The Milan criteria for HCC (< 5 cm for a single lesion or multiple lesions involving

no more than 3 lesions with the largest measuring ≤ 3 cm) were applied as the
basis for selecting this patient with cirrhosis and early HCC for liver
transplantation. Based on UNOS rules, he was awarded extra points to his Model
for End-Stage Liver Disease (MELD) score, which was assigned as 22. He was
registered on the United Network for Organ Sharing/Organ Procurement
Transplantation Network (UNOS/OPTN) waiting list for liver transplantation.

Some have argued that the Milan criteria are too restrictive for liver
transplantation and that acceptable outcomes can still be achieved using more
liberal tumor criteria. The liver transplant group at the University of California at
San Francisco (UCSF) has championed the use of larger tumor sizes and
achieved outcomes similar to those achieved when the Milan criteria are used
(Yao, 2002). The UCSF criteria for liver transplantation in patients with HCC are
as follows:

• Single lesion ≤ 6.5 cm

• Multiple lesions ≤ 3 cm

• Largest tumor diameter if multiple ≤ 4.5 cm

• Total tumor diameter if multiple ≤ 8 cm

The MELD scoring system was adopted for allocation of deceased-donor livers in
the United States in February 2002. The MELD score calculation is based on 3
objective variables: creatinine, total bilirubin, and international normalized ratio.
The MELD score accurately predicts short-term mortality in patients with end-
stage liver disease who are awaiting liver transplantation; the higher the MELD
score, the greater the risk of short-term mortality (Freeman, 2002). Although the
MELD score is predictive of pretransplant survival, it is a weak predictor of post-
transplant survival (Freeman, 2002). Efforts at improving the MELD-based
allocation scheme are ongoing (Said, 2006; Freeman, 2006).

Despite improved allocation after implementation of MELD, it became apparent

that many livers were transplanted locally into recipients with low MELD scores
even when candidates with higher MELD scores continued to wait in adjoining
donor service areas within the same region. On the basis of analyses that
transplant recipients with MELD scores < 15 do not have a significant survival
benefit, the national liver allocation policy was again revised in January 2005.
Under the new policy -- known as Share 15 -- livers are offered to candidates
with MELD scores ≥ 15 who reside outside the procuring donor service area but
within the same region, only after those livers are first offered to local Status 1
candidates and candidates with MELD scores ≥ 15 (OPTN/SRTR 2006).
Liver transplant candidates with HCC within the Milan criteria are awarded extra
MELD points and MELD exceptions are granted for liver transplant candidates
with stage T2 HCC. These patients have immediate low mortality risk, but fall into
the category of exceptional diagnosis for MELD because the driving imperative
for liver transplantation at this time is not life-threatening liver failure, but
progression of the HCC to a stage where a high probability of cure is unlikely
(Freeman, 2006). Although the allowable assignment of the MELD score is 22
(equivalent to a 15% probability of candidate death within 3 months) for stage II
Milan criteria patients, no added points are assigned for stage I HCC patients (ie,
single tumor < 2 cm). The goal of MELD exceptions is to prevent the patient from
reaching a nonmortality endpoint -- an HCC tumor burden that exceeds the Milan
criteria -- which would necessitate the patient being removed from the
transplantation waiting list. Likewise, by being awarded priority MELD points,
patients with HCC may undergo transplantation earlier in the course of their
disease in an attempt to achieve better long-term survival post-transplantation.
Additional MELD points equivalent to a 10% increase in risk of death are
awarded every 3 months until these candidates receive a transplant or are
determined to be unsuitable for transplantation based on progression of their
HCC. Candidates whose tumors shrink in response to ablation therapy remain
eligible for priority status (OPTN/SRTR, 2006).

Since incorporation of the Milan criteria into the MELD scoring system, the
number of liver transplants performed for HCC has increased from 5% to 20% in
the United States, with some regions of the country reporting transplantation
rates of nearly 30% (Sharma, 2004). The survival outcome for patients with HCC
under this system, modified in April 2003, appears to have improved.

Induction therapy (prophylactic administration of biologic agents in the immediate

post-transplant period in an attempt to prevent acute rejection) with polyclonal
and monoclonal antibodies has played an important role in renal transplant
immunosuppression, and it is likely that these agents will be used more
extensively in liver transplantation.

The activation of T cells in response to the transplanted allograft is a central

phenomenon of acute rejection. Subsequent to activation, T cells are triggered by
the interaction of interleukin-2 (IL-2) with its receptor (R, which is expressed on
the activated T cell) to proliferate; this proliferation in turn is responsible for the
emergence of large numbers of antigen-specific T cells that infiltrate the allograft
and destroy it. Thus, allograft rejection may be inhibited by IL-2R blockade, or
may prevent IL-2-induced T-cell proliferation.

Rabbit-derived antithymocyte globulin (rATG), a polyclonal antibody, is a pan T-

cell-depleting agent. The anti-IL-2R monoclonal antibodies (daclizumab and
basiliximab) are non-T-cell-depleting agents. Daclizumab is a molecularly
engineered human monoclonal antibody. Basiliximab is a chimeric
(human/murine) monoclonal antibody derived from a recombinant gene; the
entire variable region is derived from the mouse and the constant region is
human. Daclizumab and basiliximab have similar short-term efficacy and
tolerability as rATG in liver transplant recipients with HCV disease (Kamar, 2004).
There is ongoing debate regarding the risks and benefits of polyclonal vs
monoclonal preparations, as well as the use of depleting vs nondepleting agents.
Only a few small studies evaluating the safety and efficacy of induction therapy in
patients with HCV infection have been published, and the results are conflicting.

An advantage of lymphocyte-depleting agents, in addition to prevention of acute

rejection, is allowing for corticosteroid withdrawal or avoidance. Pulsed IV
corticosteroids given to treat acute rejection transiently increase HCV viremia 4-
to 100-fold and, notably, treatment of acute rejection increases the risk of death
2.4 times in patients with HCV infections (Charlton, 2005). However, lymphocyte-
depleting agents also accelerate HCV viremia. It appears that the advantage of
minimizing corticosteroid exposure does not positively influence HCV infection
recurrence (Nair, 2006), and there is substantial evidence to suggest that
induction therapy with T-cell-depleting agents accelerates allograft damage and
progression to fibrosis among HCV-infected liver transplant recipients (Shaikh,
2007).

Mycophenolic acid exhibits antiviral properties and its mechanism of action is

similar to that of ribavirin (Ramos-Casals, 2005). The impact of MMF on HCV
viremia in liver transplant recipients, however, is not entirely clear. Two
randomized trials comparing MMF with azathioprine as maintenance therapies
following liver transplantation found no differences in HCV infection recurrence
rates or patient and allograft outcomes at 1 and 4 years after transplantation
(Wiesner, 2001; Jain, 2002). More recently, the effect of MMF on the rate of
allograft loss due to HCV infection recurrence in liver transplant recipients was
assessed in a retrospective analysis of data reported to the OPTN/SRTR
(Wiesner, 2005). In contrast to earlier findings, significantly better outcomes were
observed in those patients who were discharged from the hospital on a regimen
that included MMF. Patients who were discharged on a regimen of TAC, MMF,
and corticosteroids had significantly greater 4-year patient survival (80% vs 74%)
and allograft survival (75% vs 70%) rates, and a lower incidence of acute
rejection (27% vs 32%) compared with those receiving only TAC and
corticosteroids. Moreover, 4-year patient survival rates were similar for HCV-
seropositive (80%) and HCV-seronegative (81%) recipients treated with MMF
(Wiesner, 2005).