Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for about 90% of primary malignant liver tumors in adults. It is the sixth most common cancer and the third most common cause of cancer-related death worldwide.[1] While HCC is more prevalent in Asia and Africa, its incidence has been growing in the United States and Europe, secondary to discovery of hepatitis C infection in patients who have remained asymptomatic for many years since the diagnosis.[2]
Surgical resection and orthotopic liver transplantation (OLT) offer the only potentially curative treatment options. Surgical resection of HCC is usually reserved for patients with well preserved hepatic function, intact hepatic vasculature, and no evidence of portal hypertension. However since surgical resection usually leaves a diseased liver in place, patients treated with these methods have recurrence rates of 50% at 3 years and 70% at 5 years, and this complication still represents the main cause of death.[3,4] The most recent meta-analysis addressing adjuvant treatment after hepatic resection showed no benefit from either systemic or local therapy in terms of preventing recurrences.[5]
On the other hand, OLT is a more viable option for curative treatment as it addresses both the underlying liver pathology and HCC. The fairness of organ distribution among non-HCC and HCC patients continues to be a matter of debate.
Early experience with OLT in HCC was disappointing due to high recurrence rates and poor overall survival.[6] But a landmark study by Mazzaferro et al showed that patients with single tumor ≤ 5 cm, or up to three separate lesions with none larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases, (now known as the Milan criteria) had a 4-year survival of 85%.[7] The current system allows extra MELD (Model for End-stage Liver Disease) score points in patients with HCC who are within Milan criteria. With such criteria, however, few HCC patients were eligible for OLT. Yao et al from the University of California, San Francisco (UCSF) tried to overcome this issue with their own expansion of the Milan criteria (Table 1). In a retrospective study, authors showed that outcomes using UCSF criteria were comparable to those based on the Milan criteria, with an overall survival of 90% and 75.2% at 1 and 5 years, respectively.[8]
More recently, Silva et al suggested different criteria (Table 1) and showed that 5-year survival and recurrence rates were also comparable to those using the Milan criteria.[9] However, these patients are still at risk for recurrence for many reasons including intraoperative dissemination of tumor caused by extensive manipulation of the native liver, undetected micrometastases prior to surgery, and acceleration of tumor growth by immunosuppression. A recent study looking at salvaged blood during surgery showed that up to 50% of salvaged samples were contaminated with tumor cells and responded to leukocyte depletion filters. This suggests a possible role in recurrence secondary to manipulation of the native liver, although this needs to be studied in more depth.[10]
There are no standard adjuvant treatments after OLT. But with the recent approval of sorafenib (Nexavar) in advanced HCC, there has been a renewed interest in adjuvant treatment for HCC. A large global study is currently underway (the Sorafenib as Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma [STORM] trial), looking into sorafenib therapy after potentially curative treatment with liver resection or radiofrequency ablation. This review will discuss adjuvant treatment in patients with HCC who have undergone OLT and possible future directions for management in this setting.
Prognostic Factors for Disease Recurrence After OLT
Patients who meet the Milan criteria and undergo OLT tend to have a favorable outcome, as actuarial 4-year survival and recurrence-free survival rates of 85% and 92% are achieved. However, those beyond the Milan criteria can present with both intra- and extrahepatic posttransplant recurrence, accounting for reduced survival. Therefore, it is important to identify prognostic factors that can predict high risk of tumor recurrence.
Registry review of 800 HCC patients who underwent OLT showed that nodal metastasis, tumor size > 5 cm, and histologic grade (G3 and G4) were significant predictors of a decreased probability of patient survival. Recurrence-free survival was influenced by node status, bilobar spread, tumor size > 5 cm in diameter, and vascular invasion.[11] Other studies indicate that alpha-fetoprotein levels > 1,000 ng/mL, poorly differentiated histology, age ≥ 55 years, and tumor diameter > 8 cm were associated with a reduced 1-year survival of 50%.[8] A study by Kirimlioglu et al showed that vascular invasion was the strongest predictor of disease recurrence after OLT.[12] In the absence of macroscopic or large-vessel invasion, they showed that the largest tumor size, apoptosis/mitosis ratio, and number of tumors were independent predictors of disease-free survival. Since HCC is a highly angiogenic tumor, some data suggest that vascular endothelial growth factor receptor 2 (VEGFR-2) expression was associated with poor differentiation and tumor progression.[13] Unfortunately, there are currently no effective methods to diagnose pretransplant microvascular tumor spread, despite the advances in imaging studies, and even though small studies have tried to use positron-emission tomography (PET) scan to predict tumor recurrence. In other studies, VEGF expression in HCC have been shown to correlate with shorter overall survival.[14]
