**4.3.2 University of California, San Francisco (UCSF) criteria**

Several groups have carried out studies in an effort to determine if patients with hepatocellular carcinoma exceeding Milan criteria could have similar survival and recurrence-free rates than those within the criteria. Yao and his colleagues from the University of California, San Francisco (UCSF) were the first to challenge the parameters set by the Milan criteria. In their retrospective study, cirrhotic patients with a single tumor up to 6.5 centimeters, or up to three lesions none larger than 4.5 centimeters, and total tumor diameter of no more than 8 centimeters had a 1-year and 5-year overall survival of 90% and 75.2%, respectively (Yao, 2001). The UCSF criteria were validated by the same group when they prospectively demonstrated comparable recurrence-free survival between the patients meeting Milan criteria and those meeting UCSF criteria (Yao, 2007). Unfortunately, data about overall 5-year survival was not included in that study.

#### **4.3.3 Other criteria**

286 Liver Transplantation – Basic Issues

imaging studies and is done before the treatment is decided. Some groups advocate obtaining a pretransplant liver biopsy to exclude candidates with poorly differentiated tumors and to identify patients that might need more aggressive bridging therapy. Dubay and colleagues evaluated this and found that in patients exceeding Milan criteria (single tumor not greater than 5 centimeters in diameter or up to 3 tumors none larger than 3 centimeters in diameter) there was a significant increase in overall 5-year survival (61% versus 79%, p=0.03) after the introduction of pretransplant liver biopsies and the use of aggressive bridging therapies (Dubay, 2011). The authors of this study conclude that tumor differentiation might be a more important predictor of biologic behavior than other factors

Performing liver biopsies in any patient population carries risks that although small, are not negligible. While pain is the most common complication, bleeding is the most feared and important complication. Severe bleeding events requiring hospitalization and other interventions occur anywhere from 1 in 2,500 to 1 in 10,000 in patients with diffuse, nonfocal liver disease (Rockey, 2009). However, the bleeding risk may be higher in cirrhotic patients, who usually have some degree of coagulopathy and thrombocytopenia. Similar increased risk could be expected in cirrhotic individuals in whom a highly vascular lesion such as hepatocellular carcinoma is being percutaneously biopsied (Huang, 1996). Tumor seeding along the needle track after biopsy has also been reported as a complication in this population (Dubay, 2011; Huang, 1996; Schotman, 1999; Sood, 2002). A recent systematic review and meta-analysis showed that the overall incidence of needle track tumor seeding is 2.7%, or 0.9% per year (M.A. Silva, 2008). These statistics are probably not too high because biopsy of primary hepatic cancer is not a common practice nowadays. However, the risks and benefits of biopsying a liver lesion must always be carefully weighed. This procedure should be reserved to instances when there is reasonable doubt about the diagnosis of

The field of liver transplantation has gone through many transformations since its early days. Over time this surgical procedure evolved from being a treatment option mostly for individuals with irreversible severe liver dysfunction from any acute or chronic illness to also a providing a proven curative alternative for patients with early stage hepatocellular carcinoma. Currently, the success rate and outcomes seen in this subset of liver transplant recipients is similar to that of recipients who underwent transplantation for indications other than hepatoma. This is in great part due to the knowledge and understanding obtained from outstanding clinical studies published over the last 20 years (Bismuth, 1993; Figueras, 1997; Iwatsuki, 1991; Mazzaferro, 1996; Tan, 1995). These studies have paved the way to the

The Milan criteria are at the present time the accepted and recommended measure to determine the liver transplantation candidacy of patients with hepatocellular carcinoma. This criteria described in a landmark paper by Mazzaferro and colleagues, demonstrated that in patients with cirrhosis and a single tumor up to 5 centimeters, or up to three lesions none larger than 3 centimeters, and with no evidence of extrahepatic spread or

creation of the criteria for liver transplantation and guidelines that are used today.

such as size, total tumor diameter, multifocality, and microvascular invasion.

hepatoma.

**4.3.1 Milan criteria** 

**4.3 Criteria for liver transplantation** 

Following the thought provoking findings of UCSF's study, other groups have also ventured into pushing the limits set by the Milan criteria without compromising overall patient survival and hepatoma recurrence rate. However, several shortcomings affect the validity of these studies. Most of them are retrospective studies, many do not clearly define the size of the tumors, in particular the upper limits, and others have small number of patients to provide convincing and significant findings. In contrast, the results of a recent well-designed, prospective, multi-center study from UNOS region 4 support the belief that liver transplantation could benefit patients whose hepatocellular carcinoma exceed Milan criteria. UNOS region 4 criteria showed patient, allograft and recurrence-free survival to be similar between patients meeting Milan criteria and those meeting their suggested criteria which consists of one lesion up to 6 centimeters, up to three nodules none larger than 5 centimeters, and a total tumor diameter less than 9 centimeters. It will be interesting to see if the data from their 5-year follow up still shows comparable survival rates (Guiteau, 2010). In general, the encouraging results seen from many of the extended criteria studies have stimulated the discussion about amending the current selection criteria to include this subgroup of liver cancer patients that could also benefit from transplantation.
