Despite recent advances in the care of patients with

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1 Liver Transplantation for Hepatocellular Carcinoma: Lessons from the First Year Under the Model of End- Stage Liver Disease (MELD) Organ Allocation Policy Francis Y. Yao, 1,2 Nathan M. Bass, 1 Nancy L. Ascher, 2 and John P. Roberts 2 We examined the impact of the Model for End-Stage Liver Disease (MELD) organ allocation scheme on 44 patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) between February 2002 and January 2003, and compared the outcome with 58 patients listed in the 4 years before MELD implementation. Patients undergoing living-donor liver transplantation were excluded. The Kaplan-Meier probabilities for OLT at 3, 6, and up to 8.5 months were 22.5%, 64.0%, and 88.0%, respectively, under MELD versus 17.2%, 24.7%, and 35.8% at 3, 6 and 9 months, respectively, in the pre-meld group (P.0006). In Cox regression analysis, non-o blood group (hazard ratio 2.5; P.047 versus blood group O) and 3 tumor nodules (hazard ratio 5.5; P.005) were associated with a significantly higher probability for OLT under MELD. The probabilities of dropout were 5.6% at 6 and 8.5 months under MELD versus 7.2% and 37.8% at 6 and 12 months, respectively, in the pre-meld group (P.74). The lack of a significant difference in dropout may be due to low dropout rates in the first 6 months in either group. No HCC was found in the explant in 1 patient from each group. In conclusion, the HCC-adjusted MELD system significantly improved the probability of timely OLT, albeit a significant disadvantage for blood group O was evident. Compared with preliminary UNOS data, in which 90% of patients with HCC have received OLT within 3 months, our results reflect the wide regional variation in the impact of MELD. (Liver Transpl 2004;10: ) Despite recent advances in the care of patients with acute and chronic liver failure before and after orthotopic liver transplantation (OLT), 1 the success of this potentially life-saving procedure is limited by the unrelenting mismatch between the demand and supply of donor livers. 2 For patients with hepatocellular carcinoma (HCC), prolonged waiting time often leads to tumor growth exceeding acceptable criteria for OLT in terms of the size and number of tumor nodules (dropout), a predicament that is often equivalent to death within 6 months. 3 6 A number of recently published studies have focused on the outcome of OLT for HCC based on an intention-to-treat principle, factoring in the natural history of tumor progression and dropout from the waiting list for OLT. 3 6 Under the previous system for organ allocation implemented by the United Network for Organ Sharing (UNOS) between January 1998 and February 2002, patients with HCC were eligible for status 2B listing for OLT. 7 The risk for dropout at 1 year for patients with HCC approached 40%, and that the number of dropouts approached the number of cadaveric OLT during this specified period according to a recent report from our center. 6 Similar results were also observed from the UNOS registry, 8 prompting recent changes in the organ allocation policy designed to better serve patients with HCC. The model for End-Stage Liver Disease (MELD) score, originally developed to predict outcome following the transjugular intrahepatic portosystemic shunt procedure in patients with chronic liver disease, 9 was implemented by UNOS as the new system for determining the priority for organ allocation since February 27, This scoring system is based on 3 biochemical variables: bilirubin, creatinine, and the international ratio for prothrombin time in predicting 3-month mortality. 10 The greater the risk of death, the higher the score (range 6 to 40), which also equate with a higher priority for receiving a donor liver. The ability of MELD score in predicting 3-month mortality among patients with chronic liver disease has been further validated. 11 Since patients with HCC may have preserved hepatic function and consequently a MELD score predicting a low risk of death from liver disease alone, an adjustment would need to be made to allow for the anticipated risk of dropout and death due to HCC. The current UNOS Staging classification for Abbreviations: MELD, Model for End-Stage Liver Disease; HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation; UNOS, United Network for Organ Sharing; TACE, transarterial chemoembolization; MRI, magnetic resonance imaging; UCSF, University of California, San Francisco. From the 1 Department of Medicine, Division of Gastroenterology, and the 2 Department of Surgery, Division of Transplantation, University of California, San Francisco, San Francisco, CA. Supported in part by a grant from the National Institutes of Health to the University of California, San Francisco Liver Center (P30DK26743). Address reprint requests to Francis Y. Yao, MD, 513 Parnassus Avenue, Room S-357, San Francisco, CA Telephone: ; FAX: ; yaofyk@itsa.ucsf.edu Copyright 2004 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt Liver Transplantation, Vol 10, No 5 (May), 2004: pp

2 622 Yao et al. Table 1. UNOS Staging Classification for Hepatocellular Carcinoma T0 T1 T2 T3 T4A T4B Tumor not found 1 nodule 1.9 cm 1 nodule cm; 2 or 3 nodules; all 3.0 cm 1 nodule 5.0 cm; 2 or 3 nodules, at least one 3.0 cm 4 or more nodules, any size T2, T3, or T4A plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or ultrasound Note. For the purpose of the present study, patients with T3 lesions meeting the proposed UCSF criteria (solitary tumor 6.5 cm, or 3 nodules with the largest lesion 4.5 cm and total tumor diameter 8 cm) were classified as T3A. Patients with T3 tumors exceeding these criteria were classified as T3B. HCC has incorporated the Milan criteria 12 into stages T1 and T2 (Table 1). 13 Under the initial HCC-adjusted MELD scheme of organ allocation, patients with T1 HCC were given a MELD score of 24, corresponding to an expected 15% 3-month mortality. Those with T2 HCC were assigned a MELD score of 29, which reflects an expected 30% 3-month mortality. In addition, these patients were entitled to an increase in the MELD score, corresponding to a 10% increase in mortality, for every 3 months on the waiting list. 13 The impact of the HCC-adjusted MELD system of organ allocation on intention-to-treat outcome has not been adequately evaluated. We have evaluated consecutive patients diagnosed with HCC and placed on the waiting list for OLT since January ,6 The intention-to-treat survival as well as the pattern and predictors for dropout for patients with HCC listed for OLT under the previous system of organ allocation between January 1998 and February 2002 have been previously reported. 6 As we continued to accumulate data prospectively, the primary objective of the present study was to assess the impact of the change in organ allocation policy on dropout and OLT rates, comparing these endpoints before and after implementation of the HCC-adjusted MELD system of organ allocation. This information may be helpful in the continuous effort to finalize a fair and reasonable priority scheme for organ allocation among patients with HCC. We also sought to determine if there were factors that influenced the rates and probabilities of OLT or dropout under MELD. Patients and Methods Patient Population We evaluated all patients referred to our institution for OLT between January 1998 and January 2003 with a known diagnosis of HCC or those who were discovered to have HCC while on the waiting list for OLT. After excluding 15 patients who underwent living-donor liver transplantation and domino or sequential OLT from patients with familial amyloidosis, 14 a total of 102 patients were included for analysis in the present study. We focused on 44 patients who were listed for OLT under the HCC-adjusted MELD system for organ allocation between February 2002 and January 2003 (MELD group). The outcome in terms of dropout and OLT rates was compared with 58 patients with HCC listed for OLT under the previous system of organ allocation 7 between January 1998 and January 2002 (pre-meld group). Follow-up for patients in the pre-meld group was censored on February 27, 2002, when the MELD system for organ allocation was implemented. 10,13 Censoring also applied to those who were still awaiting OLT by this specific date without dropout, whether or not they ultimately received OLT subsequent to this date under the MELD system for organ allocation. For patients in the MELD group, follow-up was censored on February 27, 2003, when further modifications in the HCCadjusted MELD scheme for organ allocation was implemented. 13 The initial tumor staging process for both groups was based on 2 imaging studies, either ultrasonography, computed tomography or MRI. During the waiting period for OLT, follow-up imaging studies for patients with known HCC included abdominal computed tomography or MRI every 3 months, and chest computed tomography every 3 months along with bone scintigraphy every 3 to 6 months for exclusion for extra-hepatic metastases. For patients without known HCC who were listed for OLT due to liver failure, HCC screening consisted of ultrasound and AFP every 6 months. Treatments for HCC while awaiting OLT included transarterial chemoembolization (TACE), percutaneous ethanol injection or radiofrequency ablation. During the study period, no protocol guiding these treatment strategies was in place at our institution. The decision for performing these treatments was made on a case-by-case basis in a multi-disciplinary tumor conference or by the discretion of the physician. During the waiting period for OLT, patients in the pre- MELD group were excluded for OLT if imaging studies suggested tumor progression exceeding the following proposed expanded criteria (University of California, San Francisco [UCSF] criteria): solitary tumor 6.5 cm, or 3 nodules with the largest lesion 4.5 cm and total tumor diameter 8 cm. 15 All 44 patients in the MELD group, on the other hand, met UNOS T1 or T2 criteria (Table 1) by imaging studies to be considered for MELD exception listing. Additional patients who underwent right-lobe living-donor liver transplantation with the technique as previously described, 1

3 MELD and Liver Transplantation for HCC 623 Table 2. Baseline Clinical and Demographic Characteristics MELD group (n 44) Pre-MELD group (n 58) Median age (yrs, range) 56.1 ( ) 52.4 ( ) Gender (M / F) 29 / / 17 Asian (number / %) 14 (31.8%) 20 (34.5%) ABO blood group (number / %) O 23 (52.3%) 20 (34.5%) A 13 (29.5%) 20 (34.5%) B 7 (15.9%) 13 (22.4%) AB 1 (2.3%) 5 (8.6%) CTP score (number / %) (43.2%) 18 (31.0%) (31.8%) 21 (36.2%) (25.0%) 19 (32.8%) Median CTP score (range) 8 (5 12) 9 (5 14) Etiology of liver disease (number / %) HCV 29 (65.9%) 39 (67.2%) HBV 8 (18.2%) 13 (22.4%) Others 7 (15.9%) 6 (10.3%) Alpha-fetoprotein (ng/ml) Median (range) 34.0 (1.6 6,155) 32.6 (0.7 2,620) Initial HCC stage by imaging studies (number / %) T1 (single lesion 2 cm) 5 (11.4%) 6 (10.3%) T2 Single lesion ( 2 cmand 5 cm) 23 (52.3%) 42 (72.4%) 2 3 lesions, none 3 cm 16 (36.4%) 10 (17.2%) Abbreviations: CTP, Child-Turcotte-Pugh; HCV, hepatitis C virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease. Note. No statistically significant difference was observed in all the baseline characteristics between the 2 groups (P 0.05 in all comparisons). More patients in the MELD group had 2 or 3 lesions compared to the pre-meld group at initial presentation, although the difference was only marginally significant (P 0.09). Baseline alpha-fetoprotein was missed in 2 patients in the pre-meld group. or had initial tumor exceeding T2 criteria and underwent down-staging procedures were not included in this study. For the purpose of the present study, patients with T3 lesions meeting the proposed UCSF criteria were classified as T3A. Patients with T3 tumors exceeding these criteria were classified as T3B (Table 1). In the analysis of histopathologic HCC characteristics in the liver explant, the individual tumor size in centimeters, total number of HCC nodules, the histologic grade of tumor differentiation based on the Edmondson and Steiner criteria (grade 1, well differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated), 16 and the presence or absence of micro- or macrovascular invasion were reported. In a patient with multicentric HCC showing different degrees of tumor differentiation, the most advanced histologic grade was reported. Statistical Analysis The Kaplan-Meier method was used to calculate the probabilities of OLT and dropout from the waiting list due to tumor growth. In the analysis of the cumulative probabilities of dropout as a function of time on the waiting list for OLT, follow-up was censored at the time of OLT. In addition, death before dropout and OLT was also counted as a censor point to fully assess the impact of HCC progression on dropout. The difference in the probabilities of dropout or OLT in different subgroups was compared by the log-rank test or Wilcoxon test as appropriate. Categorical variables were compared using 2 or Fisher s exact test as appropriate. Continuous variables were compared using the nonparametric Mann-Whitney U test. Among patients in the MELD group, Cox regression analysis was performed for the hazard rates of OLT or dropout. Results Baseline Characteristics and Treatment of HCC on the Waiting List The baseline characteristics of the 2 groups of patients are summarized in Table 2. The clinical and demographic characteristics were not significantly different between the 2 groups (P.05 for all comparisons).

4 624 Yao et al. Table 3. Treatment of HCC During the Waiting Period for OLT MELD group no. of patients (no. of treatments) Pre-MELD group no. of patients (no. of treatments) Any treatment 18 (22) 26 (49) P.89 PEI 4 (5) 6 (20) RFA 8 (8) 10 (10) Percutaneous 3 5 Open 2 2 Laparoscopic 3 3 Other ablations 0 3 (3) Microwave 1 Open cryoablation 2 TACE 7 (8)* 11 (12)* Limited resection types of treatments 2 6 TACE PEI 1 3 TACE RFA 1 1 TACE RFA PEI 1 Resection TACE RFA 1 No treatment 26 (59%) 32 (55%) Abbreviations: PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. *Not including TACE performed within 24 hours prior to OLT when a donor became available. Marginal statistical significance was observed in the comparative analysis of the number of patients with 2 or 3 lesions (P.09). All patients in the MELD group met UNOS T1 or T2 criteria. The 5 patients with T1 HCC were assigned an initial MELD score of 24, whereas those with T2 received a MELD priority score of 29. In the pre-meld group, 5 patients had progression of HCC during the waiting period from T2 to T3A by the time of OLT. Selected patients received elective ablation treatments, TACE, or limited hepatic resection intended as a bridge to OLT during the waiting period as summarized in Table 3. Eighteen of 44 patients (41%) in the MELD group and 26 of 58 patients (45%) in the pre-meld group had 1 or more types of treatments (P.89), not including TACE performed within 24 hours before OLT according to the usual protocol at our center as previously described. 17 significant (P.0006). In the MELD group, none of the 5 patients with T1 lesions (initial MELD score of24) had received OLT at the time of last follow-up after a median waiting time of 3.9 months (range 2.4 Probabilities of OLT and Explant HCC Characteristics The cumulative probabilities of OLT in the MELD group at 3, 6, and up to 8.5 months of longest follow-up were 22.5%, 64.0%, and 88.0%, respectively, versus 17.2%, 24.7%, 35.8%, and 47.2% at 3, 6, 9, and 12 months, respectively, in the pre-meld group (Fig. 1). The difference between the 2 groups was statistically Figure 1. The Kaplan-Meier cumulative probabilities of cadaveric liver transplantation according to the organ allocation system. The zero time point was the time the subject with known HCC was placed on the waiting list for OLT, or the time of diagnosis of HCC for the subject who developed HCC while waiting on the transplant list. The number of patients remaining at each time point is shown below the horizontal axis.

5 MELD and Liver Transplantation for HCC 625 Table 4. Explant Histopathologic Characteristics Among Patients Who Underwent Liver Transplantation MELD group (n 22) Pre-MELD group (n 25) Comparison (P-values) Explant HCC characteristics (number of patients) P.78 for overall comparison; P.67 for exceeding T3A T0 1 1 T1 2 2 T T3A 1 4 T3B 2 1 T4A 0 4 Histologic grade* P.44 1 (well differentiated) (moderately differentiated) (poorly differentiated) 4 5 Undetermined due to complete tumor necrosis 3 1 P.33 Microvascular invasion P.82 Yes 2 4 No Poorly differentiated or microvascular invasion 4 5 P 1.0 *Histologic grade was assigned according to the Edmondson and Steiner criteria. 16 Microvascular invasion occurred only in patients with grade 3 lesions in both groups. 6.2 months). When only the 39 patients with T2 lesions (initial MELD score of 29) within the MELD group were considered, the cumulative probabilities for OLT were 25.5%, 69.2%, and 89.7% at 3, 6, and 8.5 months, respectively. The difference in the rate of OLT between this subgroup and the pre-meld group was also statistically significant (P.0001). Pathologic HCC staging in the liver explants as well as other histologic features including histologic grade and vascular invasion in the 2 groups were compared (Table 4). More patients in the pre-meld group had pathologic HCC staging exceeding T2 criteria although the difference did not achieve statistical difference (P.79). There were 3 patients in the MELD group with pathologic HCC stage exceeding T2 criteria due to preoperative tumor stage underestimation. In the comparison of the histologic grade of differentiation 16 and the presence or absence of microvascular invasion, no statistically significant difference was observed between the 2 groups (Table 4). No patients in either group had macrovascular invasion. Unfavorable histologic features including poorly differentiated tumor grade or microvasular invasion were observed in 4 of 22 patients in the MELD group versus 5 of 25 patients in the pre-meld group (P 1.0). The short duration of follow-up for patients in the MELD group precluded comparison of postoperative survival or tumor recurrence between the 2 groups. Factor Influencing the Probability of OLT under MELD Due to the small sample size, only 5 variables were selected in the Cox regression analysis to determine if they influenced the probability for OLT under the MELD system of organ allocation (Table 5). ABO blood group was found to be a significant determinant of the probability of OLT, favoring non-o blood groups (hazard ratio 2.5; P.047) and especially blood group A (hazard ratio 3.2; P.012) in comparison with blood group O. Patients with 3 tumor nodules also had a higher likelihood for OLT (hazard ratio 5.5; P.005) versus a single lesion. None of the 5 patients with T1 lesions had received OLT at the time of last followup. When only patients with T2 lesions were included in the analysis of predictors of OLT, the results were similar with non-o blood type (hazard ratio 2.7; P.033) and especially blood group A (hazard ratio 3.2; P.023) and 3 tumor nodules (hazard ratio 4.7; P.013) being significant predictors of OLT. The impact of ABO blood type on the Kaplan- Meier probabilities of OLT is shown in Fig. 2. The Kaplan-Meier probabilities of OLT for the 23 patients in blood group O were 18.4% at 3 months, 50.8% at 6 months, and 83.6% at 8.5 months of longest follow-up, versus 27.0% at 3 months, and 85.8% at 5.9 months of longest follow-up for the 21 patients in non-o blood

6 626 Yao et al. Table 5. Factors Influencing the Probability of OLT Under MELD Hazard ratio (95% CI) P-value ABO blood group A (vs. O) 3.6 ( ).012 B or AB (vs. O) 1.6 ( ).51 A, B, or AB (vs. O) 2.5 ( ).047 Child s class (vs. child s A or CTP 5 6) B (CTP 7 9) 1.1 ( ).87 C (CTP 10) 2.3 ( ).12 Alpha-fetoprotein (ng/ml) ( ).99 Treatment (ablation or TACE) 0.57 ( ).22 Number of lesions (vs. one lesion) ( ) ( ).005 Abbreviations: CTP, Child-Turcotte-Pugh; TACE, transarterial chemoembolization. group (P.04 by log-rank test). Among the 13 patients in blood group A, the probabilities of OLT were 25.4% at 3 months and 100% by 5.8 months (P.008 compared with blood type O by log-rank test). Incidence of HCC Misdiagnosis and Complete Tumor Necrosis One patient in the MELD group and 1 in the pre- MELD group had misdiagnosis of HCC defined as the absence of HCC in the liver explant (P 1.0) (Table 4). The patient in the pre-meld group had cirrhosis due to chronic hepatitis C infection and 3 lesions up to Figure 2. The influence of ABO blood group on the Kaplan-Meier probabilities of liver transplantation among 44 patients listed under the MELD system of organ allocation. The number of patients remaining at each time point is shown below the horizontal axis. 1.5 cm on computed tomography and MRI of the abdomen at 1 month before OLT with a normal -fetoprotein. The patient in the MELD group had cirrhosis from chronic hepatitis C and was found to have 3 lesions all within 1 cm associated with an -fetoprotein level of 350 ng/ml. This patient had a pre-olt Child- Turcotte-Pugh score of 11 and a MELD score of 24 without adjustment for HCC. Neither patient received preoperative loco-regional treatments. One patient in the pre-meld group and 3 patients in the MELD group (P.33) had complete tumor necrosis and no residual HCC in the explant after receiving preoperative loco-regional treatments. The patient in the pre-meld group had a 2.5 cm lesion that was biopsied laparoscopically 19 months before OLT showing moderately differentiated HCC. This patient received 1 treatment with percutaneous ethanol injection and 2 elective TACE procedures, as well as TACE within 24 hours before OLT. Among the 3 patients in the MELD group with complete tumor necrosis, the first patient had a 3.5 cm tumor treated with percutaneous ethanol injection followed by TACE at 114 days and 17 days, respectively, before OLT. The second patient had a 4.5 cm lesion treated with TACE and then percutaneous ethanol injection at 80 days and 60 days, respectively, before undergoing OLT. The third patient had a 3.3 cm lesion treated with percutaneous radiofrequency ablation once at 115 days before OLT. None of the 3 patients had biopsy of the lesion to confirm the diagnosis of HCC before OLT. However, all had features suggestive of HCC according to preoperative imaging studies; including enhancement of the lesion following gadolinium contrast with MRI in 1 patient or a hypervascular lesion with contrast enhance-

7 MELD and Liver Transplantation for HCC 627 ment during triphasic computed tomography examination of the liver in the other 2 patients. months), including 5 patients with T1 lesion given an initial MELD score of 24. Dropout from the Waiting List and Death without OLT There were 2 dropouts due to tumor growth under MELD and 18 dropouts among patients in the pre- MELD group. More detailed information regarding the 18 dropouts in the pre-meld group had previously been reported. 6 Among the 2 dropouts in the MELD group, 1 had spontaneous rupture of a 3.6 cm lesion at 45 days after listing for OLT, associated with a dramatic increase in the -fetoprotein level to greater than 20,000 ng/ml, consistent with metastatic tumor dissemination. This patient expired 23 days after dropout from the waiting list. Another patient was found to have extra-hepatic disease at the time of exploratory laparotomy when a donor for OLT was available 78 days after listing for OLT with HCC. The transplant surgery was aborted, and the patient died 2 days later due to liver failure. The date of exploratory laparotomy was counted as the date of dropout from the waiting list. Exclusion for OLT occurred in 1 patient resulting from the diagnosis of metastatic melanoma in the lung 62 days after listing for OLT with HCC. Since this event was unrelated to HCC, it was counted as a censor point. Two other patients died from liver failure without OLT after being listed for OLT with HCC for 25 days and 213 days, respectively. The date of death in these 2 patients was treated as censoring points in the analysis of dropout. The cumulative probabilities of dropout due to HCC in the MELD group were 5.6% at 3, 6, and up to 8.5 months of longest follow-up without OLT. The probability of dropout in the pre-meld group was 7.2% at 6 months, then increased to 19.2% at 9 months, 37.8% at 12 months, and 55.1% at 18 months. The difference in the probabilities of dropout between the 2 groups was not statistically significant (P.74). After applying the current UNOS T2 criteria for patient exclusion in a hypothetical analysis of dropout for patients in the pre-meld group, the number of dropouts increased from 18 to 24 patients. The cumulative probabilities of dropout would have been 11.0%, 57.4%, and 68.7% at 6, 12, and 18 months, respectively. The difference in the probability of dropout when compared with the MELD group was also not statistically significant (P.68). When follow-up was censored on February 27, 2003 in the MELD group, there were 17 patients still awaiting OLT after a median waiting time of 3.9 months (range 1.6 months to 8.5 Extended Donors and Other Donor Issues We also examined donor issues that might have impacted on our study endpoints in the MELD group. Only 1 patient had a true MELD score exceeding the HCC-adjusted MELD score. This patient was in blood group O with a MELD score of 36 at the time of OLT. Three patients received extended liver donors, including 1 patient in blood group B who received a non-heart-beating donor and 2 patients in blood group O with HBV-cirrhosis who received hepatitis B core positive donors. Repeat analyses of the cumulative probabilities of OLT and dropout, as well as factors influencing the probability of OLT were performed to adjust for these confounding donor variables. Since the HCC-adjusted MELD scheme was not applicable to the patient with a MELD score of 36, this patient was excluded in the repeat analysis. For the 3 patients who received extended liver donors, the date of OLT was counted as only censoring points. Following these adjustments, the Kaplan-Meier probabilities of OLT were 13.8%, 60.0%, and 86.7% at 3, 6, and 8.5 months of longest follow-up, respectively (P.005 vs. the pre-meld group). The cumulative probabilities of dropout were 5.0% at 3 months and up to 8.5 months of longest follow-up (P.43 vs. the pre-meld group). Non-O blood group (hazard ratio 3.9 vs. O blood group, P.01), especially blood group A (hazard ratio 6.6 vs. blood group O, P.0009) and 3 tumor nodules (hazard ratio 7.3 vs. a single nodule, P.002) remained the only statistically significant predictors for OLT. Discussion The HCC-adjusted MELD scheme, implemented on February 27, 2002, was designed to limit the dropout rate for patients with HCC placed on the waiting list for OLT. 13 The present study did not show a significant difference in the dropout rate before and after implementation of MELD, largely because of the small number of dropouts in either group within the first 6 months and the low number of patients remaining at risk for dropout beyond 6 months under the MELD scheme. The relatively small number of patients in this study may also be a contributing factor. Our results did confirm a significant advantage conferred to patients with HCC in the MELD era in terms of a higher probability of timely OLT (Fig. 1). In our MELD group, the

8 628 Yao et al. probability of OLT after being on the waiting list for 6 months was close to 70% for patients with T2 HCC, whereas none with T1 HCC had received OLT after a median waiting time of 3.9 months. The median MELD score at the time of OLT for adult patients over the age of 18 years with or without HCC was 30 at our institution in the first year since MELD implementation. With the regional variations in waiting time and MELD scores at the time of OLT, it is likely that patients with HCC listed at many other transplant centers have received OLT significantly faster. Indeed, according to preliminary UNOS data, 18 25% of patients with T1 HCC and 43% of those with T2 lesions approved for MELD priority listing had received cadaveric OLT within 1 month of listing. Furthermore, the majority of patients with T1 (86%) and T2 (90.2%) HCC approved for MELD priority listing had been transplanted within 3 months of listing. 18 The percentage of OLT for HCC increased from 8.8% between 2/2001 and 8/2001 before MELD, to 21.3% in the first 6 months after MELD implementation. 19 The premise that patients with HCC are given too high a priority score in the first year under MELD is now supported by preliminary UNOS data showing a 90% OLT rate within 3 months on the waiting list, 18 despite the reported low probability of dropout due to tumor progression of about 10% after being on the waiting list for 6 months. 6 As of February 27, 2003, UNOS implemented a modification of the MELD priority scheme for HCC, in which the initial MELD score was reduced from 29 to 24 points for patients with T2 HCC, and from 24 to 20 points among those with a T1 lesion. 13 The decision to downgrade the initial MELD score allocated to patients with HCC may be further justified by the apparent increase in mortality for those without HCC but a MELD score between 25 to 30 based upon preliminary UNOS data. 20 In the present study, we were not able to provide data on the impact of the HCC-adjusted MELD scheme on patients without HCC awaiting OLT. In the latest proposal by UNOS, 13 patients with T1 HCC are no longer eligible for MELD priority listing, but should be monitored closely with serial imaging studies to evaluate for evidence of tumor progression and appropriate priority listing during follow-up. This policy also takes into consideration the differing risks of dropout according to baseline HCC characteristics and may better protect those with T2 HCC at higher risk for dropout. 6 On the other hand, the rate of OLT shown in the present study probably reflects the far end of the regional variation in waiting time and MELD score at the time of OLT, and allows for a narrow margin in limiting the dropout rate under this revised organ allocation scheme. This is based on the premise that the majority of patients with HCC should be transplanted within 6 months on the waiting list, beyond which the probability of dropout increases exponentially. 6 Our analysis also suggests a significant disadvantage for patients with blood type O in terms of the rate of OLT when compared with other blood groups in the first year under MELD (Fig. 2). This finding is not surprising as patients in blood group O generally have a longer median waiting time for OLT, irrespective of HCC status. 8 According to current UNOS guidelines, blood group O donors generally do not cross the blood group barrier for OLT with the exception that an O liver may go to a blood group B patient with fulminant hepatic failure or primary graft non-function listed status I for OLT. A previous study from the NIDDK Liver Transplantation Database also showed a significantly longer waiting time and a higher mortality while on the waiting list for OLT among patients with blood type O. 21 Under the HCC-adjusted MELD system for organ allocation, the waiting time was relatively short, and thus the safety margin with respect to dropout from the waiting list was wider. Consequently, the slower rate of OLT among patients with blood group O was not translated into a higher rate of dropout. In fact, there were only 2 dropouts under MELD in the present study. In the previous analysis from our center on the outcome of patients with HCC in the pre-meld era, 6 we focused on dropout as the endpoint in Cox regression analysis and did not find ABO blood group to be a determinant for dropout. This parameter also did not significantly influence the probability of OLT in the pre-meld group (data not shown). Based on these observations, the influence of blood group on the rate of OLT may be dependent upon the length of waiting time. Our analysis also suggested 3 tumor nodules to be associated with a higher likelihood for OLT. There is no obvious explanation for this finding, since tumor characteristics presently do not influence priority for OLT, other than the distinction made between T1 and T2 HCC. Furthermore, only a minor impact of extended liver donors outside the usual MELD allocation scheme was observed in our cohort. A confounding factor in the interpretation of our results is the lack of a consistent approach in applying preoperative loco-regional treatments, which might have contributed to the high rate of dropout in the pre-meld era. In our previous analysis, 6 loco-regional treatment was not associated with a lower dropout rate according to the T3A criteria for patient exclusion in the pre-meld era. However, in a hypothetical analysis

9 MELD and Liver Transplantation for HCC 629 applying the UNOS T2 criteria for exclusion, the probability of dropout was significantly lower among patients who received preoperative loco-regional treatment. Another recent study reported a low dropout rate when TACE was used as a bridge to OLT, even when the waiting time for OLT exceeded 6 months. 5 Under the MELD system of organ allocation, the impact of loco-regional treatment is difficult to assess due to the small number of dropouts and the relatively short waiting time. Another concern since the implementation of the HCC-adjusted MELD scheme is the high rate of misdiagnosis of HCC in the liver explant. According to a recent analysis of UNOS data, no HCC was found in the explant among 21% of HCC cases reported to UNOS. 22 In the present study, the number of patients transplanted for HCC in the MELD era was small and only 1 patient in each group was classified as misdiagnosis. Whether those with complete tumor necrosis in the explant liver (Table 4) represent favorable response to preoperative loco-regional therapies versus misdiagnosis is often difficult to determine with certainty. More stringent preoperative diagnostic criteria for HCC 23 may be one potential solution to the problem of misdiagnosis leading to inappropriate utilization of resources. If the UNOS data confirm a higher rate of misdiagnosis among those with T1 or small single T2 lesions, then the argument for restricting priority listing to those with more advanced T2 HCC would be further strengthened, since these patients appear to be also at significantly higher risk for dropout. 6 In conclusion, our results confirm that access to timely OLT for patients with HCC significantly improved in the first year under the MELD system between February 2002 and February 2003 when compared to the pre-meld era. The relatively small number of patients and the lack of long-term follow-up data under MELD are limitations of the present study. Further refinements in the MELD organ allocation scheme for HCC have been made since February 2003, 13 with a reduction in the priority score for HCC that seems more consistent with the natural history of tumor progression and the risk of dropout. 6 However, our results in the first year since the implementation of MELD also reflect the wide regional variation in the rate of OLT for HCC, and a significant disadvantage among patients with blood group O. 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