Cirrhotic patients with solitary hepatocellular carcinoma

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1 ORIGINAL ARTICLES Survival of Cirrhotic Patients With Early Hepatocellular Carcinoma Treated by Percutaneous Ethanol Injection or Liver Transplantation Angelo Andriulli, 1 Ilario de Sio, 2 Luigi Solmi, 3 Luciano De Carlis, 4 Roberto Troisi, 5 Alessandro Grasso, 6 Virginia Festa, 1 Eugenio Caturelli, 1 Alessandro Giacomoni, 4 Camillo Del Vecchio Blanco, 2 Bernard De Hemptinne, 5 Andrew Burroughs, 6 and Francesco Perri 1 For early hepatocellular carcinoma (HCC), surgery, orthotopic liver transplantation (OLT) and percutaneous ethanol injection (PEI) improve the natural history of the disease. We performed a retrospective study to evaluate the outcome of patients with cirrhosis and early HCC treated by PEI (n 417) or OLT (n 172). Overall, 589 patients with cirrhosis were studied. The proportion of patients in Child-Turcotte-Pugh (CTP) classes A, B, and C was 52.5%, 33.6%, and 13.9%, respectively. Most patients (78.9%) had solitary HCC. Overall 5-year and 10-year cumulative survival rates were 36.1% and 15.5% after PEI, and 66.3% and 49.1% after OLT, respectively (P <.0001). Overall 5-year and 10-year cumulative tumor-free survival rates were 25.3% and 18.0% after PEI, and 84.6% and 82.2% after OLT, respectively (P <.0001). When patients were sorted according to the severity of cirrhosis, mean survival times in PEI and OLT patients were 67 and 80 months in CTP class A (P.05), 38 and 90 months in class B (P <.0001), and 31 and 95 months in class C (P.0004). Similarly, mean tumorfree survival times in the 2 series of patients were 49 and 98 months in CTP class A (P <.0001), 39 and 121 months in class B (P <.0001), and 35 and 139 months in class C (P <.0001). In conclusion, this study challenges the therapeutic efficacy of PEI for patients with cirrhosis and early HCC, when compared to OLT: the proportion of both long-term survivors and tumor-free survivors was increased by OLT over PEI. The benefit of OLT extends to all patients, regardless of the degree of liver impairment. (Liver Transpl 2004;10: ) Cirrhotic patients with solitary hepatocellular carcinoma (HCC) less than 5 cm in diameter or, if multifocal, with up to 3 lesions not more than 3 cm each, and no evidence of vascular invasion or extrahepatic spread, are commonly classified as having early HCC. In these patients, surgical resection, orthotopic liver transplantation (OLT), and percutaneous ethanol injection (PEI) are curative treatments that are assumed to improve the natural history of the disease and increase survival. 1,2 So far, randomized clinical trials on the comparative evaluation of the 3 therapeutic modalities on patient survival are lacking, and for a variety of ethical and logistical issues, it appears unlikely they will ever be performed. The best evidence-based approach to the management of these patients relies on retrospective cohort studies that compared hepatic resection to either PEI or OLT. When hepatic resection and PEI were compared, the meta-analysis of 5 studies showed no significant difference for both 3-year survival and 3-year tumor-free survival. 3 OLT has theoretic advantages over the other 2 therapeutic modalities, as it eliminates both the tumor and the neoplastic potential of the underlying cirrhosis. Indeed, when compared to hepatic resection, the meta-analysis of 12 cohort studies showed survival rates in favor of OLT. 3 Results from early studies on OLT for HCC were so disappointing in terms of both tumor recurrence (30%- 50% at 3 years) and survival (less than 50% at 3 years), 4 6 that HCC patients were not considered eligible for OLT in most transplant centers. In Italy, the policy has changed only recently, when more favorable Abbreviations: HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation; PEI, percutaneous alcohol injection; CTP, Child-Turcotte-Pugh. From the 1 Department of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy, the 2 Gastroenterology Unit, Ultrasonography Section, University Hospital, Naples, Italy, 3 Gastroenterology and Digestive Endoscopy, S. Orsola- Malpighi University Hospital, Bologna, Italy, the 4 Liver Transplantation Unit, Niguarda Hospital, Milan, Italy, the 5 Department of General, Hepato-Biliary, and Transplantation Surgery, Ghent University Hospital, Ghent, Belgium, and the 6 Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK. Address reprint requests to Angelo Andriulli, M.D., Division of Gastroenterology, Ospedale Casa Sollievo Sofferenza - IRCCS, San Giovanni Rotondo, Italy. Telephone: ; FAX: ; a.andriulli@operapadrepio.it This work has been accepted as an oral presentation at the 2003 Annual Meeting of the American Association for the Study of Liver Diseases. Copyright 2004 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt Liver Transplantation, Vol 10, No 11 (November), 2004: pp

2 1356 Andriulli et al. results were achieved after proper selection of patients. 7,8 Further reasons to deny OLT to early HCC Italian patients were the limited number of established transplant centers, the shortage of donor organs due to very low rates of donations, which has increased only recently, and the 60-year-old age limit to enlist patients. Consequently, in Italy, all these patients were almost exclusively treated with PEI, since Italian studies, 9,10 in accordance with other international studies, 11 provided survival data after PEI comparable or even better than those reported after hepatic resection, with less procedure-related morbidity and mortality. Meanwhile, in other centers that adopted restrictive criteria for tumor size and number, OLT has emerged as the best long-term treatment for patients with HCC, 7,8 regardless of the degree of liver dysfunction. 12 The majority of physicians in charge of these patients would agree that those with limited HCC and moderate-to-severe liver cirrhosis should receive a donor liver. Whether early HCC in patients who have mild liver dysfunction should be treated with OLT has engendered considerable controversy, mainly due to the shortage of donor organs. The database of cirrhotic patients with early HCC who have been treated with PEI in 3 Italian centers, and that of similar patients transplanted at 3 different centers were used to compare the long-term survival and tumor-free survival and to determine the best prognostic factors. Moreover, we attempted to determine whether OLT could be a therapeutic option for patients with early HCC and preserved hepatic reserve. Materials and Methods Center and Patient Selection In this multicenter, retrospective study, patients with early HCC were recruited from 4 centers in Italy, and 1 each in Ghent (Belgium) and London (UK). Of the 6 participating centers, 3 Italian centers were from general hospitals, located in San Giovanni Rotondo, Naples, and Bologna, in which a liver transplant program was unavailable, or, if available (like in Bologna), had HCC as an exclusion criterion for OLT. In order to avoid selection bias, the centers had to submit data about all consecutive patients with small HCC treated with PEI and on regular follow-up at the respective institutions. Portions of these experiences were reported previously. 16 The other 3 centers were in general hospitals located in Milan (Italy), Ghent, and London, and had a transplant program in place. They were also asked to provide data about the consecutive series of patients enlisted for OLT and successfully transplanted for HCC as the main indication, after excluding incidental HCC discovered at the pathological examination of the explanted liver. Portions of these experiences were reported previously. 10 All cases diagnosed between January 1992 and August 2002 were eligible for the study. No minimum diagnostic criteria were imposed. After successful completion of PEI sessions or after an uneventful OLT, patients had to be regularly followed-up at the respective institutions, with measurement of -fetoprotein levels and abdominal ultrasound evaluation every 3 months. Additional imaging techniques (such as dynamic computed tomography, angiography, or magnetic nuclear resonance) were performed if tumor recurrence was suspected. Data Collection Original records were used to collect the following data for each patient: age, gender, etiology of liver disease, preexisting cirrhosis, degree of liver function as assessed by the Child-Turcotte-Pugh (CTP) classification and its constitutive variables (albumin, bilirubin, prothrombin time, ascites, and encephalopathy), stage of the tumor evaluated after the number of nodules and the size of each of them was assessed by triple phase computed tomography scan (imaging before contrast, arterial and portal venous phase), -fetoprotein levels, date of initial diagnosis and treatment of HCC (whether PEI or OLT), number of PEI sessions, adjuvant therapy before OLT, date of recurrence and / or death, and cause of death. Statistics Univariate analysis was performed for all variables by sorting patients according to centers (for within-center analysis) and treatment (for between-center analysis). Continuous variables were expressed as mean standard deviation (or mean standard error), and categorical variables as percentage values. Comparison between groups was performed by using Student s t test and analysis of variance for quantitative variables, and by means of the 2 test (or Fisher s exact test when needed) for categorical variables. Patient survival was the main endpoint used in the analysis and was defined as the time elapsed from the diagnosis of HCC and death or last followup. Tumor-free survival was the secondary endpoint and was defined as the time between the date of treatment and the tumor recurrence. The follow-up was closed on September 30, The Kaplan-Meier product-limit method with the Mantel-Cox log-rank test was used to evaluate patient and tumor-free survival rates for the following prognostic factors: age (a cutoff value of 60 years was used), gender, etiology of liver diseases, CTP classification, number of HCC nodules, and serum -fetoprotein levels. Finally, Cox logistic regression analysis was carried out to determine variables independently associated with overall survival or tumor-free survival. Patients age was used as a time-dependent covariate in the Cox regression model. All the calculations were performed using the statistical software package of SPSS / PC (SPSS, Chicago, IL). Significance levels were set at a P value less than.05.

3 PEI or OLT in Cirrhotic Patients With Early HCC 1357 Table 1. Univariate Analysis (Within Centers) of Characteristics of Patients Who Underwent Percutaneous Ethanol Injection and Orthotopic Liver Transplantation* Factor SGR (n 135) PEI Centers BO (n 83) NA (n 199) P Value LO (n 47) OLT Centers GH (n 31) MI (n 94) P Value Age mean SD years 30 (22) 17 (20) 26 (13) (75) 31 (100) 87 (93) years 105 (78) 66 (80) 173 (87) 12 (25) 0 7 (7) Gender Male 105 (78) 55 (66) 147 (74) (89) 24 (77) 83 (88).24 Female 30 (22) 28 (34) 52 (26) 5 (11) 7 (23) 17 (12) PEI sessions mean SD Etiology of cirrhosis HCV 85 (63) 51 (61) 169 (85) (53) 19 (61) 34 (36).02 HBV 18 (13) 14 (17) 8 (4) (24) 4 (13) 27 (29).20 Ethanol 13 (16) 4 (2) (13) 6 (19) 12 (13).63 Crypto 26 (19) 5 (6) 12 (6) (6) 2 (7) 8 (8).87 Other 6 (5) 6 (3).16 2 (4) 13 (14).02 Child-Turcotte- Pugh class A 90 (67) 24 (29) 156 (78) (32) 10 (32) 14 (14).03 B 39 (29) 46 (55) 41 (21) (36) 15 (48) 40 (43).55 C 6 (4) 13 (16) 2 (1) (32) 6 (19) 40 (43).05 No. of nodules 1 (1 50 mm) 124 (92) 68 (82) 154 (77) (77) 18 (58) 65 (69).22 1( 30 mm) 92 (68) 58 (70) 80 (40) (53) 13 (42) 48 (51).59 1 (31 50 mm) 32 (24) 10 (12) 74 (37) (24) 5 (16) 17 (18) (8) 14 (17) 29 (15).11 7 (15) 10 (32) 21 (22) (1) 16 (8) (8) 3 (10) 8 (9).97 FP (ng/ml) (63) 46 (55) 126 (63) (57) 15 (48) 53 (57) (24) 34 (41) 43 (22) (15) 9 (29) 20 (21) (12) 2 (2) 18 (9).05 6 (13) 6 (19) 18 (19) (1) 1 (1) 12 (6).04 7 (15) 1 (4) 3 (3).02 Abbreviations: SGR, San Giovanni Rotondo; BO, Bologna; NA, Naples; LO, London; GH, Ghent; MI, Milan; PEI, percutaneous alcohol injection; HCV, hepatitis C virus; HBV, hepatitis B virus; FP, alpha fetoprotein, OLT, orthotopic liver transplantation. *Data between parentheses are percent values. Results Patient Selection Data on 696 patients with HCC, 484 treated by PEI and 212 transplanted, were received from the 6 participating centers. Overall, 107 patients (67 and 40 patients from the PEI or OLT series, respectively) were dropped from the final analysis owing to one of the following reasons: single lesion larger than 50 mm (n 15), more than 3 nodules (n 13), multifocal ( 3 lesions) disease with at least 1 nodule larger than 30 mm (n 33), extrahepatic spread (n 11), portal thrombosis (n 7), and incomplete data (n 28). The final dataset refers to 589 patients with early HCC, as identified by the Milan criteria (7); of them, 417 (70.8%) had been treated with PEI and the remaining 172 (29.2%) had been successfully transplanted. Baseline Features Among the 417 patients treated with PEI, age and gender were not differently distributed within the 3 centers, the majority of patients being males older than 60 years of age (Table 1). Hepatitis C virus infection was the leading cause of liver disease, although the distribution of the single etiologic factors varied significantly from one center to another. The centers in San Giovanni Rotondo and Naples had treated mainly patients in CTP class A, whereas the majority of those

4 1358 Andriulli et al. Table 2. Univariate Analysis (Between Centers) of Characteristics of Patients Who Underwent Percutaneous Ethanol Injection and Orthotopic Liver Transplantation* Factor PEI (n 417) OLT (n 172) P Value Age (years) mean SD years 73 (17) 153 (89) years 344 (83) 19 (11) Gender Male 307 (74) 149 (87).0006 Female 110 (26) 23 (13) Etiology of cirrhosis HCV 305 (73) 78 (45).0001 HBV 40 (10) 42 (24).0001 Ethanol 17 (4) 24 (14).0001 Crypto 43 (10) 13 (8).3 Other 12 (3) 15 (9).002 Child-Turcotte-Pugh class A 270 (65) 39 (23).0001 B 126 (30) 72 (42).006 C 21 (5) 61 (35).0001 No. of nodules 1 (1 50 mm) 346 (83) 119 (69) ( 30 mm) 230 (55) 86 (50).25 1 (31 50 mm) 116 (28) 33 (19) (13) 38 (22) (4) 15 (9).02 FP (ng/ml) (62) 95 (55) (26) 36 (21) (8) 30 (18) (4) 11 (6).13 Abbreviations: PEI, percutaneous alcohol injection; OLT, orthotopic liver transplantation; HCV, hepatitis C virus; HBV, hepatitis B virus; FP, alpha fetoprotein. *Data between parentheses are percent values. from the Bologna center were staged B or C. The distribution of both number and size of HCC nodules varied significantly from one center to another; however, no significant correlation was found between number of PEI sessions and number and size of HCC nodules (P.12). The 172 patients who underwent OLT showed more homogeneous baseline features in the within-center analysis (Table 1). Statistically significant differences were observed for age (in the London center, 25% of patients were older than 60 years), hepatitis C virus etiology (in the Milan Center, patients were less frequently infected by hepatitis C virus), and CTP score (patients in stage A were less frequently transplanted in the Milan center). Median waiting times in the Milan, London, and Ghent centers were 247, 36, and 90 days, respectively. While on the waiting list, 105 patients (61%) had been treated with PEI (n 20), thermal ablation (n 6), or arterial embolization (n 79). Only 6 enlisted patients at the Milan center did not receive a donor liver for HCC progression. When the whole series of patients treated with PEI was compared with the transplant series (Table 2), all considered baseline features were differently distributed. The 417 patients treated with PEI were older than the transplanted ones; the majority of patients in each of the 2 series were males and infected with hepatis C virus, but with a significantly different distribution between them; most CTP A patients were treated with PEI, whereas more than two-thirds of transplanted patients were in stages B or C; unifocal disease was predominant in the PEI series, whereas multifocal disease was slightly more frequently observed in the OLT series.

5 PEI or OLT in Cirrhotic Patients With Early HCC 1359 for OLT complications, 20 for liver / other diseases, and 11 for unknown causes). The overall 1-year, 3-year, 5-year, and 10-year cumulative tumor-free survival rates after PEI were 70.7%, 38.3%, 25.3%, and 18.0%, respectively, and were 97.2%, 94.6%, 84.6%, and 82.2%, respectively, after OLT (P.0001) (Fig. 2). Figure 1. Patient survival rates in the PEI-treated group compared with the OLT group. Mortality and Short-Term Results At the time of analysis, 233 patients (55.6%) from the PEI series and 56 (32.6%) from the OLT series had died (P.0001). The mean follow-up was (range: 1-156) months and (range: 1-158) months in the 2 series of patients, respectively (P.14). Perioperative deaths (within 1 month of treatment) occurred in 2 and 17 patients who underwent PEI or OLT, respectively (P.0001). None of these patients died of complication related to HCC. The surgical mortality rate was 12.8%, 3.2%, and 10.6% in the London, Ghent, and Milan centers (P.36), respectively. Overall Patient Survival and Tumor-Free Survival Rates The 1-year, 3-year, 5-year, and 10-year overall cumulative survival rates after PEI were 85.3%, 58.3%, 36.1%, and 15.5%, respectively, and were 80.7%, 70.2%, 66.3%, and 49.1%, respectively, after OLT (Fig. 1). There was a significant difference in overall survival (P.0001). Of the 233 PEI treated patients who died during the follow-up, 145 had HCC recurrence and died for either tumor progression (n 116) or liver-related or other diseases (n 29). The remaining 88 died without HCC recurrence and the causes of deaths were ascribed to liver / other disease (n 82) or to unknown reasons (n 6). When HCC recurred, the administered treatment consisted of further PEI sessions (n 123), thermal ablation (n 11) or arterial embolization (n 11). Of the 56 OLT-treated patients who died during the follow-up, 14 had HCC recurrence (5 died for HCC and 9 for liver / other diseases) and 42 did not (11 died Prognostic Factors The influence of various prognostic factors on overall and tumor-free survival is shown in Table 3. In PEItreated patients, survival was significantly related to CTP status, with a mean survival time of 67, 38, and 31 months for classes A, B, and C, respectively (P.0001). In these patients, survival was also related to the etiology of the underlying cirrhosis, with a mean survival time of 54 and 68 months for viral (hepatitis C virus and hepatitis B virus related) and nonviral cirrhosis, respectively (P.03). Conversely, neither the number of nodules nor other variables included in the analysis, such as age, gender, and serum levels of -fetoprotein were significantly related to survival. In OLT patients, survival was unrelated to CTP status, with a mean survival time of 80, 90, and 95 months in classes A, B, and C, respectively (P.95). In these patients, survival was also unrelated to the etiology of the underlying cirrhosis, with a mean survival time of 87 and 105 months for viral and nonviral cirrhosis, respectively (P.76). Neither the number of nodules nor other factors included into the analysis, such as age, gender, and serum levels of -fetoprotein were significantly related to survival. The proportions of surviving patients in relation to the hepatic functional reserve are given in Figure 3: survival was significantly better in OLT- than in PEI- Figure 2. Tumor-free survival rates in the PEI-treated group compared with the OLT group.

6 1360 Andriulli et al. Table 3. Univariate Analysis of Prognostic Factors for Patient and Tumor-Free Survival Rates Factor PEI (n 417) Patient Survival (Mean in Months SE) OLT (n 172) P* PEI (n 417) Tumor-Free Survival (Mean in Months SE) OLT (n 172) P* Age (years) 60 years years Gender Male Female Child-Turcotte-Pugh class A B C No. of tumors Size of tumors (mm) Etiology of cirrhosis Viral (B and C) Nonviral FP levels (ng/ml) Abbreviations: PEI, percutaneous alcohol injection; OLT, orthotopic liver transplantation; FP, alpha fetoprotein. *The significance of the difference was tested for each subgroup by the Mantel-Cox log-rank test. Value could not be computed because all observations were censored at a maximum of 115 months (i.e., no recurrence occurred). Value could not be computed because all observations were censored at a maximum of 132 months (i.e., no recurrence occurred). Included only patients with unifocal HCC. treated patients. In particular, mean survival times in OLT- and PEI-treated patients were 80 and 67 months in CTP class A (P.057), 90 and 38 months in class B (P.0001), and 95 and 31 months in class C (P.0005) (Table 3). Similarly, when patients were sorted according to the number of nodules, survival was significantly better in OLT-treated than in PEI-treated patients. In particular, mean survival times in the 2 treatment groups were, respectively, 96 and 58 months in patients with unifocal disease (P.0002), 82 and 54 months in patients with 2 nodules (P.025), and 83 and 41 months in patients with 3 nodules (P.48) (Table 3). The lack of statistical significance in the last subgroup of patients is likely to reflect the small size of patients with 3 HCC nodules (n 32) available for the analysis. By considering only patients with unifocal lesion less than 30 mm in size, the mean survival was longer in transplanted patients than in those treated with PEI (98 and 59 months, respectively, P.004) (Table 3). Cox logistic regression analysis was performed to evaluate the influence on survival of the following factors: treatment (OLT vs. PEI), CTP status, number of nodules, and etiology (viral vs. nonviral) of cirrhosis. Only 2 variables were significantly and independently associated with the outcome of patients with early HCC: treatment (P.0001) and CTP status (P.0001). When patient age was included as a time-dependent covariate in the Cox regression model, OLT and CTP status remained as the best outcome predictors. Conversely, neither the number of nodules nor the etiology of the underlying liver cirrhosis entered into the model. The proportions of tumor-free surviving patients in

7 PEI or OLT in Cirrhotic Patients With Early HCC 1361 relation to CTP class are given in Figure 4: tumor-free survival was significantly better in OLT- than in PEItreated patients. In particular, mean tumor-free survival times in OLT and PEI patients were 98 and 49 months in CTP class A (P.0001), 121 and 39 months in class B (P.0001), and 139 and 35 months in class C, respectively (P.0001) (Table 3). Similarly, when patients were sorted according to the number of nodules, tumor-free survival was significantly better in OLT- than in PEItreated patients. In particular, mean tumor-free survival times in the 2 treatment groups were 141 and 50 months in patients with unifocal disease (P.0001), 103 and 41 months in patients with two nodules (P.0001), and 92 and 29 months in patients with 3 nodules, respectively (P.005) (Table 3). Cox logistic regression analysis showed that only treatment was independently associated with the tumor-free survival of patients with early HCC Figure 3. Patient survival rates in the PEI-treated group compared with the OLT group when the patients were sorted according to their preoperative CTP status. Figure 4. Tumor-free survival rates in the PEI-treated group compared with the OLT group when the patients were sorted according to their preoperative CTP status.

8 1362 Andriulli et al. (P.007). When patient age was included as a timedependent covariate in the regression model, treatment remained as the best predictor of recurrence in HCC patients. Conversely, CTP status, the number of nodules, and the etiology of the underlying liver cirrhosis did not enter into the model. Discussion For cirrhotic patients with HCC diagnosed at an early stage according to the Milan criteria, 7 recently issued guidelines propose surgical resection, OLT, and percutaneous ablation procedures, such as PEI, as curative treatments capable of improving the natural history of the disease. 1,2 However, evidence supporting the value of OLT as the primary therapeutic option for patients with early HCC arising on a cirrhotic liver are rapidly growing. With the assumption that surgical resection and PEI achieve comparable outcomes, 3,9 11 the present study clearly shows a survival advantage and a very low tumor recurrence rate for patients treated with OLT over those treated with PEI. The benefit in overall survival and tumor-free survival has been clearly demonstrated in transplanted patients in CTP classes B and C, independently from the number or size of HCC nodules. In OLT patients in CTP class A, the benefit was still significant for tumor-free survival, whereas it approached significance for overall survival. However, a statistical error could not be excluded in our study, since only 39 cirrhotic patients in CTP class A underwent OLT. Future studies should better address this issue by enrolling more OLT patients with early HCC and good liver function. Our findings are even more impressive if one considers that the 2 series of patients had different baseline features, with OLT patients having a more impaired liver function and a higher tumor burden when compared to PEI patients. Indeed, 77% of transplanted patients were in CTP class B or C in comparison to 35% of those treated with PEI, and multifocal (2 or 3 nodules) HCC occurred in 31% and 17% of OLT and PEI patients, respectively. These findings are not unexpected as both surgical resection and PEI are targeted at removing or destroying the tumor, whereas only OLT has the advantage of replacing the diseased liver together with the tumor itself. Survival rate in our OLT patients could be influenced by their younger age in comparison to the age of patients treated with PEI. Although this age difference reflects the policy of transplant centers to reserve OLT for younger patients, it actually has no influence on overall and tumor-free survival rates, as shown by the results of the Cox regression analysis: when patient age was entered into the model, it did not reach statistical significance. Conversely, only treatment and, to a lesser degree, CTP class remained the best predictors of a favorable outcome. Another interesting finding of our study is that survival rate in transplanted patients is somewhat inferior to the rates reported from other studies. 7,8,17 For instance, in the classical paper by Mazzaferro et al., 7 the actuarial 4-year survival rate of transplanted patients with early HCC was 75%, slightly higher than we observed. Likely explanations of this finding are the exclusion, in our study, of patients with incidental tumors discovered during pathological examination of the explanted liver, and the median size of tumor, which was 1.5 cm in the Mazzaferro series, 7 and 2.2 cm in our study. The good survival outcome in OLT patients could be somehow weakened by taking into account all patients with early HCC who were enlisted for OLT but dropped out due to tumor growth while waiting for a donor organ. In centers with long waiting times before OLT, the intention-to-treat analysis of patient survival after OLT revealed poor figures. 18 In OLT patients, we actually performed a per-protocol analysis of overall survival and tumor-free survival. However, the mean waiting times for OLT in the 3 transplant centers were equal to or less than 8 months and only 6 enlisted patients were unable to receive a donor liver due to tumor progression during the study time. Moreover, it is of interest that, in an attempt to prevent tumor growth and dissemination before OLT, an active treatment with ablation therapies, surgical resection, or arterial embolization has been reported to have a favorable effect on post-olt survival. 19,20 Indeed, 61% of the HCC patients eligible for OLT in the current study underwent some type of adjuvant therapy while waiting for transplantation. Consequently, we believe that survival rates in our OLT patients would have not changed if an intention-to-treat analysis in place of a per-protocol analysis had been carried out. In conclusion, in patients with early HCC and still preserved liver function, OLT provided a survival advantage over PEI, although a nonsignificant one. However, the ablative procedures did not protect patients from tumor recurrence, which approached 80% after 10 years from initial treatment. Conversely, OLT should be proposed as the mainstay of therapy for all patients with early HCC and impaired liver function. In the future, this therapeutic option will be the preferred one even for patients with good liver function, whether perioperative mortality will further decrease and the problem of organ shortage will be solved.

9 PEI or OLT in Cirrhotic Patients With Early HCC 1363 References 1. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma: conclusion of the Barcelona-2000 EASL Conference, European Association for the Study of the Liver. J Hepatol 2001; 35: Hassoun Z, Gores GJ. Treatment of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2003;1: Hoshida Y, Shiratori Y, Omata M. Difficulties in conducting controlled trials in radical therapies for non advanced hepatocellular carcinoma. Hepatology 2000;32: Iwatsuki S, Starzl TE, Sheahan DG, Yokoyama I, Demetris AJ, Todo S, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214: Ringe P, Pichlmayr R, Wettekind C, Tusch G. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg 1991;15: Moreno P, Jaurrieta E, Figueras J, Benasco C, Rafecas A, Fabregat J, et al. Orthotopic liver transplantation: treatment of choice in cirrhotic patients with hepatocellular carcinoma? Transplant Proc 1995;27: Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: Llovet JM, Bruix J, Fuster J, Castells A, García-Valdecasas JC, Grande L, et al. Liver transplantation for treatment of small hepatocellular carcinoma: the TNM classification does not have prognostic power. Hepatology 1998;27: Livraghi T, Bolondi L, Buscarini L, Cottone M, Mazziotti A, Morabito A, Torzilli G. No treatment, resection and ethanol injection in hepatocellular carcinoma: a retrospective analysis of survival in 391 patients with cirrhosis. J Hepatol 1995;22: Colella G, Bottelli R, De Carlis L, Sansalone CV, Rondinara GF, Alberti A, et al. Hepatocellular carcinoma: comparison between liver transplantation, resective surgery, ethanol injection, and chemoembolization. Transpl Int 1998;11(Suppl 1):S193 S Castells A, Bruix J, Brú C, Fuster J, Vilana R, Navasa M, et al. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993;18: Figueras J, Jaurrieta E, Valls C, Ramos E, Serrano T, Rafecas A, et al. Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy. J Am Coll Surg 2000;190: Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD, Howard RJ. Liver transplantation for hepatocellular carcinoma. Ann Surg 2001;233: Yamamoto J, Iwatsuki S, Kosuge T, Dvorchik I, Shimada K, Wallis MJ, et al. Should hepatomas be treated with hepatic resection or transplantation? Cancer 1999;86: Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH, DeMatteo RP. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003;238: Di Stasi M, Buscarini L, Livraghi T, Giorgio A, Salmi A, de Sio I, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J Gastroenterol 1997;32: Molmenti EP, Klintmalm GB. Liver transplantation in association with hepatocellular carcinoma. An update of the International Tumor Registry. Liver Transpl 2002;8: Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30: Llovet JM, Mas X, Aponte J, Fuster J, Navasa M, Bruix J, BCLC Group. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50: Harnois DM, Steers J, Andrews JC, Rubin JC, Pitot HC, Burgart L, et al. Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl Surg 1999;5: