Journal of Gastrointestinal Surgery

, Volume 16, Issue 11, pp 2120–2125

Comparison Between Living Donor Liver Transplantation Recipients Who Met the Milan and UCSF Criteria After Successful Downstaging Therapies

Authors

  • JY Lei
    • Liver Transplantation CenterWest China Hospital of Sichuan University
    • Liver Transplantation CenterWest China Hospital of Sichuan University
Original Article

DOI: 10.1007/s11605-012-2019-y

Cite this article as:
Lei, J. & Yan, L. J Gastrointest Surg (2012) 16: 2120. doi:10.1007/s11605-012-2019-y

Abstract

Background and Aims

Various downstaging therapies were introduced to liver recipients who could not meet the relative criteria for liver transplantation, and many endpoints were reported. The most common criteria used were the Milan criteria and the University of California, San Francisco (UCSF) criteria. However, no comparison was made between them, and we attempted to find possible differences between the living donor liver transplantation (LDLT) patients who met the Milan criteria and those who met the UCSF criteria after accepting preoperative downstaging therapies.

Materials and Methods

We performed a retrospective study of all 72 patients at our center from January 2003 to March 2009 who were diagnosed with advanced hepatocellular carcinoma but accepted various downstaging therapies. Some patients met the Milan criteria (group 1), and some met the UCSF criteria (group 2) but not the Milan criteria. We collected the data from the two groups and then compared the preoperative demographic data, downstaging therapies, intraoperative data from LDLT, and the recovery and complications after LDLT. Survival rates were compared using Kaplan–Meier analysis.

Results

Only 44 patients (61.1 %) met the criteria for liver transplantation, 21 cases met the Milan criteria (group 1), and 23 cases met the UCSF criteria (group 2) but not the Milan criteria. All of the 44 patients accepted right lobe living liver donor liver transplantation in our center. The difference in the baseline characteristics between the two groups did not reach statistical significance. The mean number of downstaging treatments per patient was 1.81 ± 0.35 in group 1 and 1.83 ± 0.41 in group 2 (P = 0.928). Most of the patients received only one downstaging treatment, and transcatheter arterial chemoembolization (TACE) was the most common downstaging therapy. Four patients suffered complications after downstaging therapies: intra-abdominal hemorrhage after right hepatectomy, upper gastrointestinal hemorrhage after TACE, biliary fistula after resection, and hand–foot syndrome after taking sorafenib. All complications after LDLT, classified according to the Clavien–Dindo system, were compared within the two groups, and the calculated score of the complications in group 1 was 1.48 ± 1.63, which was greater than that of group 2 (1.39 ± 1.64), but this difference did not reach statistical significance (P = 0.865). The 1-, 3-, and 5-year survival rates were 90.4, 76.2, and 71.4 % in group 1 and 91.3, 73.9, and 69.6 % in group 2, respectively (P > 0.05). Seven patients (three in group 1 and four in group 2) had tumor recurrence after a median follow-up period of 72 months. The pathology findings were not different between the two groups.

Conclusion

Recipients who meet the Milan or UCSF criteria after accepting successful preoperative downstaging therapy in LDLT can achieve the same result.

Keywords

DonorLiverTransplantationDownstaging

Abbreviations

UCSF

University of California, San Francisco

HCC

Hepatocellular carcinoma

LDLT

Living donor liver transplantation

TACE

Transcatheter arterial chemoembolization

LT

Liver transplantation

RAF

Radiofrequency ablation

EI

Ethanol injection

UNOS

United Network for Organ Sharing

AFP

Alpha-fetoprotein

BMI

Body mass index

ICU

Intensive care unit

GRWR

Graft-to-recipient weight ratio

OLT

Orthotopic liver transplantation

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide1,2 and the third most common cause of cancer death.3 In the Asia-Pacific region, the incidence of liver cancer is 14–36 per 100,000 men, and China alone accounts for 55 % of HCC cases worldwide.1 The high incidence of liver cancer is closely linked to the risk factors for HCC, namely chronic infection with hepatitis B virus in the Chinese and hepatitis C virus in the Japanese.

Liver transplantation (LT) has been shown to be the best treatment option for patients who meet the Milan criteria (one lesion ≤5 cm in diameter or two to three lesions <3 cm in diameter) or the University of California, San Francisco (UCSF) criteria (1 lesion ≤6.5 cm in diameter or two to three lesions, each ≤4.5 cm in diameter with a total diameter of ≤8 cm). In 1996, Mazzaferro et al.4 introduced the “Milan criteria” and reported those patients' recurrence-free survival rates at 85 and 92 %, respectively, at 4 years. In 2001, Yao et al.5 proposed an expansion of the Milan criteria for HCC liver transplant candidates, which is termed the UCSF criteria. He reported that patients transplanted with the UCSF criteria demonstrated 1- and 5-year survival rates of 90 and 75 %, respectively, which were equivalent to the survival rates of those transplanted within the Milan criteria. Now, the Milan criteria and the UCSF criteria are the two main criteria for liver transplantation in liver carcinoma recipients, although there are other criteria5,6 used in the local region and not accepted widely.

For patients with advanced HCC, LT yields a disappointing 5-year survival rate (18–32 %) largely because of tumor recurrence.7,8 Various locoregional procedures, such as transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RAF), ethanol injection (EI), resection, and sorafenib, were introduced to downstage advanced HCC so the patients would meet the criteria for LT. Most of the published reports have used the Milan criteria as the endpoint of downstaging. The Milan criteria and the UCSF criteria were the two main criteria for liver carcinoma liver transplantation with similar recurrence and free survival rates. Many downstaging strategies were introduced to the patients whose initial tumor size and number were out of the UNOS criteria9, but few reports focused on the use of downstaging in living donor liver transplantation.10 In our study, we aimed to detect the possible different outcomes of patients who accepted the downstaging therapies and met the Milan criteria or the UCSF criteria in living donor liver transplantation.

Materials and Methods

From January 2003 to March 2009, 72 patients who were diagnosed with advanced HCC that exceeded the Milan criteria or the proposed UCSF criteria were considered for living donor liver transplantation at our institution. All 72 patients underwent multimodal treatment, including TACE, RAF, EI, sorafenib, and resection, to downstage their tumors so as to meet the criteria for liver transplantation. Every patient accepted one to three downstaging therapies. The HCC diagnoses and the efficiency of the downstaging therapy were based on the radiological characteristics of the HCC and the level of serum AFP. The main exclusive criteria were major vascular invasion and extrahepatic disease. There was no limit to upper size or number of lesions in our study design. Five different therapies (TACE, RFA, EI, resection, and sorafenib) were introduced for the downstaging procedures. The types and numbers of treatments were tailored to each patient according to the tumor characteristics and response. Salvage hepatectomy and radiofrequency ablation were the first choices for a single lesion. TACE was used to control multiple tumors. RFA or EI were applied to address the small lesions in the remnant liver after the salvage hepatectomy. Sorafenib was recommended to Child A patients with advanced HCC after they had accepted other locoregional therapies; Sorafenib alone was never suggested to patient owing to the lack of evidence of its effectiveness as a bridge toward liver transplantation.11

TACE was performed using the standard techniques.12 The treatment was performed using 30 mg of mitomycin, 30 mg of adriamycin, and 100 mg of cisplatinum mixed with lipiodol as the drug carrier. Then, embolization using permanent occlusive particles was performed.

All of the procedures were performed after approval from the Ethics Committee of Sichuan University and local authority was obtained. The donors voluntarily agreed to the transplant and were required to be within the third degree of consanguinity with the recipients in all cases. The preoperative evaluation, the surgical procedure, and the postoperative management of living donor liver transplantation were described in our previous report.13

Statistical Analysis

A two-tailed, unpaired Student's t test was used to compare the mean values for the two groups. The Fisher's exact test was used to compare categorical data. Probabilities (P) were two-sided, and a P value <0.05 was considered significant. The data are presented as the mean ± standard deviation or as the median and range. Overall patient survival and tumor-free rates estimated by the Kaplan–Meier method were compared with log-rank tests. The data were analyzed using SFSS 17.0 computer software.

Results

After one to three downstaging therapies, 44 cases (61.6 %) showed successful downstaging and accepted living donor liver transplantation. The 44 successful cases were divided into two groups based on the outcome of the downstaging result. The downstaged tumors of 21 patients (group 1) met the Milan criterion (one lesion ≤5 cm in diameter or two to three lesions <3 cm in diameter); 23 patients (group 2) ended up within the UCSF criteria (one lesion ≤6.5 cm in diameter or two to three lesions, each ≤4.5 cm in diameter with a total diameter of ≤8 cm) but not the Milan criteria. All of the 44 cases accepted living right lobe liver transplantations in our transplantation center.

No intergroup differences existed between the type or number of treatment modalities (Table 1). The mean number of treatments per patient was 1.81 ± 0.35 in group 1 and 1.83 ± 0.41 in group 2. Most patients (68.2 %) received only one downstaging treatment, 15 patients accepted a single treatment modality in group 1 (71.4 %), and 15 patients in group 2 (65.2 %). TACE was the most common single treatment, followed by resection. Of the 12 patients who underwent combination treatment, seven patients (three in group 1 and four in group 2) had combined resection and RAF, two patients had combined resection and EI, two patients had combined resection and sorafenib, and one patient in group 1 had combined TACE and sorafenib. One patient in group 2 received three different modalities and was diagnosed with advanced liver carcinoma. He underwent local resection of a 7.0-cm lesion in the right lobe, and 12 days later, he accepted TACE for the remaining tumors in the left lobe. When he was discharged, he started sorafenib (400 mg, bid, PO); 2 months after his discharge, he accepted TACE again for obvious enhancement at arterial phase CT. From the 44 patients, a 36-year-old patient required laparotomy for intra-abdominal hemorrhage 9 h after right hepatectomy (Clavien, grade 3). Additionally, a 44-year-old patient was diagnosed with massive hemorrhage of the upper alimentary tract 2 days after TACE (Clavien, grade 2), and a Sengstaken–Blakemore tube successfully achieved hemostasis. Three weeks after starting sorafenib, a patient suffered hand–foot syndrome, and a decreased dosage of sorafenib (800 to 600 mg) resolved the syndrome to the tolerance range (CTC, grade 3). One patient needed persistent drainage for a biliary fistula, and the tube was exacted 21 days after resection (Clavien, grade 1). No complication was observed in the failed downstaging patients (28 cases).
Table 1

Types and number of downstaging treatments

 

Group 1

Group 2

Type of treatments

21

23

Resection only

5 (6)

6 (6)

Resection + RAF

3 (6)

4 (9)

Resection + EI

1 (2)

1 (2)

Resection + sorafenib

1 (2)

1 (2)

Resection + TACE + sorafenib

0

1 (4)

RFA only

2 (3)

1 (1)

TACE only

8 (16)

9 (18)

TACE + sorafenib

1 (3)

0

Number of treatments per patient

1.81 ± 0.35

1.83 ± 0.41

The demographic features of the two patient groups are shown in Table 2. There were no intergroup differences with respect to age, gender, body weight, height, body mass index (BMI), underlying liver disease, relationship with the donor and Meld score, or Child score at the time of living donor liver transplantation.
Table 2

Baseline characteristics of the two groups of patients

 

Group 1

Group 2

P value

21

23

Age

41.90 ± 10.32

40.87 ± 11.23

0.753

Gender (M/F)

9:12

10:13

0.967

Weight (kg)

68.24 ± 9.49

64.72 ± 10.49

0.251

Height (cm)

163.43 ± 11.15

166.57 ± 10.76

0.348

BMI (kg/m2)

22.87 ± 1.96

22.75 ± 2.74

0.865

Underlying liver disease

  

0.462

 HBV

18

21

 

 HCV

1

2

 

 No hepatic virus

1

0

 

Relationship with donor

  

0.961

 Parent

5

6

 

 Sibling

6

5

 

 Spouse

3

5

 

 Children

2

1

 

 Relative

5

6

 

Meld score

8.57 ± 5.22

9.26 ± 6.67

0.706

Child score

  

0.685

 A

15

14

 

 B

3

6

 

 C

3

3

 
The average intraoperative blood loss of group 1 was 940.48 ± 509.32 ml, which was greater than that in group 2 (743.48 ± 364.10 ml), but the difference did not reach statistical significance (P = 0.145). The average operative time was similar (11.11 ± 1.67 h for group 1 and 10.64 ± 2.33 h for group 2; P = 0.449). The graft liver volume did not differ between the two groups (475.52 ± 91.31 g for group 1 and 502.63 ± 81.73 g for group 2; P = 0.305) (Table 3).
Table 3

The intraoperative and postoperative data of the two groups of patients

 

Group 1

Group 2

P value

21

23

Graft size (g)

475.52 ± 91.31

502.63 ± 81.73

0.305

GRWR

0.76 ± 0.06

0.76 ± 0.05

0.989

Operative time (h)

11.11 ± 1.67

10.64 ± 2.33

0.449

Blood loss (ml)

940.48 ± 509.32

743.48 ± 364.10

0.145

ICU stay hours

59.14 ± 23.46

62.65 ± 22.2

0.613

Hospital stay days

35.33 ± 15.18

32.91 ± 10.31

0.536

Clavien score

1.48 ± 1.63

1.39 ± 1.64

0.865

The cost of downstaging therapies (dollars)

6,569.7 ± 4,032.1

6,998.5 ± 5,929.7

0.783

The cost of liver transplantation (dollars)

38,538.3 ± 13,968.3

36,413.8 ± 15,266.9

0.634

The recovery of the two groups is shown in Table 3. No significant difference was observed in ICU stay hours (59.14 h in group 1 vs. 62.65 h in group 2; P = 0.613) or in hospital stay days (35.33 day in group 1 vs. 32.91 day in group 2; P = 0.536). The overall cost of the downstaging therapies was US$6,569.7 in group 1, which was slightly less than the US$6,998.5 in group 2 (P = 0.783). There was no significant difference in the overall cost of the liver transplantation (excluding the donors' costs) between the two groups (US$38,538.3 ± 13,968.3 for group 1 and US$36,413.8 ± 15,266.9 for group 2).

All postoperative surgical complications, classified according to the Clavien–Dindo system, were compared within the two groups. The calculated score of the complications in group 1 was 1.48 ± 1.63, which was greater than that in group 2 (1.39 ± 1.64), but this difference did not reach statistical significance (P = 0.865). The total complication rates of groups 1 and 2 were 57.1 and 52.2 %, respectively, and the complication rates were not statistically significant (P = 0.842). Four recipients died, each after the following: multiple organ failure, pulmonary infection, acute rejection, and vascular complication. The most common complication was biliary complication, mainly bile leak. The 1-, 3-, and 5-year survival rates were 90.4, 76.2, and 71.4 % in group 1 and 91.3, 73.9, and 69.6 % in group 2 (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs11605-012-2019-y/MediaObjects/11605_2012_2019_Fig1_HTML.gif
Fig. 1

Survival rates of the two groups

Of all 44 successful downstaging recipients, seven patients (three in group 1 and four in group 2) had tumor recurrence after a median follow-up period of 72 months (range, 62–102 months) after LDLT. The histological analysis indicated that the recurrent tumors of five patients were poorly differentiated. One patient was moderate and another was well. Three patients (one in group 1 and two in group 2) died from liver tumor metastasis; one patient (in group 2) accepted OLT and remained without recurrence after 3 years of follow-up; another patient (group 1) accepted RFA, and no active lesions have been found in the transplanted liver by CT or MRI as of now.

In the explanted livers, there were 33 lesions in group 1 and 39 lesions in group 2. Three lesions in group and two lesions in group 2 were discovered during histological examination and ranged from 0.5 to 1.5 cm. Those five lesions had not been apparent during radiological investigations before the LDLT. Of the 72 lesions, 26 (36.1 %) lesions had complete necrosis, 32 (44.4 %) lesions showed partial response (>30 % necrosis), and 14 (19.4 %) lesions showed no signs of response (<30 % necrosis). Of all the 44 patients, 10 patients had poorly differentiated tumors, 22 patients had moderately differentiated tumors, and 12 patients had well-differentiated tumors. All tumor lesions were proven to be hepatocellular carcinoma. No vascular invasion was detected in the 72 lesions. There was no significant difference in the pathology findings between the two groups.

Discussion

Liver transplantation is the primary treatment for early HCC whenever possible. However, traditional values and religious beliefs in Asia, which limit deceased donor liver transplantation, have led to a shortage of grafts. Living donor liver transplantation is therefore a practical alternative for HCC patients. According to available estimates, more than 90 % of patients have advanced disease with a dismal prognosis at the time of diagnosis owing to the lack of routine check-ups, especially in the developing countries.14 For patients with advanced HCC, LT yields a disappointing 5-year survival rate (18–32 %), largely due to tumor recurrence.8,9 Fortunately, disease downstaging by locoregional therapy may offer patients, who are not initially candidates, a chance to undergo a curative treatment, such as LDLT. The tumor response to downstaging treatment should be based on radiological measurements of the size of viable tumors (by contrast-enhanced computed tomography or magnetic resonance imaging). Many transplant centers continue to apply the Milan criteria or the UCSF criteria for the selection of candidates for LT after downstaging therapy.15,16 However, no comparison has been made to analyze the short- and long-term results. Although most published reports suggest that successful preoperative downstaging therapy may improve outcome after orthotic liver transplantation, a few investigate the outcome after living donor liver transplantation.10

Many eligibility criteria for downstaging were introduced to us, but with respect to the tumor size and number, the majority of the published reports did not provide upper limits before downstaging.15,17 Only a few, such as the UCSF version, have clearly stated the upper limits of the tumor burden before downstaging. The upper limits for downstaging are listed as follows: a single tumor with a diameter up to 8 cm; two to three tumors with individual diameters up to 5 cm and with total diameters up to 8 cm; and four to five tumors with individual diameters up to 3 cm with total diameters up to 8 cm.18 Patients with extrahepatic HCC metastases and patients with radiological evidence of vascular invasion should be excluded from downstaging owing to the high rate of tumor recurrence. We chose the UCSF version as our criteria for screening subjects for downstaging therapy in our study.

Many locoregional downstaging therapies have been reported to be effective and safe. TACE18,19, RAF18, arterial chemoinfusion17, alcohol injection18,19, resection18,19, and radioembolization15 are the most common. Patients who undergo downstaging with TACE have better posttransplant survival rates than those who do not.20 The alcohol injection has been reported unable to reduce the tumor burden21, so only several patients in our study underwent alcohol injection as the adjuvant therapy for resection of small target lesions in the remnant liver. Sorafenib is an oral multikinase inhibitor of tumor growth and angiogenesis, which inhibits cell surface tyrosine kinase receptors (such as VEGFR and PDGFR), as well as flt-3 and c-kit and downstream intracellular serine/threonine kinases in the Ras/RAF/MAPK cascade.22 This targeted therapy is recommended to Child A patients with advanced HCC and World Health Organization performance status equal or inferior to 223; however, many centers are attempting to demonstrate its curative effect on early or middle stage HCC. There is one phase 3 randomized clinical trial, called the STORM study (http://clinicaltrails.gov/ct2/show/NCT00692770), the endpoints of which are the efficacy and safety of sorafenib vs. placebo in the adjuvant treatment of hepatocellular carcinoma after potentially curative treatment (surgical resection or local ablation). Four advanced HCC patients took sorafenib tablets; however, sorafenib was an adjuvant downstaging therapy in our study as no patient took this drug as a sole therapy.

Several studies have reported the mortality rate of downstaging therapy. For example, Yao et al. reported a mortality rate of 3.3 % after resection or laparoscopic RFA for downstaging18, and Chapman et al. reported a 2.2 % mortality rate for patients undergoing TACE.16 However, there was no mortality in the 72 patients who accepted various downstaging therapies possibly because of the careful screen and small sample size. The hand–foot syndrome was the complication from the sorafenib24, which required the reduction, suspension, or discontinuance of this treatment. Seven patients had tumor recurrence after LDLT, and most of patients' tumors (five cases) were poorly differentiated. Among the poorly differentiated tumor patients, tumors recurred in 50 % of patients. This result suggests that poorly differentiated tumors will lead to a high rate of recurrence, which is in accordance with previous reports.5,25

As of yet, the Milan criteria and the UCSF criteria are the two established selection criteria for liver transplantation in HCC patients. Similar survival has been shown in the patients who met either one of the two criteria.5 In our study, we attempted to detect differences between living donor liver transplantation recipients who met the Milan criteria and those who met the UCSF criteria after accepting preoperative downstaging therapy. After various therapies, a portion of patients met the Milan criteria and the rest met only the UCSF criteria; however, no significant difference was observed between two groups in the type and number of downstaging treatments, baseline characteristics, intraoperative data, postoperative recovery, and the 1-, 3-, and 5-year survival rates. Despite the negative results of our study, we think that the observations will guide us in establishing the definition of treatment success for downstaging therapies.

In our study, we evaluated the downstaging therapies and compared two different acceptable LT criteria. All previous reports that evaluated the downstaging therapies in patients who accepted orthotopic liver transplantation emphasize the importance of downstaging therapies for patients who are on the waiting list for deceased donor livers. In contrast, we studied the effect of downstaging therapies on living donor liver transplantation.

In conclusion, similar complication rates and 1-, 3-, and 5-year survival rates were achieved in the two groups of living donor liver transplantation patients who met the Milan criteria or UCSF criteria after downstaging therapies. We believe that a large number of patients and a multicenter study design will be useful in comparison and analysis in the future.

Acknowledgements

This study was supported by grants from The National Sciences and Technology Major Project of China (2012ZX10002-016 and 2012ZX10002-017).

Conflict of Interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

Copyright information

© The Society for Surgery of the Alimentary Tract 2012