Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide, with a 626,000 new cases reported yearly [1
]. The incidence of HCC remains high in Asia and parts of Africa, but there is clear evidence of increasing incidence in the USA and Europe, likely related, at least in part, to an increasing incidence of Hepatitis C infection. Although HCC can present in a patient with a noncirrhotic liver, cirrhosis remains the main risk factor that predisposes to the development of HCC.
Although surgical resection remains an accepted form of therapy for noncirrhotic patients with HCC, liver transplantation currently remains the optimal treatment for the cirrhotic patient. Early results with liver transplantation were unfavorable, plagued by poor survival rates and a high incidence of post-transplantation recurrence [2
]. It was not until 1996, when Mazzaferro et al. defined a subset of patients with unresectable HCC for whom liver transplantation was the appropriate treatment, now referred to as the “Milan criteria” [3
]. Transplantation within the Milan criteria (single tumor ≤5 cm in diameter, or two to three tumors ≤3 cm in diameter) resulted in overall and recurrence-free survival rates of 85% and 92%, respectively, at 4 years.
Liver transplantation for HCC with tumor burden within the Milan criteria has gained wide acceptance as a legitimate, and optimal, treatment. The excellent results obtained subsequently prompted further investigation into whether the Milan criteria could be expanded to include patients with a larger HCC tumor burden. In 2001, Yao et al. proposed expansion of the Milan criteria for HCC liver transplant candidates [4
]. Termed the UCSF criteria, these patients had a single tumor ≤6.5 cm in diameter, or two or three tumors none exceeding 4.5 cm in diameter and whose sum of tumor diameters did not exceed 8 cm. Patient transplanted within the UCSF criteria demonstrated 1- and 5-year survival rates of 90% and 75%, respectively, results which were equivalent when compared with survival rates of those transplanted within the Milan criteria.
The shortage of organs, in conjunction with the risk of HCC progression beyond the Milan criteria prompting dropout from the liver transplant waitlist, has fueled investigation into a wide array of locoregional therapies for the management of HCC in candidates awaiting liver transplantation. These therapies range from surgical resection, cryotherapy, radiofrequency ablation, percutaneous ethanol injection, microwave ablation, interstitial laser coagulation, and transarterial chemoembolization. Locoregional therapy has been proposed as a strategy to not only retard HCC progression and prevent dropout from the transplant waitlist, but also as a means of downstaging patients to within Milan criteria, and thus achieve eligibility for transplantation [5
]. In addition, pre-transplant locoregional therapy may serve a role in improving survival following liver transplantation for HCC [6
]. Data from the Scientific Registry of Transplant Recipients demonstrated improved patient and graft survival rates at 3 years for patients with HCC treated with pre-operative locoregional therapy, when compared to untreated patients (patient survival, 79% versus 75%, p
0.03; graft survival, 76% versus 71%, p
]. The optimal form of locoregional therapy has yet to be determined. Indeed, to achieve complete tumor necrosis may require multiple sessions, or even multiple forms, of locoregional therapy. Therapy not only serves as a bridge for those patients within the Milan criteria awaiting transplantation, but also may allow for those patients with tumors beyond the Milan criteria to obtain eligibility for transplantation by demonstrating a response to locoregional therapy.
HCC is highly refractory to traditional cytotoxic chemotherapy, with no evidence to date of a survival benefit from its use [8
]. The relatively chemo-resistant phenotype has prompted further investigation into the use of novel small molecule drugs for improved clinical efficacy in the treatment of HCC. Recently, the SHARP trial, a large randomized phase III study of patients with biopsy-proven advanced HCC, was completed. In this study, patients were randomized to receive either oral sorafenib or a placebo. Sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals–Onyx Pharmaceuticals), a small molecule multi-kinase inhibitor, acts via inhibition of tumor-cell proliferation and tumor angiogenesis, as well as augmentation of the rate of apoptosis. The SHARP trial was the first randomized systemic therapy trial in patients with advanced HCC which demonstrated an overall, albeit modest, survival benefit. Patients receiving sorafenib, versus the placebo group, demonstrated improvement in both overall survival (median 10.7 months versus 7.9 months) as well as time to progression (median 5.5 months versus 2.8 months) [10
]. A second phase III study of sorafenib versus placebo was completed in an Asian-Pacific population, and also demonstrated significant improvement in overall survival (median 6.5 months versus 4.2 months) as well as progression-free survival (median 2.8 months versus 1.4 months) in patients treated with sorafenib versus placebo, respectively [11
We present a remarkable case of HCC tumor response to adjuvant sorafenib therapy, with effective downstaging to allow for liver transplant listing. Although there has been demonstration of improved survival in patients with unresectable HCC treated with sorafenib, the tumor response rate of patients with HCC treated with sorafenib has remained low (2%) [10
]. However, it remains to be determined whether sorafenib, in conjunction with locoregional therapy, can prove to be either effective in preventing progression beyond the Milan criteria or facilitating downstaging to within the Milan criteria, in patients with HCC awaiting liver transplantation [12