillance, noninvasive diagnostic tests are available to make an accurate diagnosis. Treatment should be individualized, based on the characteristics of the tumor and the degree of liver dysfunction.
KEY POINTS
- Surveillance for HCC is indicated in all patients with cirrhosis, regardless of the cause of the cirrhosis.
- Liver biopsy is not needed to make the diagnosis if the findings on four-phase multidetector computed tomography or dynamic contrast-enhanced magnetic resonance imaging are typical of HCC (arterial hyperenhancement with venous-phase or delayed-phase washout).
- Many treatments are available, including surgical resection, liver transplantation, ablative therapy, perfusion-based therapy, chemotherapy, and palliative therapy.
PERFUSION-BASED LOCOREGIONAL THERAPIES
Perfusion-based locoregional therapies deliver embolic particles, chemotherapeutic agents, or radioactive materials into the artery feeding the tumor. The portal blood flow allows for preservation of vital liver tissue during arterial embolization of liver tumors. Perfusionbased therapies include transarterial chemoembolization, transarterial chemoembolization with doxorubicin-eluting beads (DEB-TACE), “bland” embolization, and radioembolization.
Transarterial chemoembolization
Transarterial chemoembolization is a minimally invasive procedure in which the hepatic artery is cannulated through a percutaneous puncture, the branches of the hepatic artery supplying the tumor are identified, and then embolic particles and chemotherapeutic agents are injected. This serves a dual purpose: it embolizes the feeding vessel that supplies the tumor, causing tumor necrosis, and it focuses the chemotherapy on the tumor and thus minimizes the systemic effects of the chemotherapeutic agent.
This therapy is contraindicated in patients with portal vein thrombosis, advanced liver dysfunction, or a transjugular intrahepatic portosystemic shunt. Side effects of the procedure include a postembolization syndrome of abdominal pain and fever (occurring in about 50% of patients from ischemic injury to the liver), hepatic abscesses, injury to the hepatic artery, development of ascites, liver dysfunction, and contrast-induced renal failure.
In addition to bridging patients to liver transplantation, transarterial chemoembolization is recommended as palliative treatment to prolong survival in patients with HCC who are not candidates for liver transplantation, surgical resection, or radiofrequency ablation.9,42 Patients who have Child-Pugh grade A or B cirrhosis but do not have main portal vein thrombosis or extrahepatic spread are candidates for this therapy. Patients such as these who undergo this therapy have a better survival rate at 2 years compared with untreated patients.43,44
Transarterial chemoembolization has also been used to reduce the size of (ie, to “downstage”) tumors that are outside the Milan criteria in patients who are otherwise candidates for liver transplantation. It induces tumor necrosis and has been shown to decrease the tumor size in a selected group of patients and to bring them within the Milan criteria, thus potentially enabling them to be put on the transplant list.45 Studies have shown that patients who receive a transplant after successful down-staging may achieve a 5-year survival rate comparable with that of patients who were initially within the Milan criteria and received a transplant without the need for down-staging.45 However, factors that predict successful down-staging have not been clearly established.
Newer techniques have been developed. A randomized controlled trial found transarterial chemoembolization with doxorubicin-eluting beads to be safer and better tolerated than conventional transarterial chemembolization.46
Bland embolization is transarterial embolization without chemotherapeutic agents and is performed in patients with significant liver dysfunction who might not tolerate chemotherapy. The benefits of this approach are yet to be determined.
Radioembolization
Radioembolization with yttrium-90 microspheres has recently been introduced as an alternative to transarterial chemoembolization, especially in patients with portal vein thrombosis, a portocaval shunt, or a transjugular intrahepatic portosystemic shunt.
In observational studies, radioembolization was as effective as transarterial chemoembolization, with a similar survival benefit.47 However, significant pulmonary shunting must be ruled out before radioembolization, as it would lead to radiation-induced pulmonary disease. Randomized controlled trials are under way to compare the efficacy of the two methods.
CHEMOTHERAPY
Sorafenib
Sorafenib is an oral antiangiogenic agent. A kinase inhibitor, it interacts with multiple intracellular and cell-surface kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and Raf proto-oncogene, inhibiting tumor cell proliferation and angiogenesis.
Sorafenib has been shown to prolong survival in patients with advanced-stage HCC.48 A randomized placebo-controlled trial in patients with Child-Pugh grade A cirrhosis and advanced HCC who had not received chemotherapy showed that sorafenib increased the life expectancy by nearly 3 months compared with placebo.47 Sorafenib therapy is very expensive, but it is usually covered by insurance.
Sorafenib is recommended in patients who have advanced HCC with vascular invasion, extrahepatic dissemination, or minimal constitutional symptoms. It is not recommended for patients with severe advanced liver disease who have moderate to severe tumor-related constitutional symptoms or Child-Pugh grade C cirrhosis, or for patients with a life expectancy of less than 3 months.
The most common side effects of sorafenib are diarrhea, weight loss, and skin reactions on the hands and feet. These commonly lead to decreased tolerability and dose reductions.47 Doses should be adjusted on the basis of the bilirubin and albumin levels.49
Other chemotherapeutic agents
Several molecular targeted agents are undergoing clinical trials for the treatment of HCC. These include bevacizumab, erlotinib, brivanib, and ramucirumab. Chemotherapeutic agents such as doxorubicin and everolimus are also being studied.
PALLIATIVE TREATMENT
Patients with end-stage HCC with moderate to severe constitutional symptoms, extrahepatic disease progression, and decompensated liver disease have a survival of less than 3 months and are treated for pain and symptom control.9
