The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P ‫؍‬ .87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P ‫؍‬ .0001). An ␣-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < 6.5 cm, or < 3 nodules with the largest lesion < 4.5 cm and total tumor diameter < 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P ‫؍‬ .0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT. (HEPATOLOGY 2001;33:1394-1403.)Orthotopic liver transplantation (OLT) is a rational therapeutic option for patients with hepatocellular carcinoma (HCC), because it addresses the multifocal potential of HCC in many patients that limits the success and applicability of resection, and also treats the underlying liver disease. The early experience of OLT for HCC in unselected patients included those with extensive and bulky tumors, and was associated with a dismal outcome primarily as a result of aggressive tumor recurrence after OLT. 1,2 The observation that small HCC discovered incidentally at the time of pathologic examination of the explanted liver had a much lower recurrence rate after OLT 1,2 provided the impetus for subsequent studies evaluating OLT mainly for patients with small HCC. [3][4][5][6] In a study by Bismuth et al., 3 the subgroup of patients with no more than 3 tumor nodules and none greater than 3 cm in greatest diameter had a 3-year disease-free survival of 83% with OLT, compared with only 18% treated by resection. In a subsequent study by Mazzaferro et al., 5 35 patients with a solitary tumor not exceeding 5 cm or no more than 3 tumors with none greater than 3 cm had excellent overall and recurrence-free survival rates of 85% and 92%, respectively, at 4 years after OLT. In the report by Figueras et al.,6 the 5-year survival rate for OLT in 38 patients with small HCC not exceeding 5 cm in maximal diameter was 7...

We report long-term intention-to-treat outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing down-staging to within Milan/UNOS T2 criteria before liver transplantation (LT) since 2002, and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The down-staging subgroups include 1 lesion >5 cm and ≤8 cm (n=43), 2 or 3 lesions at least one >3 cm and ≤5 cm with total tumor diameter ≤8 cm (n=61), or 4 to 5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n=14). In the down-staging group, 64 patients (54.2%) had received LT, and 5 (7.5%) developed HCC recurrence. Two of the 5 patients with HCC recurrence had 4–5 tumors at presentation. The 1- and 2-year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the down-staging group, versus 20.3% and 25.6% in the T2 group (p=0.04). The Kaplan-Meier 5-year post-transplant survival and recurrence-free probabilities were 77.8% and 90.8%, respectively, in the down-staging group, versus 81% and 88%, respectively, in the T2 group (p=0.69 and p=0.66, respectively). The 5-year intention-to-treat survival was 56.1% in the down-staging group, versus 63.3% in the T2 group (p=0.29). Factors predicting dropout in the down-staging group included pre-treatment alpha-fetoprotein ≥1000 ng/mL (multivariate HR 2.42, p=0.02) and Child’s B versus Child’s A cirrhosis (multivariate HR 2.19, p=0.04). Conclusion: Successful down-staging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post-transplant survival, comparable to those meeting T2 criteria without down-staging. Due to the small number of patients with 4–5 tumors, further investigations are needed to confirm the efficacy of down-staging in this subgroup.

Background Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the MELDNa score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in cirrhotics. Methods Consecutive outpatients listed for LT at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting due to sickness). We selected the Frailty Index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the Frailty Index to MELDNa. Results Included were 536 cirrhotics with median MELDNa of 18. 107(20%) died/were delisted. The final Frailty Index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the Frailty Index to correctly rank patients according to their 3-mo waitlist mortality risk (i.e., C-statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa + Frailty Index together. Compared with MELDNa alone, MELDNa + Frailty Index correctly re-classified 16% of deaths/delistings (p=0.005) and 3% of non-deaths/delistings (p=0.17) with a total NRI of 19% (p<0.001). Compared to those with robust Frailty Index scores (<20%ile), cirrhotics with poor Frailty Index Scores (>80%ile) were more impaired by gait speed, IADL difficulty, exhaustion, and low physical activity [p<0.001 for each]. Conclusions Our Frailty Index for cirrhotics, comprised of 3 performance-based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone.

We previously reported encouraging results of down-staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer-term outcome data on HCC down-staging in a larger cohort of 61 patients with tumor stage exceedingT2criteriawhowere enrolled between June 2002 and January 2007. Eligibility criteria for down-staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down-staging was required before OLT. Tumor down-staging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) had received OLT, including two who had undergone live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after down-staging were 87.5% and 69.3%, respectively. The 1-year and 4-year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein > 1,000 ng/mL. Conclusion Successful down-staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome.

We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5-year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1-and 5-year recurrence-free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1-and 5-year recurrence-free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under-staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1-and 5-year recurrence-free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under-staging when compared to the Milan criteria.