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Neoadjuvant Therapy for Hepatocellular Carcinoma: Is There An Optimal Approach?

Neoadjuvant Therapy for Hepatocellular Carcinoma: Is There An Optimal Approach?

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. The incidence of hepatocellular carcinoma is increasing in the United States and worldwide. Orthotopic liver transplantation (OLT) is a viable and potentially curative option for selected patients with HCC. Locoregional therapy has been used to control HCC before transplantation because of the limited number of donor organs, to prevent tumor progression, and to decrease the incidence of dropouts from the transplant waiting list. Traditionally, multiple investigational locoregional modalities such as tumor resection, radiofrequency ablation, transarterial chemoembolization, and systemic chemotherapy have been used as "bridging" therapies. While the investigation of novel neoadjuvant treatments is justified in an effort to prevent tumor progression, the absence of randomized controlled trials leaves uncertainty about the utility of these maneuvers in improving outcome. This review summarizes the current data on the different modalities used worldwide in the neoadjuvant treatment of hepatocellular carcinoma, the rationale for these approaches, efficacy, potential complications, and future prospects.

Primary hepatocellular carcinoma (HCC) is the eighth most common cancer, and is responsible for up to 1 million deaths worldwide every year. The incidence of HCC varies widely according to geographic location, with the highest incidence in sub-Saharan Africa, China, Hong Kong, and Taiwan. Distribution of HCC also differs among ethnic groups and between regions within the same country.[1]

The incidence of HCC in the United States is on the rise, with around 19,000 new cases and more than 16,000 estimated deaths expected in 2007. This rise is thought to be, at least in part, secondary to hepatitis B and hepatitis C infection.[2] It is expected that the number of patients with HCC will continue to increase over the next 2 decades. With the limited success of currently available screening strategies, most patients will present with advanced disease.

Treatment Background

HCC is usually diagnosed late in its course, with a median survival of 8 months following diagnosis.[3] While resection is the preferred treatment option, this is not always feasible because of the tumor extent or underlying liver dysfunction. After resection, the rate of recurrence is high. Recurrence occurs mostly in the remaining liver and is rarely extrahepatic.

Treatment of advanced HCC had remained stagnant following the initial pioneering work that led to an understanding of the link between cirrhosis and HCC. Recently, further headway has been achieved with the refining of criteria for orthotopic liver transplantation (OLT), which is a potential curative treatment. The purpose of OLT is to treat the underlying liver disease and eradicate the tumor. There is a worldwide shortage of liver donors, and liver transplant waiting time is a major prognostic factor, as many patients will drop off the transplant list because of disease progression. Historical data suggest that the median tumor doubling time in HCC is 3 to 6 months,[4] but the waiting time for liver transplantation continues to increase and is up to 24 months in the United States.

Neoadjuvant Therapy

Practitioners have shown increasing interest in "bridging" or neoadjuvant modalities in the management of HCC, devised in an effort to delay tumor progression and decrease the rate of dropouts from the transplant list. This strategy represents an intriguing clinical challenge, since it is not clear that any of these interventions improve overall outcome. The most common strategies used to prevent dropout of HCC patients on the waiting list for transplantation are systemic chemotherapy, chemoembolization, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and hepatic resection.

Many centers in the United States and around the world pursue some form of bridging therapy while patients are on the transplant list, even though no prospective randomized trials are being conducted. In this article, we will review the various neoadjuvant modalities and their effects on dropout rate, disease recurrence, and survival.

Radiofrequency Ablation

RFA involves the local application of radiofrequency thermal energy to the tumor. The movement of ions within the tissue heats the area, resulting in an area of necrosis surrounding the electrode. RFA is a safe and effective local treatment option, particularly for cirrhotic patients with small, unresectable hepatocellular carcinomas.[5,6]

RFA safety and efficacy, when used alone prior to liver transplant, has been evaluated in few studies (Table 1). These investigations were mostly small prospective or retrospective trials, including heterogeneous populations and using different tumor size criteria for treatment and varying types of radiofrequency generators. Johnson et al showed in a small pilot study that patients who underwent RFA were able to remain on the waiting list longer compared to those who received no neoadjuvant therapy (median: 484 vs 253 days, P = .03), thus improving their chance to receive a new liver.[7] Lu et al presented retrospective data on 53 patients who received RFA prior to OLT. The dropout rate was only 5.8%, and 1- and 3-year post-OLT survival rates were 85% and 76%, respectively.[8]

One small prospective study in 33 patients used RFA as a bridging therapy that showed promising results.[9] In this study, despite a radiologic response rate of 66%, 54% experienced progression of disease post-RFA. However, 15 of 23 candidates were successfully bridged to liver transplantation. The 3-year posttransplantation survival rate was 85%. Another prospective study in 50 patients came to a similar conclusion.[10] In this study the post-RFA complete response rate was 55% and the posttransplant 3-year survival rate was 83%. The RFA procedure was well tolerated with no mortality. Most importantly, no dropouts were reported in patients who met the Milan criteria—ie, no evidence of extrahepatic tumor, unifocal tumor mass < 5 cm in diameter or fewer than four multifocal tumors, each < 3 cm in diameter.

In summary, the lack of controlled clinical trials notwithstanding, few uncontrolled studies support the use of RFA as a neoadjuvant therapy in patients who meet the Milan criteria. In numerous small series, RFA has been shown to control tumor progression and decrease the dropout rate, but for larger tumors, the role of RFA is uncertain.

Percutaneous Ethanol Injection

Before the advent of RFA, PEI had been the most widely accepted, minimally invasive method of treating small HCC tumors. The procedure is inexpensive, requires a minimal amount of equipment, and can induce tumor necrosis and shrinkage. Histopathologic studies have shown that PEI may lead to complete ablation of about 70% of tumors smaller than 3 cm in diameter.[11] Data suggest that PEI may be equivalent to surgical resection in HCC.[12,13]

Although PEI has been replaced by RFA in many centers, it has been proposed as a neoadjuvant therapy for HCC in patients awaiting transplantation. In one small retrospective study, PEI was found to be a safe neoadjuvant therapy for HCC in patient on the liver transplant waiting list.[14] The investigators found no evidence of tumor seeding in the needle track. Pain and self-limited fever were the most frequent complications.

Another retrospective analysis looked at both PEI and RFA as methods of bridging therapy prior to OLT.[15] In this study, RFA, PEI, or a combination of both treatments produced a complete response/necrosis in 75% of patients, with the treatment proving most effective in nodules smaller than 3 cm. However, the data regarding dropout and overall survival were not available.

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