As liver transplantation was accepted as primary therapy for end-stage liver disease in the 1980s, interest in transplantation for primary hepatic malignancy increased. With improvements in operative technique and immunosuppression, routine survival extended beyond the first few months and the nonmalignant indications for transplantation expanded. During this decade, it would be shown that recurrence following transplantation for HCC was unacceptably high at 65 to 75% likely due in part to accelerated tumor growth associated with immunosuppression.[39,40] Tumor recurrence was the rule. Several studies documented high recurrence rates and adjuvant therapy had little, if any, impact. In 1985, Iwatsuki et al published the initial experience of the Pittsburgh/Colorado group with transplantation for malignancy. They found that no recurrence was noted in 12 patients with incidental tumors (median follow-up 16 months), while those with known malignancy had a 74% recurrence rate (median time to recurrence 8 months). Olthoff et al published the initial University of California Los Angeles (UCLA) experience of 16 patients who underwent transplantation for HCC. Of the 12 patients that survived the first 3 months following transplantation, eight (67%) developed recurrence within 2 months to 2 years. These high recurrence rates and the ever-growing number of patients with nonmalignant indications for transplantation diminished interest in liver replacement for hepatic malignancy and a moratorium was placed on liver transplant for HCC outside of clinical trials in 1989.
In 1996, Mazzaferro et al published their landmark article that led to internationally renewed interest in liver transplantation for HCC and still forms the framework for transplant policy in North America and much of the world. This prospective cohort study included 48 cirrhotic patients who underwent transplantation for HCC with single tumors ≤5cm or up to three tumors, the largest of which is ≤3cm. The actuarial 4-year survival rate was 75% and was not different from the expected survival of patients with nonmalignant indications for transplantation. Based on this report and several studies validating these results, interest in transplantation as a therapeutic option for patients with early stage HCC was renewed.[43,44] In an analysis of the Organ Procurement and Transplant Network (OPTN) dataset, Yoo et al examined 34,324 patients who underwent liver transplantation from 1987 to 2001 in the United States. One- and 5-year patient survival rates were significantly worse in those transplanted for HCC when compared with those transplanted for non-HCC indications (1-year 77.0% vs. 86.7%, p < 0.001; 5-year 48.3% vs. 74.7%, p < 0.001). In fact, HCC was a strong predictor of worse survival at 1 and 5 years (hazard ratio [HR] 1.6 and 2.02, respectively). However, the authors did find a significant improvement in survival of patients with HCC over time without a concomitant increase in survival of the control, non-HCC group. Five-year survival rates of HCC patients increased from 25.3% in the 1987 to 1991 period, to 61.1% during 1996 to 2001. This study validated the supposition that improvement in survival of patients transplanted for HCC was due to better patient selection as selection criteria became more rigorous in the late 1990s.
Given the dramatically improved results of transplantation for early-stage HCC and the shortcomings and the CTP, time-based allocation system, many believed that HCC patients were distinctly disadvantaged in organ allocation. Although waiting time was the cornerstone of the tripartite CTP-based allocation system, time spent on the waitlist failed to correlate with risk of death while waiting for a deceased donor organ. This led to efforts to improve deceased donor allocation and find a method to better predict waitlist dropout due to death or tumor progression. In 1998, the United States Health Resources and Services Administration of the Department of Health and Human Services issued the "Final Rule" calling for the development of a new allocation policy based on disease severity and likelihood of dying or becoming nontransplantable while awaiting liver transplantation.
In February 2002, the Model for End Stage Liver Disease (MELD) was introduced as the system for deceased donor liver allocation in the United States. Three laboratory values (international normalized ration [INR], bilirubin, and creatinine) determine MELD score and this score determines waitlist ranking. Thus, severity of liver disease became the major determinant of organ allocation. Several studies have validated MELD as an accurate predictor of mortality in patients with end-stage liver disease.[48,49] Soon after its implementation, additions to the waitlist decreased, the rate of transplantation increased, and linear relationship between MELD score and waitlist mortality was retrospectively demonstrated. Although MELD clearly had a beneficial impact on organ allocation in patients with end-stage liver disease, the dilemma arose of how to allocate livers to patients with transplantable HCC and low MELD score before they progressed outside of Milan criteria. Initially, patients with HCC were arbitrarily assigned a score thought to allow for timely transplantation. The goal was to equate risk of progression beyond stage 2 disease (based on the American Liver Tumor Study Group modified TNM staging system) for HCC patients with risk of death on the waitlist for non-HCC transplant candidates over a similar period. Patients with stage 1 disease were assigned a MELD of 24, which estimates a 15% chance of progressing beyond Milan criteria in 3 months. Those with stage 2 disease were assigned 29 points approximating a 30% risk of progression within 3 months. Every 3 months thereafter, MELD points estimating a 10% increase in progression beyond stage 2 disease were added to the initial allocation score.
Soon after implementation of the new allocation scheme for HCC, the number of transplants for HCC increased from 7% the year preceding MELD to 22% in the year after, and 87% of patients with HCC were transplanted within 3 months of listing.[10,51] Furthermore, the number of HCC patients who became nontransplantable or died was actually lower than the number of noncancer patients with a similar MELD score who died awaiting an organ. As a result of these and other data, concern grew that HCC patients were given excess priority and the allocation model was changed in 2003 to give patients with stage 1 disease 20 points (or an 8% chance of dying or disease progression in 3 months) and stage 2 patients 24 points. This reduced the number of patients transplanted for HCC from 22% to 14%, although it did not significantly change the time on the waitlist or waitlist dropout in a study of the United Network for Organ Sharing (UNOS) database. In an analysis of explant pathology reports, 31% of patients transplanted for stage 1 HCC were found to have no evidence of malignancy in the specimen compared with 9% of those with stage 2 disease. This led to a cessation of MELD allocation priority to those with stage 1 tumors. Under current UNOS policy, patients receive an allocation priority MELD of 22, which is increased by an estimated 10% risk of dropout every 3 months.
Several studies have retrospectively validated improved survival of patients with HCC within Milan criteria undergoing liver transplantation. In the largest North American single-center experience, Duffy et al from UCLA presented the outcomes of 467 patients who underwent transplantation for HCC from 1984 to 2006. Recurrence-free survival rates were significantly higher in patients within Milan criteria compared with those beyond (74% vs. 27%, respectively; p < 0.01). Notably, patients who underwent transplantation after the institution of MELD-based allocation had a 74% 5-year overall survival rate versus 47% of those transplanted prior to implementation of MELD (p = 0.001). In another report from a large American center, Onaca and Klintmalm demonstrate similar improvement in outcome following implementation of Milan criteria in selection for transplantation. Five-year overall survival rates improved from 28.6% in 1987 to 1992 to 42.3% in 1992 to 1997, likely reflecting general improvements in liver transplantation. These results were inferior to those achieved in non-HCC patients. After 1997, 5-year survival rates improved to 76% for HCC patients, similar to the survival in nonmalignant indications. Tumor recurrence rates dropped from 52.9% (1987-1992) and 48.2% (1992-1997) to 11.4% (1997-2002). Again, it was demonstrated that MELD-based allocation reduced median wait time for patients with HCC.
Semin Liver Dis. 2013;33(3):282-292. © 2013 Thieme Medical Publishers