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.
LIVER TRANSPLANTATION
Orthotopic liver transplantation is the preferred treatment for patients with HCC complicated by cirrhosis and portal hypertension. It has the advantage not only of being potentially curative, but also of overcoming liver cirrhosis by replacing the liver.
To qualify for liver transplantation, patients must meet the Milan criteria (ie, have a single nodule less than 5 cm in diameter or up to three nodules, with the largest being less than 3 cm in diameter, with no evidence of vascular invasion or distant metastasis). These patients have an expected 4-year survival rate of 85% and a recurrence-free survival rate of 92% after transplantation, compared with 50% and 59%, respectively, in patients whose tumors exceeded these criteria.29
Some believe that the Milan criteria are too restrictive and could be expanded. Yao et al at the University of California-San Francisco30 reported that patients with HCC meeting the criteria of having a solitary tumor smaller than 6.5 cm or having up to three nodules, with the largest smaller than 4.5 cm, and total tumor diameter less than 8 cm, had survival rates of 90% at 1 year and 75.2% at 5 years after liver transplantation, compared with 50% at 1 year for patients with tumors exceeding these limits. (These have come to be known as the UCSF criteria.) However, the United Network for Organ Sharing (UNOS) has not adopted these expanded criteria. UNOS has a point system for allocating livers for transplant called the Model for End-Stage Liver Disease (MELD). Patients who meet the Milan criteria receive extra points, putting them higher on the transplant list. This allows for early transplantation, thus reducing tumor progression and dropout from the transplant list. UNOS allocates a MELD score of 22 to all patients who meet the Milan criteria, and the score is further adjusted once every 3 months to reflect a 10% increase in the mortality rate. However, patients who have a single lesion smaller than 2 cm and are candidates for liver transplantation are not assigned additional MELD points per UNOS policy, as the risk of tumor progression beyond the Milan criteria in these patients is deemed to be low.
Therapies while awaiting transplantation
Even if they receive additional MELD points to give them priority on the waiting list, patients face a considerable wait before transplantation because of the limited availability of donor organs. In the interim, they have a risk of tumor progression beyond the Milan criteria and subsequent dropout from the transplant list.31 Patients on the waiting list may therefore undergo a locoregional therapy such as transarterial chemoembolization or radiofrequency ablation as bridging therapy.
These therapies have been shown to decrease dropout from the waiting list.31 A prospective study showed that in 48 patients who underwent transarterial chemoembolization while awaiting liver transplantation, none had tumor progression, and 41 did receive a transplant, with excellent posttransplantation survival rates.32 Similarly, radioembolization using yttrium-90-labeled microspheres or radiofrequency ablation while on the waiting list has been shown to significantly decrease the rate of dropout, with good posttransplantation outcomes.33,34
However, in spite of these benefits, these bridging therapies do not increase survival rates after transplantation. It is also unclear whether they are useful in regions with short waiting times for liver transplantation.
Adjuvant systemic chemotherapy has not been shown to improve survival in patients undergoing liver transplantation. For example, in a randomized controlled trial of doxorubicin given before, during, and after surgery, the survival rate at 5 years was 38% with doxorubicin and 40% without.35
ABLATIVE LOCOREGIONAL THERAPIES
Locoregional therapies play an important role in managing HCC. They are classified as ablative and perfusion-based.
Ablative locoregional therapies include chemical modalities such as percutaneous ethanol injection; thermal therapies such as radiofrequency ablation, microwave ablation, laser ablation, and cryotherapy; and newer methods such as irreversible electroporation and light-activated drug therapy. Of these, radiofrequency ablation is the most widely used.
Radiofrequency ablation
Radiofrequency ablation induces thermal injury, resulting in tumor necrosis. It can be used as an alternative to surgery in patients who have a single HCC lesion less than 3 to 5 cm in diameter, confined to the liver, and in a site amenable to this procedure and who have a reasonable coagulation profile. The procedure can be performed percutaneously or via laparoscopy.
Radiofrequency ablation is contraindicated in patients with decompensated cirrhosis, Child-Pugh class C cirrhosis (the most severe category), vascular or bile duct invasion, extrahepatic disease, or lesions that are not accessible or are adjacent to structures such as the gall bladder, bowel, stomach, or diaphragm.
Radiofrequency ablation has been compared with surgical resection in patients who had small tumors. Though a randomized controlled trial did not show any difference between the two treatment groups in terms of survival at 5 years and recurrence rates,36 a meta-analysis showed that overall survival rates at 3 years and 5 years were significantly higher with surgical resection than with radiofrequency ablation.37 Patients also had a higher rate of local recurrence with radiofrequency ablation than with surgical resection.37 In addition, radiofrequency ablation has been shown to be effective only in small tumors and does not perform as well in lesions larger than 2 or 3 cm.
Thus, based on current evidence, surgical resection is preferable to radiofrequency ablation as first-line treatment. The latter, however, is also used as a bridging therapy in patients awaiting liver transplantation.
Percutaneous ethanol injection
Percutaneous ethanol injection is used less frequently than radiofrequency ablation, as studies have shown the latter to be superior in regard to local recurrence-free survival rates.38 However, percutaneous ethanol injection is used instead of radiofrequency ablation in a small number of patients, when the lesion is very close to organs such as the bile duct (which could be damaged by radiofrequency ablation) or the large vessels (which may make radiofrequency ablation less effective, since heat may dissipate as a result of excessive blood flow in this region).
Microwave ablation
Microwave ablation is an emerging therapy for HCC. Its advantage over radiofrequency ablation is that its use is not limited by blood vessels in close proximity to the ablation site.
Earlier studies did not show microwave ablation to be superior to radiofrequency ablation.39,40 However, current studies involving newer techniques of microwave ablation are more promising.41
