Clinics and Research in Hepatology and Gastroenterology (2015) 39, 93—97

Available online at

ScienceDirect www.sciencedirect.com

ORIGINAL ARTICLE

Salvage liver transplantation for hepatocellular carcinoma recurrence after primary liver resection Wei Qu a,b, Zhi-Jun Zhu a,b,∗, Li-Ying Sun b, Lin Wei b, Ying Liu b, Zhi-Gui Zeng b a b

Tianjin Medical University, 300070 Tianjin, PR China Liver Transplant Section, Beijing Friendship Hospital, 100050 Beijing, PR China

Available online 21 August 2014

Summary Objective: To evaluate the clinical efficacy and prognostic factors for salvage liver transplantation (SLT) for hepatocellular carcinoma (HCC) recurrence after primary liver resection. Methods: One hundred and eleven patients underwent SLT for HCC recurrence after primary liver resection from April 2000 to June 2011. We analyzed statistically the operative characteristics, survival rate, and effect of pathological characteristics on prognosis of SLT. Results: The overall survival rates at 6 months, and 1, 3 and 5 years after SLT were 87.9%, 75.5%, 56.3% and 49.1%, respectively. The mean age of the patients receiving SLT was 53.5 ± 9.6 years (range: 26.8—76.4 years), with a median follow-up of 28.8 months. The mean operating time was 10.34 ± 3.05 hours, and mean blood loss was 2925.0 ± 2373.51 ml. However, factors such as Edmondson grade, TNM stage, and invasion of hepatic and portal veins significantly affected the prognosis of SLT. Conclusions: SLT for HCC recurrence after primary liver resection does not show increased surgery-related risks or reduced long-term survival rate, and thus SLT is an effective treatment for patients with HCC recurrence after primary liver resection. © 2014 Published by Elsevier Masson SAS.

Introduction ∗

Corresponding author. Liver Transplantation Department, Beijing Friendship Hospital, Capital Medical University, 95# Yong-an Road, Xi-Cheng District, 100050 Beijing, PR China. Tel.: +86 10 6313 8350; fax: +86 10 6313 8350. E-mail address: [email protected] (Z.-J. Zhu). http://dx.doi.org/10.1016/j.clinre.2014.07.006 2210-7401/© 2014 Published by Elsevier Masson SAS.

Hepatocellular carcinoma (HCC) that meets the Milan or University of California, San Francisco (UCSF) criteria is a reasonable indication for liver transplantation, and has a 5year survival rate higher than 70% [1]. The current organ shortage, however, makes it impossible to satisfy all the

94 patients with HCC on the waiting list. Patients diagnosed with HCC in the compensatory phase of liver function can undergo primary liver resection as a first-stage treatment, so as to prolong the waiting time for liver transplantation. Due to the invasive and metastatic nature of HCC, recurrence is still the main problem after liver resection. Patients with intrahepatic recurrence should be given an accurate assessment, and considered for salvage LT (SLT). The indications and selection criteria for SLT are still controversial, and there is no sufficient demonstration about the surgical risk [2—5]. In our study, we analyzed 111 patients who received SLT, including operative characteristics, survival rate, and prognostic factors, and we also evaluated the feasibility of SLT retrospectively.

Patients and methods Ethics statement This study was verified and approved by Beijing Friendship Hospital Ethics Committee. All clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. All patients were informed about the surgical risks before the operation, and gave signed informed consent. All consent documents were stored in the hospital database and are available upon request. All data are accessible at China Liver Transplant Registry (www.cltr.org/en/).

Patients From April 2000 to June 2011, 111 patients (103 male and 8 female) underwent SLT for HCC recurrence after primary liver resection (SLT group). In the SLT group, the average age was 53.5 ± 9.6 years (range: 26.8—76.4 years), and median follow-up time was 28.8 months. One hundred and one patients had primary liver resection once, and the other 10 patients had the operation twice. Twenty-four patients met the Milan criteria, 83 were beyond the Milan criteria, and the other 4 had missing data. Eighty-six patients had hepatitis B, 15 patients had hepatitis C, 3 had hepatitis B and C, and 7 had no hepatitis. One hundred and eight patients received whole-graft orthotopic LT, 2 received split liver transplantation, and the other underwent living donor LT (Table 1).

W. Qu et al. Table 1 group.

Variables of salvage liver transplantation (SLT) SLT group (n = 111)

Age (years) Sex Male Female Milan criteria Within Beyond Missing Hepatitis B C B+C None Graft type LDLT Split LT OLT Liver resection Once Twice Median follow-up (months)

53.5 ± 9.6 103 8

(92.79%) (7.21%)

24 83 4

(21.62%) (74.77%) (3.60%)

86 15 3 7

(77.48%) (13.51%) (2.70%) (6.31%)

1 2 108

(0.90%) (1.80%) (97.30%)

101 10 28.84

(90.99%) (9.01%)

LDLT: living donor liver transplantation; OLT: orthotopic liver transplantation.

independent samples t-test was used. Kaplan—Meier survival analysis and log-rank test were used for comparing the survival rate among primary liver transplantation (PLT) and SLT groups. Single factor analysis was used for the prognostic factors in the SLT group.

Results Survival analysis The cumulative survival rate after SLT for HCC recurrence after primary liver resection was 87.9%, 75.5%, 56.3% and 49.1% at 6 months, 1 year, 3 years and 5 years, respectively (Fig. 1).

Operating time and bleeding volume Database For this retrospective study, we collected the following data about the SLT group. Intraoperative data: operating time and blood loss; pathological data: number of tumors, size of tumors, Milan criteria, hepatic vein invasion, branch portal vein tumor thrombus, tumor capsule, satellite lesions, portal vein tumor thrombus, celiac lymph nodes, infringement of hilar lymph nodes, TNM stage, and new Edmondson grade; follow-up data: survival status, and cause of death.

Statistics The clinical data were analyzed retrospectively. For descriptive data such as SLT operation time and bleeding volume,

In the SLT group, the mean operating time was 10.34 ± 3.05 hours, and the mean volume of bleeding was 2925 ± 2373.51 ml, with 11 patients having a volume ≥ 5000 ml. There were 7 patients with no transfusion of red blood cells.

Prognostic factors for SLT We analyzed variation in new Edmondson grade, hepatic vein invasion, portal vein invasion, and Milan criteria, to evaluate the prognostic factors and therapeutic efficacy in the SLT group. The results suggest that there was no significant difference between types of hepatitis, presence of a tumor capsule, satellite lesions, hilar lymph node metastasis, or

Salvage liver transplantation for hepatocellular carcinoma recurrence Table 2

95

Single factor analysis.

Factor

n

Cumulative survival rate (%) 6 months

HCC Hepatitis B Hepatitis C No hepatitis Milan criteria Yes No Number of tumor nodules 1 1—3 >3 New Edmondson grade High differentiation Moderate differentiation Low differentiation Hepatic vein invasion Yes No Tumor capsule Yes No Satellite lesions Yes No Branch portal vein invasion Yes No Portal vein invasion Yes No Infringement of hilar lymph nodes Yes No TNM stage I II III IV

P

1 year

3 years

5 years

89 15 7

89.5 80.0 85.7

78.1 80.0 42.9

56.2 70.0 42.9

48.1 70.0 42.9

0.479

24 83

83.1 88.8

78.2 74.3

67.4 53.8

59.9 46.7

0.326

19 24 58

84.2 91.3 86.0

66.5 81.4 73.6

39.9 69.9 54.5

31.9 54.4 50.3

0.334

63 34 11

86.9 85.1 100

81.9 53.9 100

64.8 35.1 64

62.1 20.1 64

0.001

49 58

85.2 92.9

64.6 87.1

40.3 72.0

34.1 63.5

0.001

9 99

88.6 88.9

76.0 77.8

55.6 66.7

49.2 53.3

0.808

20 85

83.5 89.2

65.6 80.1

52.5 59.9

42.0 53.0

0.210

39 68

79.1 93.8

64.5 82.4

36.5 67.6

29.2 60.6

0.002

11 96

51.9 92.5

20.8 82.0

10.4 61.8

10.4 53.8

0.000

10 95

90.0 89.2

77.1 76.3

25.7 59.6

25.7 51.4

0.282

5 44 39 10

100 90.7 83.9 90.0

100 81.0 59.7 90.0

100 63.4 32.0 78.8

100 53.5 27.4 0.0

0.012

within or beyond Milan criteria. However, new Edmondson grade, tumor TNM stage, hepatic and portal vein invasion did have a significant impact on long-term outcome (Table 2). Forty-eight of the 111 patients in the SLT group died during the 28.8 months follow-up period. The main cause of death could be divided into three categories:

distributed in the 6 months to 2 years postoperatively. The distribution of deaths due to other reasons had no obvious time-related characteristics (Fig. 2).

• HCC recurrence-related (26, 54.17%); • multiple organ failure as a result of infection, and bleeding (18, 37.50%); • other causes (4, 8.33%).

We showed that with the development of surgical skills and knowledge of functional hepatic anatomy, SLT for HCC recurrence after primary liver resection is technically feasible [6,7], and does not increase surgical risks or complications. The technical difficulty of SLT mainly lies in the previous liver resection adhesion between the area of operation, omentum and bowel. Although some patients suffered from portal hypertension, bleeding during dissection of tissue

The distribution of cause of death was time-related, with multiple organ failure mainly concentrated in the first 6 months after SLT, and HCC recurrence-related death mainly

Discussion

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W. Qu et al.

Figure 1 Kaplan—Meier survival analysis of salvage liver transplantation (SLT).

adhesion is more common and undesirable, which is the main reason why surgeons are not willing to practice SLT. According to our experience, there is no shortcut to separate tissue adhesion, apart from technique and patience. After releasing the adhesion, the following steps are similar to orthotopic LT. The majority of cases in our study only received primary liver resection once, and the extent of resection was relatively small, so there was no additional increase in blood loss and blood products transfusion intraoperatively. In the study of Zhenhua Hu, the median blood loss in the SLT group was 2 L (1—4 L), and the median operation time in the SLT recipients was 8 hours. Also in this study, there was no significant difference was observed in the 1year, 3-year, and 5-year overall survival rates between the

two groups within selected patients: 80.26%, 65.14%, and 60.31% in PLT recipients and 80.13%, 62.10%, and 54.18% in SLT recipients [8]. Some of the patients underwent SLT in the early 2000s, when surgical techniques and experience were limited, therefore, bleeding volume was larger. With advances in technology, especially after 2006, the average bleeding volume decreased, using intermittent control such as portal vein blocking and extracorporeal venous bypass. With the accumulation of experience, we can make more effort to shorten the duration of the operation and reduce the bleeding volume. Through analysis of the causes of death, the complexity of the operation, infectious diseases, bleeding events and other factors during the perioperative period take a slightly higher proportion, but there was no significant difference compared with the primary orthotopic LT patients. Although the Milan or UCSF criteria are a standard indication for LT, for SLT a 3D variables model should be used to evaluate the overall prognosis of SLT, including the data on HCC for primary liver resection and SLT for HCC recurrence, and also the interval from primary liver resection to HCC recurrence. The small cohort of the patients was one of the limitations of the present study. If there is hepatic or portal vein invasion, it is clear that the survival rate will significantly decrease. The degree of tumor histological differentiation will affect the prognosis of patients, to the same extent as primary orthotopic LT patients. Our retrospective analysis indicated that the overall survival rate after SLT for HCC recurrence in patients receiving primary liver resection was similar to that in patients receiving primary LT. Especially in the era of organ shortage, there is wide scope for the application of SLT, which can help to control effectively tumor progression, as well as reduce the risk of metastasis. Primary liver resection can not only downstage HCC, but also yield information about tumor size, tumor number, degree of differentiation, pathological type, presence of vascular invasion, and other important pathological data, providing valuable information for LT to achieve the optimal selection of recipients and maximum benefit.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

References

Figure 2

Distribution of deaths.

[1] Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. New Eng J Med 1996;334(11):693—700. [2] Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003;238(4):508. [3] Poon RTP, Fan ST. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy? Ann Surg 2004;240(5):925—8. [4] Kim BW, Park YK, Kim YB, et al. Salvage liver transplantation for recurrent hepatocellular carcinoma after liver resection: feasibility of the Milan criteria and operative risk. Transplant Proc 2008;40(10):3558—61.

Salvage liver transplantation for hepatocellular carcinoma recurrence [5] Vennarecci G, Ettorre GM, Antonini M, et al. First-line liver resection and salvage liver transplantation are increasing therapeutic strategies for patients with hepatocellular carcinoma and child a cirrhosis. Transplant Proc 2007;39(6):1857—60. [6] Wu LW, Hu AB, Tam N, et al. Salvage liver transplantation for patients with recurrent hepatocellular carcinoma after curative resection. PloS One 2012;7(7):e41820.

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[7] Liu F, Wei Y, Wang W, et al. Salvage liver transplantation for recurrent hepatocellular carcinoma within UCSF criteria after liver resection. PloS One 2012;7(11):e48932. [8] Hu Z, Zhou J, Xu X, et al. Salvage liver transplantation is a reasonable option for selected patients who have recurrent hepatocellular carcinoma after liver resection. PloS One 2012;7(5):e36587.

Salvage liver transplantation for hepatocellular carcinoma recurrence after primary liver resection.

To evaluate the clinical efficacy and prognostic factors for salvage liver transplantation (SLT) for hepatocellular carcinoma (HCC) recurrence after p...
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