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10.1245/s10434-006-9204-8
Annals of Surgical Oncology 13:1500-1510 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Applicability of the Milan Criteria for Determining Liver Transplantation as a First-Line Treatment for Hepatocellular Carcinoma

Daisuke Morioka, MD, PhD1,2, Kuniya Tanaka, MD, PhD1, Ken-ichi Matsuo, MD, PhD1, Kazuhisa Takeda, MD, PhD1, Michio Ueda, MD, PhD1, Mitsutaka Sugita, MD, PhD1, Yasuhiko Nagano, MD, PhD1, Itaru Endo, MD, PhD1, Hitoshi Sekido, MD, PhD1, Shinji Togo, MD, PhD1 and Hiroshi Shimada, MD, PhD1

1 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
2 Organ Transplant Unit, Kyoto University Hospital, 54, Shogoin-Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan

Correspondence: Address correspondence and reprint requests to: Daisuke Morioka, MD, PhD; E-mail: dmorioka{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: To determine whether or not the Milan criteria (MC) should be used to determine the applicability of liver transplantation (LT) as a first-line treatment for patients with cirrhosis with hepatocellular carcinoma (HCC) who are able to endure hepatectomy.

Methods: Retrospective analysis of 82 patients with cirrhosis with HCC who were treated by hepatectomy without LT at our institution between 1990 and 2003.

Results: Of these 82 patients, 48 met the MC. Proportional hazard regression analyses to determine the independent prognostic factors for postoperative cumulative patient and disease-free survival showed that meeting the MC is the strongest prognostic factor for both patient and disease-free survival. The cumulative patient and disease-free survival rates were 76.7% and 28.9%, respectively, at 5 years in patients who met the MC. The cumulative disease-free survival was markedly inferior to those in previously reported series of LT for HCC who met the MC, but the cumulative patient survival was comparable to those in the previously reported series. A comparison of cumulative postoperative survival between patients who met the MC and fulfilled all five factors listed below and patients who met the MC but did not fulfill any of the five factors demonstrated that the latter patients showed statistically significantly worse postoperative patient survival than the former. The five factors included: Model for End-Stage Liver Disease score <10, indocyanine green retention rate at 15 minutes <20%, absence of microscopic fibrous capsular invasion and microscopic intrahepatic metastases, and earlier grade (T1 or T2) of American Joint Committee on Cancer tumor classification.

Conclusions: The MC should not be used to determine the applicability of LT as a first-line treatment for patients with HCC considered able to endure hepatectomy. However, modifying MC with some clinicopathological factors could satisfy the appropriate criteria for applying LT as a first-line treatment for these patients.

Key Words: Hepatocellular carcinoma • Milan criteria • Liver transplantation • Hepatectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Liver transplantation (LT) has been the standard treatment for patients with cirrhosis with hepatocellular carcinoma (HCC) in Western countries ever since Mazzaferro et al.1 reported that the post-LT survival rate for patients with cirrhosis with HCC who met what are known as the Milan criteria (MC) was similar to that for patients with other chronic liver diseases. To meet the MC, the number of tumors must be no more than three, the largest tumor must be no larger than 3 cm in diameter, or there must be a solitary tumor with a diameter no greater than 5 cm. In addition, the tumors must not involve any major portal or venous branches. In Western countries that use LT, the question of whether LT should be used for HCC is no longer debated. Instead, the main debates involving LT for HCC have focused on whether or not to expand the indication for LT to include patients with HCC who deviate from the MC, how to prevent patients on the waiting list from dying as a result of HCC progression, and what the independent prognostic factors are for patients undergoing LT for HCC.2–7 Furthermore, at some transplant centers, LT is the first-line treatment for patients with HCC who meet the MC, regardless of the degree of liver dysfunction.4,7,8

On the other hand, it has been reported that partial hepatectomy in patients with HCC who meet the MC and have adequate liver reserves can be performed with minimal morbidity, and can achieve a 5-year survival rate comparable to that reported for LT.9,10 Furthermore, there is no current evidence that outcomes of LT for patients with HCC who meet the MC and can endure other locoregional treatments, of which hepatectomy is the mainstay,11–14 are better than the outcomes of the other locoregional treatments.

In the present study, we examined patients with cirrhosis with HCC who were treated by hepatectomy without LT to elucidate whether or not MC should be used for determining the applicability of LT as a first-line treatment for patients with cirrhosis with HCC who meet the MC, irrespective of whether individual patients would be able to endure other locoregional treatments in which hepatectomy is the mainstay. The outcomes and independent prognostic factors were assessed, and the survival outcomes were compared between our patients with HCC who met the MC and previously reported series of LT for patients with HCC who met the MC.1,15–17


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between January 1990 and December 2003, a total of 183 patients with nonfibrolamellar HCC were surgically treated without LT at the Department of Gastroenterological Surgery of Yokohama City University Hospital. Of these, 95 patients were excluded from the study because their background nontumoral hepatic parenchyma was normal or indicative of chronic hepatitis. Furthermore, six patients with cirrhosis were excluded because they had received ablation therapy alone at the initial surgery. The remaining 82 patients with cirrhosis with HCC who were treated by hepatectomy were enrolled into the present study. The diagnosis of HCC was established by the dynamic study of computed tomography18 or dynamic magnetic resonance imaging.19 In this monograph, the hepatic segments were classified into nine segments (segment I, Spiegel lobe; to segment IX, paracaval portion) according to Couinaud’s nomenclature for liver segmentations.

The operative procedures were defined as follows: segmentectomy, a complete resection of a Couinaud’s segment; partial resection, resection of tumors independent of the Couinaud’s segments; major hepatectomy, a surgery consisting of four or more segmentectomies; minor hepatectomy, a surgery consisting of three or fewer segmentectomies; anatomical resection, a surgery consisting entirely of segmentectomies; nonanatomical resection, a surgery consisting of at least one partial resection and, in some cases, local ablation therapies such as microwave coagulation therapy, radiofrequency ablation, and ethanol injection;13,20 and anatomical + non-anatomical resection, a surgery consisting of at least one segmentectomy as well as one or more partial resections and/or ablations.

Our basic therapeutic strategy for HCC was as follows. Patients with HCC were evaluated to determine whether they would be able to endure surgical tumor resection, except in patients with uncontrollable ascites. We used the prediction score (PS) introduced by Yamanaka et al.21 to determine the safety limit for the extent of hepatectomy in each patient. The PS was calculated by the following formula: PS = –84.6 + .933X1 + 1.11X2 + .999X3. The three variables were as follows: X1, resection volume (%) of nontumoral hepatic parenchyma calculated by computed tomography or magnetic resonance imaging volumetry with contrast enhancement; X2, indocyanine green retention rate (%) at 15 minutes (ICGR15) investigated within 1 week before the surgery in each patient; and X3, the age of each patient. In this series, a hepatic nontumoral parenchymal resection was performed so that the PS did not exceed a value of 40 for patients with cirrhotic liver diagnosed by preoperative imaging and biochemical assessment.

We applied anatomical resection to all tumors unless the PS exceeded the safety limit for a particular patient, in which case we performed anatomical resection + nonanatomical resection or nonanatomical resection as appropriate. In addition, although we basically attempted to surgically remove all tumors, tumors <3 cm in size were sometimes treated with ablation therapies rather than being resected. Between January 1992 and December 2000, transcatheter arterial infusion was performed for the patients in whom at least one of the following factors was observed: microscopic fibrous capsular invasion, microscopic intrahepatic metastases, and microscopic vascular invasion, as we previously reported.22 After January 2001, hepatic arterial infusion immunochemotherapy with 5-fluorouracil and interferon alfa23 was performed for patients with tumor invasion of the major portal and/or venous branches. Hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin was provided24 to patients who met the earlier criteria for transcatheter arterial infusion described above. For cases of recurrent HCC, the selection criteria for repeat hepatectomy were the same as those for the initial surgery.

For these 82 patients, we collected the following data: age at initial surgery, sex, hepatitis B and/or C virus infection, Child-Pugh classification, Model for End-Stage Liver Disease (MELD) score,25 preoperative serum alfa-fetoprotein level (ng/mL), ICGR15 (%), the history of preoperative treatment and operative procedures, and tumor characteristics (number of tumors, maximum diameter, staging according to the staging system of the American Joint Committee on Cancer [AJCC], the histopathological findings of the tumors, and whether or not the tumor characteristics met the MC). When counting the number of tumors, small intrahepatic metastases that could only be identified microscopically were excluded. We also collected data on the postoperative therapies for preventing recurrence, disease-free survival, site of recurrence, and patient survival. The tumor characteristics were ultimately determined by the histopathological findings of resected specimens. Two pathologists evaluated the pathological findings in each resected specimen and came to a final consensus.

The follow-up was continued until November 2004 or death.

The statistical analysis was performed by a univariate analysis as follows. Fisher’s exact probability test was used for categorical variables. Numerical variables were analyzed by the Mann-Whitney U-test, the Kolmogorov-Smirnov test, or the Kruskal-Wallis test. Survival was assessed by Kaplan-Meier life table analysis with the Breslow-Gehan-Wilcoxon test. By multivariate analysis, variables found to be significant at P < .05 by univariate analyses and/or considered important on the basis of logical and/or biomedical grounds were entered into the backward step-down Cox proportional hazard regression analysis to identify independent prognostic factors. The methods of May and Hosmer were used to compute overall goodness-of-fit {chi}2 measures for the final Cox models. Results are shown as percentages of patients or as median (range). Commercial statistical software (SPSS 12.0 for Windows; SPSS, Chicago, IL) was used, and two-tailed P values less than .05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of Patients and Tumors
Most patients were men in their 60s who had the hepatitis B or C virus (Table 1Go). Twenty patients received preoperative treatments for HCC. In 48 of the 82 patients, the tumor characteristics clinicopathologically met the MC.


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  		TABLE 1. Patients and tumor characteristics
 
Most variables related to the patient characteristics, operative procedures, and tumor characteristics showed statistically significant differences between the patients who met the MC and those who did not (Table 2Go).


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  		TABLE 2. Comparison of perioperative variables between patients with hepatocellular carcinoma who met Milan criteria and those who did not
 
Surgical Outcomes
The postoperative observation period after the initial surgery ranged from .4 to 181.2 months, with a median of 37.6 and a mean of 43.4 months. Four patients who did not meet the MC in the early years (1990 to 1992) of our treatment program for HCC died as a result of hepatic failure after hepatectomy in the recuperative hospital stay after the surgery for HCC. Neither major surgical complications, such as postoperative hemoperitoneum or major bile leakage necessitating relaparotomy, nor any events necessitating readmission to an intensive care unit stay were observed in the other 78 patients. To date, recurrent HCC has developed in 54 of the 82 patients. The time from the initial surgery to recurrence was significantly (P < .001) longer in patients who met the MC than in those who did not (Table 3Go). Of these 54 patients with recurrent HCC diagnosed for the first time, 45 had HCC in the remaining liver, whereas only 4 patients had an extrahepatic recurrence alone, and the remaining 5 patients had recurrent HCC either in the remaining liver or in extrahepatic sites. There were no statistically significant differences between the sites of recurrence; nevertheless, the availability and mode of treatment for the first recurrence were significantly different between patients who met the MC and those who did not (Table 3Go). The overall cumulative patient survival rates were 97.4% at 1 year, 48.3% at 5 years, and 23.8% at 10 years. The overall cumulative disease-free survival rates were 72.0% at 1 year, 12.8% at 5 years, and 10.7% at 10 years (Fig. 1Go).


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  		TABLE 3. Comparison of site of recurrence and treatments for the recurrence between patients who met Milan criteria and those who did not
 

Figure 1
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  		FIG. 1. Cumulative postoperative patient and disease-free survival rates of cases overall.

 
In patients who met the MC and who were treated by hepatectomy, the cumulative patient and disease-free survival rates were 100% and 83.3% at 1 year, 76.7% and 28.9 at 5 years, and 56.0% and 23.1% at 10 years, respectively. For patients who did not meet the MC, the cumulative patient and disease-free survival rates were 74.8% and 48.6% at 1 year, 15.1% and 0% at 5 years, and 0% and 0% at 10 years, respectively. The patient and disease-free survival rates were significantly higher in patients who met the MC than in those who did not (P < .001) (Fig. 2Go).


Figure 2
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  		FIG. 2. Comparison of the cumulative postoperative patient (A) and disease-free (B) survival rates between patients who met the Milan criteria (MC) and those who did not.

 
Independent Prognostic Factors for Disease-Free and Patient Survival in Overall Cases
Variables that univariately affected overall patient survival significantly are listed in Table 4Go. In addition, patient age (<65 years or ≥65 years), sex, MELD score (<10, or ≥10), ICGR15 (<20% or ≥20%), and postoperative therapy for preventing recurrence (provided or not) were entered into the backward step-down Cox proportional hazard regression analysis to identify independent factors that affected disease-free/patient survival.


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  		TABLE 4. Factors significantly affecting overall patient survival by univariate analyses
 
As a result, meeting the MC and absence of microscopic intrahepatic metastases are the preferred independent prognostic factors for disease-free survival (Table 5Go), and meeting the MC, MELD score <10, maximum tumor size <30 mm, earlier grade (T1 or T2) of AJCC tumor (T) classification, and absence of microscopic intrahepatic metastases are preferred for patient survival (Table 5Go). For both disease-free and patient survival, meeting the MC is the most advantageous independent prognostic factor.


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  		TABLE 5. Results of the backward step-down Cox proportional hazard regression analysis to identify factors independently affecting overall disease-free and patient survival
 
Comparison of Survival Outcomes Between Our Patients With HCC Treated by Hepatectomy Who Met the MC and Previously Reported Series of LT for HCC That Met the MC
Table 6Go compares the survival outcomes between our patients with HCC who met the MC and previously reported series of LT for HCC that met the MC. In the present series, patients with HCC who met the MC and were considered able to endure hepatectomy had a cumulative disease-free survival rate of 28.9% and a cumulative patient survival rate of 76.7% at 5 years. The cumulative patient survival rate was as good as or better than those in previously reported series of LT for HCC that met the MC. In contrast, the disease-free survival rate was markedly inferior to those in previously reported series.


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  		TABLE 6. Comparison of survival outcomes between patients with cirrhosis with hepatocellular carcinoma (HCC) who met Milan criteria and previously reported series concerning liver transplantation for patients with cirrhosis with HCC who the Milan criteria
 
Independent Prognostic Factors for Disease-Free and Patient Survival Rates in 48 Patients Treated by Hepatectomy Who Met the MC
Variables that univariately significantly affected postoperative patient survival of the 48 patients who met the MC are listed in Table 7Go. In addition, patient age (<65 or ≥65 years), sex, ICGR15 (<20% or ≥20%), MELD score (<10 or ≥10), tumor surgical margin (<5 mm or ≥5 mm), and postoperative therapy for preventing recurrence (provided or not) were entered into the backward step-down Cox hazard proportional analysis to identify the independent prognostic factors for disease-free or patient survival of the 48 patients who met the MC (Table 8Go). As a result, the absence of microscopic venous invasion and microscopic intrahepatic metastases is preferred for disease-free survival of the 48 patients who met the MC. Furthermore, MELD score <10, ICGR15 <20%, absence of microscopic fibrous capsular invasion, absence of microscopic intrahepatic metastases, and earlier grade (T1 or T2) of AJCC T classification are the preferred prognostic factors for postoperative patient survival of the 48 patients who met the MC (Table 8Go).


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  		TABLE 7. Factors significantly affecting patient survival by univariate analyses for 48 patients who met Milan criteria
 

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  		TABLE 8. Results of backward step-down Cox proportional hazard regression analysis to identify factors independently affecting disease-free and patient survival of 48 patients who met Milan criteria
 
Figure 3Go compares the postoperative cumulative patient survival rates between patients who met the MC and fulfilled all five preferred prognostic factors—including ICGR15 <20%, MELD score <10, absence of microscopic fibrous capsular invasion, absence of microscopic intrahepatic metastases, and AJCC T1 or T2—and patients who met the MC but who did not have at least one of the five preferred prognostic factors. The cumulative postoperative patient survival rates were 100% at 1, 3, 5, 7, and 9 years in patients who met the MC and fulfilled all five factors. For the other patients, the rates were 100% at 1 year, 91.7% at 3 years, 68.9% at 5 years, 57.4% at 7 years, and 47.8% at 9 years. Thus, among patients who met the MC, the rates were far higher in those with all five factors than in the others.


Figure 3
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  		FIG. 3. Comparison of cumulative postoperative patient survival between patients who met Milan criteria (MC) and fulfilled all five preferred prognostic factors, and patients who met the MC but missed at least one factor.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we corroborated that the survival outcomes of patients with HCC who met the MC and were considered able to endure surgical treatments other than LT were similar to those of previously reported series, as Poon et al.9 and Cha et al.10 previously reported. Further, we demonstrated that the MC in themselves are the strongest advantageous independent prognostic factor for patients with HCC who can endure hepatectomy. In other words, although the MC can be a good predictor of survival outcomes for patients with cirrhosis with HCC in whom liver dysfunction has progressed and in whom surgical treatments other than LT are not an option,1,11,15–17 the MC are not integrated sufficiently to determine the usefulness of LT as a first-line treatment of patients with HCC who have good hepatic reserves and can endure non-LT surgical treatments in which hepatectomy is the mainstay. Recently, there has been controversy as to which of the following should be the preferred therapeutic strategy for patients with HCC with good hepatic reserves who meet the MC and can endure surgical treatments other than LT in Western countries: straightforward LT4 or the use of hepatectomy as a bridge to LT.6 From the results of the present study, it is expected that straightforward LT could provide a survival benefit to very few of our patients with HCC who meet the MC. Meanwhile, if the strategy of using hepatectomy as a bridge to LT were applied to our patients with HCC who met the MC, a certain population of our patients with HCC who meet the MC would not benefit from LT as a result of extrahepatic recurrence or an aggressive form of intrahepatic recurrence, such as major vascular involvement or numerous intrahepatic recurrent lesions.

On the other hand, we also demonstrated that the survival outcomes of our patients with HCC who met the MC and fulfilled the five preferred prognostic factors, including ICGR15 <20%, MELD score <10, absence of microscopic fibrous capsular invasion, absence of microscopic intrahepatic metastases, and earlier grade (T1 or T2) of AJCC T classification, were statistically significantly better than those who met the MC but missed at least one of those factors. In this series, recurrent HCC was likely to occur extrahepatically or to be characterized by numerous intrahepatic recurrent lesions or major vascular involvement, or the hepatic reserves were apt to be deteriorated at the time of recurrence, such that it was not possible to perform any interventional therapies for recurrence in patients who met the MC but missed one of the five factors. Thus, straightforward LT might be beneficial for such patients.

With regard to the use of hepatectomy as a bridge to LT, repeat hepatectomy was frequently chosen as the treatment for recurrent HCC after hepatectomy before the standardization of LT for HCC.12,26–29 Minagawa et al.12 reported that the absence of portal invasion at the second hepatectomy, single HCC at primary hepatectomy, and a disease-free interval of 1 year or more after primary hepatectomy were the independent advantageous prognostic factors for a second hepatectomy for recurrent HCC, and patients with all three of these factors showed 3- and 5-year survival rates of 100% and 86%, respectively, after the second hepatectomy.12 Thus, LT might be the treatment of choice for patients with recurrent HCC that does not fulfill any of these three criteria. In either case—i.e., whether straightforward LT or hepatectomy as a bridge to LT was chosen for patients with HCC—the present study confirmed that the MC are not sufficiently integrated criteria for patients with HCC with good hepatic reserves who can endure hepatectomy. Thus, further studies will be needed to determine more suitable criteria for the use of LT for patients with cirrhosis with HCC who can endure hepatectomy.

At present, however, it is difficult to conclude that straightforward LT is a reasonable strategy for such patients, because locoregional therapies in which hepatectomy is the mainstay could provide survival outcomes similar to those of LT. One explanation for the seemingly contradictory findings—that on the one hand, disease-free survival of our patients with HCC who met the MC was markedly inferior to that reported for LT for patients with HCC who met the MC, while on the other hand, the patient survival of our patients with HCC who met the MC was comparable to that reported for LT—may be that dynamic computed tomography or magnetic resonance imaging in our follow-up of patients with HCC was performed every 3 months after surgery for 2 years, and thereafter every 6 months. If recurrent HCC was diagnosed, we promptly selected the available treatments for recurrence and administered those. On the basis of these results in the present study, it may be concluded that approximately three-quarters of straightforward LTs for such patients with HCC are unnecessary, representing a substantial waste of LT donors.

In conclusion, the MC should not be used to determine the applicability of LT as a first-line treatment for patients with HCC who can endure other locoregional treatments in which hepatectomy is the mainstay. However, modifying the MC with some clinicopathological variables might lead to integrated criteria that could be useful for determining the applicability of LT as a first-line treatment for patients with HCC, irrespective of the degree of liver dysfunction.


   ACKNOWLEDGMENTS
 
Supported in part by grants from the Yokohama City University Liver Transplant Indication Committee.

Received for publication July 18, 2006. Accepted for publication July 20, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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