The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatoce...

Wei Chen, Xiaoli Yang, Yakun Wu

American Journal of Cancer Prevention

The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatocellular Carcinoma

Wei Chen1, Xiaoli Yang2, Yakun Wu3,

1Department of General Surgery, Hospital of traditional Chinese medicine of Yubei, Chongqing, 400010, China

2Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

3Department of Hepatobiliary Surgery, Suining Central Hospital, Suining 629000, China

Abstract

Background and Objective: This study aims to use meta-analysis to evaluate whether pre-transplantation local regional therapy (LRT) can improve the survival of patients with hepatocellular carcinoma who accepted liver transplantation. Methods: Relevant studies were identified by searching PUBMED, EMBASE and Web of Science Datebases up to May 2015. Endpoints were 1 year, 3 years, and 5 years survival rate after liver transplantation. Results: Analysis of nine retrospective studies including 1097 patients did not reveal significant difference in 1year, 3 years and 5 years survival rate between the patients who got LRT or not. Analysis of four retrospective studies including 504 patients showed patients with complete response to LRT have higher 5 years survival rate. Conclusions: The results of this meta-analysis suggest that the patients with complete response to LRT have higher post-transplantation survival rate. But LRT before liver transplantation can’t improve the overall survival rate.

Cite this article:

  • Wei Chen, Xiaoli Yang, Yakun Wu. The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatocellular Carcinoma. American Journal of Cancer Prevention. Vol. 4, No. 1, 2016, pp 18-22. http://pubs.sciepub.com/ajcp/4/1/4
  • Chen, Wei, Xiaoli Yang, and Yakun Wu. "The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatocellular Carcinoma." American Journal of Cancer Prevention 4.1 (2016): 18-22.
  • Chen, W. , Yang, X. , & Wu, Y. (2016). The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatocellular Carcinoma. American Journal of Cancer Prevention, 4(1), 18-22.
  • Chen, Wei, Xiaoli Yang, and Yakun Wu. "The Effect of Local Regional Therapy on Post-transplantation Survival Rate in Patients with Hepatocellular Carcinoma." American Journal of Cancer Prevention 4, no. 1 (2016): 18-22.

Import into BibTeX Import into EndNote Import into RefMan Import into RefWorks

At a glance: Figures

1. Introduction

Liver cancer is the fifth most commonly diagnosed cancer and the second most frequent cause of cancer death in men worldwide [1]. During the current treatments for HCC, liver transplantation is considered as the best one [2]. However, due to an increased waiting period caused by the limited availability of suitable donors, more and more transplantation centers adopt pre-transplantation local regional therapy (LRT) to control tumor progression, reduce dropout or down stage the tumors beyond Milan{1} or BCLC criteria [3]. LRT mainly includes radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI), which can induce tumor necrosis and control progression. But if LRT before liver transplantation can improve survival rate in patient with hepatocellular is still disputed. Sourianarayanane’ research showed LRT followed by liver transplantation in HCC appears not to have an impact on post-transplant outcome [4]. Kim et al. showed that Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower 3 years HCC recurrence and better three-year survival in patients meeting R4T3 criteria [5]. Bharat et al. also indicated that the LRT group had better 5-year survival [6]. In addition, some studies indicated that the patients with complete response (CR) to LRT have higher 5 years survival rate [7, 8, 9, 10], but their samples were small. So, we use meta-analysis to compare if the patients accepted LRT before liver transplantation have higher post-operation survival rate and if the patients achieving complete response (CR) to LRT have higher survival rate.

2. Method

2.1. Study Selection

A literature search was performed using Embase, Medline and Web of Science Datebases up to May 2015. The following terms were used: “liver transplantation”, “local regional therapy(LRT)”, “bridge therapy”, “bridging therapy”, “transarterial chemoembolization (TACE)”, “Radio-frequency ablation (RFA)” and “Percutaneous ethanol injection (PEI)”. All abstracts, studies, and citations scanned were reviewed.

2.2. Data Extraction

Two reviewers independently selected studies, accessed quality and extracted data. Discrepancies were resolved by consensus.

2.3. Inclusion Criteria

To enter our analysis, studies had to:

Take the liver cancer patients accepting liver transplantation as object of the research. Compare the patients who accepted LRT before liver transplantation and the patients who didn’t. Or observe the response to LRT using RECIST/EASL criteria [11, 12]. Report the 1 year, 3 years, 5 years survival rate post liver transplantation. When 2 studies were reported by the same institution, our analysis included either the one of better quality, or the most recent publication.

2.4. Exclusion Criteria

Object of study, intervention measures, observed indexes didn’t meet the inclusion criteria or data was not complete.

2.5. Outcomes

The outcome was 1 year, 3 years, 5 years survival rate after liver transplantation.

2.6. Statistical Analysis

Analysis was conducted by using Review Manager Version 5.2. Statistical analysis for generic inverse variance was carried out using the hazard ratio (HR) as the summary statistic.

3. Results

3.1. Characteristics of Included Studies

We identified 184 articles during the initial search. With strict screening, 13 case control studies were ultimately included in this meta-analysis (Figure 1). Nine retrospective studies [4,10,13-19] contained 1097 patients published from 2005 to 2012 were included to analyze the effect of LRT on survival rate after liver transplantation. In total, 579 patients accepted LRT before liver transplantation and 518 patients didn’t. The characteristics are shown in Table 1. Four retrospective studies [7, 8, 9, 10] contained 504 patients were included to compare if CR-group have higher survival rate after liver transplantation. Among them 176 patients have CR to LRT and 328 have non-CR to LRT. The characteristics are shown in Table 2.

Figure 1. Flow diagram of selection and disposition of studies

Table 1. Basic characteristics of included studie

Table 2. Basic characteristics of CR and non-CR group

3.2. Survival Rate after Liver Transplantation

Nine studies [4,6,14-19] compared the 1 year, 3 years, 5 years survival rate of study group and control group. The pooled HR for 1 year survival rate in the included studies calculated using the IV models model was 0.69 (95% CI 0.45–1.05, p=0.08; I2=0%, P=0.60) (Figure 2). The pooled HR for 3 years survival rate in the included studies calculated using the IV models model was 0.86 (95% CI 0.63–1.18, p=0.35; I2=0%, P=0.53) (Figure 3). The pooled HR for 5 years survival rate in the included studies calculated using the IV models model was 1.06 (95% CI 0.78–1.44, p=0.71; I2=0%, P=0.73) (Figure 4).

Figure 2. Comparision of 1y survival rate between LRT group and control group
Figure 3. Comparision of 3y survival rate between LRT group and control group
Figure 4. Comparision of 5y survival rate between LRT group and control group
Figure 5. Comparision of 5y survival rate between CR group and non-CR group
3.3. Years Survival Rate between CR Group and Non-CR Group

Four studies [7, 8, 9, 10] were also used to compare the 5 years survival rate between CR group and non-CR group. The pooled HR for 5 years survival rate in the included studies calculated using the IV models model was 0.59 (95% CI 0.41–0.85, p=0.005; I2=0%, P=0.59) (Figure 5).

4. Discussion

To the best of our knowledge, this is the first meta-analysis to assess the long-term outcomes of liver transplantation followed by LRT and transplantation alone in HCC patients. The present meta-analysis provided a relatively high level of evidence showing that HCC patients treated with liver transplantation followed by LRT exhibited a equal 1 year survival rate (HR=0.69, 95% CI 0.45–1.05, p=0.08; I2=0%, P=0.60), 3 years survival rate (HR=0.86, 95% CI 0.63–1.18, p=0.35; I2=0%, P=0.53) and 5 years survival rate (HR=1.06, 95% CI 0.78–1.44, p=0.71; I2=0%, P=0.73) with those treated with liver transplantation alone. But patients with CR to LRT showed higher 5 years survival rate (HR=0.59, 95% CI 0.41–0.85, p=0.005; I2=0%, P=0.59).

Liver transplantation is the best choice for patients within accepted criteria. LRT can induce tumor necrosis, decrease tumor stage and put off tumor progression. Also, some article showed LRT can reduce dropout rate in the waiting list [20]. So, in the condition of worldwide donor liver shortage, many transplantation centers adopt LRT to expect a higher survival rate after liver transplantation. But published studies got disputed results [4, 5, 6]. Our meta-analysis showed LRT before liver transplantation can’t improve survival rate after liver transplantation. But it doesn’t means that LRT before liver transplantation is useless. The most widely accepted criteria for liver transplantation is Milan criteria, but many doctors doubt the criteria is too strict to reject many patients who can benefit from liver transplantation. Some researches showed that patients with CR to LRT have higher survival rate and suggested CR to LRT may become one index of the inclusion criteria for liver transplantation [7, 8, 9, 10]. Our meta-analysis also observed that the patients getting CR have a better prognosis. So we can set this as an index of prognosis and we support taking this as one of the inclusion criteria for candidates selection. But it still has obvious shortage. In the included studies, only 34.9% patients got CR. So, indicators to predict CR is essential to avoid unnecessary LRT. Fortunately, Allard MA et al. found a maximal tumor size <30 mm, a single tumor and an preoperative AFP < 100 ng/ml were associated with CPR [10].

Our meta-analysis included relatively less studies and patients. Moreover, all the included studies are retrospective. So, more high-quality, multiple-center, large-sample randomized controlled trials are required.

In conclusion, this meta-analysis revealed the patients with complete response to LRT have higher post-transplantation survival rate. But LRT before liver transplantation can’t improve the overall survival rate. Further studies, such as large sample case-controls or cohorts, will be necessary to determine the role of LRT in the patients with hepatocellular carcinoma.

Note

1. Milan criteria: one lesion smaller than 5 cm, up to 3 lesions smaller than 3 cm, no extrahepatic manifestations, no vascular invasion

References

[1]  Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D, “Global cancer statistics”, CA Cancer J Clin,61(2):69-90, Mar-Apr 2011.
In article      View Article  PubMed
 
[2]  Duan C, Liu M, Zhang Z, Ma K, Bie P, “Radiofrequency ablation versus hepatic resection for the treatment of early-stage hepatocellular carcinoma meeting Milan criteria: a systematic review and meta-analysis”, World J Surg Oncol,11 (1):190-199, Aug 2013.
In article      View Article  PubMed
 
[3]  Forner A1, Reig ME, de Lope CR, Bruix J, “Current strategy for staging and treatment: the BCLC update and future prospects”, Semin Liver Dis, 30(1):61-74, Feb 2010.
In article      View Article  PubMed
 
[4]  Sourianarayanane A, El-Gazzaz G, Sanabria JR, Menon KV, Quintini C, Hashimoto K, Kelly D, Eghtesad B, Miller C, Fung J, Aucejo F, “Loco-regional therapy in patients with Milan Criteria-compliant hepatocellular carcinoma and short waitlist time to transplant: an outcome analysis”. HPB (Oxford),14(5):325-32, May 2012.
In article      View Article  PubMed
 
[5]  Kim PT, Onaca N, Chinnakotla S, Davis GL, Jennings LW, McKenna GJ, Ruiz RM, Levy MF, Goldstein R, Klintmalm GB, “Tumor biology and pre-transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation”, Clin Transplant, 27(2):311-8, Mar-Apr 2013.
In article      View Article  PubMed
 
[6]  Bharat A, Brown DB, Crippin JS, Gould JE, Lowell JA, Shenoy S, Desai NM, Chapman WC, “Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival”, J Am Coll Surg 203(4):411-20, Oct 2006.
In article      View Article  PubMed
 
[7]  Cucchetti A, Cescon M, Bigonzi E, Piscaglia F, Golfieri R, Ercolani G, Cristina Morelli M, Ravaioli M, Daniele Pinna A, “Priority of candidates with hepatocellular carcinoma awaiting liver transplantation can be reduced after successful bridge therapy”, Liver Transpl, 17 (11):1344-54. Nov 2011.
In article      View Article  PubMed
 
[8]  Bargellini I, Vignali C, Cioni R, Petruzzi P, Cicorelli A, Campani D, De Simone P, Filipponi F, Bartolozzi C, “Hepatocellular carcinoma: CT for tumor response after transarterial chemoembolization in patients exceeding Milan criteria--selection parameter for liver transplantation”, Radiology, 255 (1):289-300, Apr 2010.
In article      View Article  PubMed
 
[9]  Millonig G, Graziadei IW, Freund MC, Jaschke W, Stadlmann S, Ladurner R, Margreiter R, Vogel W, “Response to preoperative chemoembolization correlates with outcome after liver transplantation in patients with hepatocellular carcinoma” Liver Transpl, 13(2):272-9, Feb 2007.
In article      View Article  PubMed
 
[10]  Allard MA, Sebagh M, Ruiz A, Guettier C, Paule B, Vibert E, Cunha AS, Cherqui D, Samuel D, Bismuth H, Castaing D, Adam R, “Does pathological response after transarterial chemoembolization for hepatocellular carcinoma in cirrhotic patients with cirrhosis predict outcome after liver resection or transplantation?” J Hepatol, 63(1):83-92, Jul 2015.
In article      View Article  PubMed
 
[11]  Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS, “Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria”, J Clin Oncol, 25(13):1753-1759, May 2007.
In article      View Article  PubMed
 
[12]  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verwei J, “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)”, Eur J Cancer, 45(2):228–247, Jan 2009.
In article      View Article  PubMed
 
[13]  Eswaran SL, Pierce K, Weaver F, Rogers T, Brems JJ, Sontag SJ, Borge M, “Transarterial chemoembolization for HCC in patients with extensive liver transplantation waiting times”, Angiology, 63(3):206-12, Apr 2012.
In article      View Article  PubMed
 
[14]  DuBay DA, Sandroussi C, Kachura JR, Ho CS, Beecroft JR, Vollmer CM, Ghanekar A, Guba M, Cattral MS, McGilvray ID, Grant DR, Greig PD, “Radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation”, HPB (Oxford), 13(1):24-32, Jan 2011.
In article      View Article  PubMed
 
[15]  Heckman JT, Devera MB, Marsh JW, Fontes P, Amesur NB, Holloway SE, Nalesnik M, Geller DA, Steel JL, Gamblin TC, “Bridging locoregional therapy for hepatocellular carcinoma prior to liver transplantation”, Ann Surg Oncol, 15(11):3169-77. Nov 2008.
In article      View Article  PubMed
 
[16]  Maluf DG, Stravitz RT, Williams B, Cotterell AH, Mas VR, Heuman D, Luketic V, Shiffman ML, Sterling R, Posner MP, Fisher RA, “Multimodality therapy and liver transplantation in patients with cirrhosis and hepatocellular carcinoma: 6 years, single-center experience”, Transplant Proc, 39(1):153-9, Jan-Feb 2007.
In article      View Article  PubMed
 
[17]  Stockland AH, Walser EM, Paz-Fumagalli R, McKinney JM, May GR, “Preoperative chemoembolization in patients with hepatocellular carcinoma undergoing liver transplantation: influence of emergent versus elective procedures on patient survival and tumor recurrence rate”, Cardiovasc Intervent Radiol 30(5):888-93, Sep-Oct 2007.
In article      View Article  PubMed
 
[18]  Pérez SB, Meneu JC, Moreno E, García I, Moreno A, Fundora Y, “Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma?” Am J Surg 190 (3):383-7, Sep 2005.
In article      View Article  PubMed
 
[19]  Decaens T, Roudot-Thoraval F, Bresson-Hadni S, Meyer C, Gugenheim J, Durand F, Bernard PH, Boillot O, Boudjema K, Calmus Y, Hardwigsen J, Ducerf C, Pageaux GP, Dharancy S, Chazouilleres O, Dhumeaux D, Cherqui D, Duvoux C, “Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma”, Liver Transpl, 11(7):767-75, Jul 2005.
In article      View Article  PubMed
 
[20]  Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, Margreiter R, Vogel W, “Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome”, Liver Transpl 9(6):557-63, Jun 2003.
In article      View Article
 
[21]  Shillcutt SK, Ringenberg KJ, Chacon MM, Brakke TR, Montzingo CR, Lyden ER, Schulte TE, Porter TR, Lisco SJ, “Liver Transplantation: Intraoperative Transesophageal Echocardiography Findings and Relationship to Major Postoperative Adverse Cardiac Events”, J Cardiothorac Vasc Anesth 30(1):107-14, Jan 2016.
In article      View Article
 
  • CiteULikeCiteULike
  • MendeleyMendeley
  • StumbleUponStumbleUpon
  • Add to DeliciousDelicious
  • FacebookFacebook
  • TwitterTwitter
  • LinkedInLinkedIn