Although radiofrequency ablation (RFA) may achieve 5-year survival rates comparable to resection for patients with Stage I HCC (≤2 cm single lesion) (Lau and Lai 2009) including achieving “cure” in some cases, surgical removal of all tumor tissue is considered the only curative option for most patients. This is likely because most patients present with a more advanced stage of HCC and/or are cirrhotic with the attendant risk of ongoing hepatocarcinogenesis in the diseased liver.

Surgical resection of HCC remains a highly utilized therapy with relatively favorable survival rates, particularly for noncirrhotic patients (or highly selected cirrhotic patients) with unifocal or unilobar tumor burden (Iwatsuki et al. 1991). However, even with favorable survival, recurrence of HCC after resection is common, in some series exceeding 60 % at 3 years (Bismuth et al. 1993). Unrecognized micro-metastases in the unresected liver or in the case of cirrhotic patients, de-novo tumor formation in the diseased remnant liver parenchyma, likely account for the high recurrence rates associated with resection.

Early experience with liver transplantation (LT) for HCC was quite poor (Ismail et al. 1990; Ringe et al. 1989). However, in this era there were no standardized eligibility criteria regarding tumor size or number. Furthermore, imaging capability was relatively limited. Thus the initial low rates of long-term survival were likely driven by the inclusion of patients with large and/or multiple tumors. Mortality in such patients was driven largely by aggressive tumor recurrence after LT. In many centers HCC was considered a contraindication to LT.

At the same time, there were observations that patients with small, incidental hepatomas discovered at explant experienced low rates of HCC recurrence and fared well (Pichlmayr et al. 1994). This led to consideration of LT for patients with small HCCs. Ultimately, Mazzaferro’s seminal report of successful LT for patients meeting certain criteria to limit tumor burden for LT eligibility transformed the previous pessimism about LT in the setting of HCC (Mazzaferro et al. 1996). The so-called Milan criteria (single lesion ≤ 5 cm or up to 3 lesions none > 3 cm, no macrovascular invasion or extrahepatic spread) have since served as the most widely accepted eligibility standards for patients with HCC seeking LT in the United States. Since implementation of the Model for End-Stage Liver Disease (MELD) prioritization system for organ allocation in 2002, selected patients with HCC have been able to receive artificially increase MELD scores via MELD exception points. This policy was driven by awareness of long waiting times that led to HCC progression and waitlist “dropout” before the current system (Wiesner et al. 2004). The Milan criteria are the most commonly utilized to determine which patients are eligible for MELD exception points in the setting of HCC. As a result, HCC has become one of the most common indications for LT, being present in as much as 1/3 of transplant recipients in some UNOS regions.

Due to concerns about increasing waiting time on the transplant list, as demand for LT has grown, most transplant centers have utilized some form of locoregional therapy (LRT) in an effort to prevent growth and spread of HCC for patients awaiting LT. Although data showing that LRT confers a survival advantage after LT has been limited, LRT is widely utilized as a bridge to transplantation. The goal of LRT in this setting is to preserve patients’ eligibility for LT by preventing waitlist dropout that could result from unchecked tumor progression. Transarterial chemoembolization (TACE) and RFA have been the most commonly utilized LRTs in patients awaiting LT. Increasingly, intra-arterial delivery of drug-eluting beads (DEBs) impregnated with doxorubicin and Yttrium-90 microspheres (radioembolization) have been employed.