American Journal of Transplantation 2006; 6: 2644–2650 Blackwell Munksgaard
C 2006 The Authors C 2006 The American Society of Journal compilation Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2006.01509.x
Transarterial Chemoembolization as a Bridge to Liver Transplantation for Hepatocellular Carcinoma: An Evidence-Based Analysis b M. Lesurtela , B. Mullhaupt ¨ , B. C. Pestalozzic , d T. Pfammatter and P.-A. Claviena, ∗ a
Swiss HPB (Hepato-Pancreato-Biliary) Center, Departments of Visceral and Transplant Surgery, b Gastroenterology and Hepatology, c Oncology and d Radiology, University Hospital, Zurich, Switzerland ∗ Corresponding author: Pierre-Alain Clavien,
[email protected] The aim of this review was to assess the impact of transarterial chemoembolization (TACE) as a neoadjuvant therapy prior to orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). An electronic search on the Medline database (1990–2005) was used to identify relevant articles. The studies were reviewed and ranked according to their quality of evidence using the grading system proposed by the Oxford Centre for Evidence-based Medicine. As a bridge to OLT, pretransplant TACE does not improve long-term survival (grade C). There is currently no convincing evidence that TACE allows to expand the current selection criteria for OLT, nor that TACE decreases dropout rates on the waiting list (grade C). However, TACE does not increase the risk for postoperative complications (grade C). There is insufficient evidence that TACE offers any benefit when used prior to OLT, neither for early nor for advanced HCC. Well-designed randomized controlled trials are needed to define the role of TACE in OLT patients. Key words: Chemoembolization, evidence-based medicine, hepatocellular carcinoma, liver transplantation, neoadjuvant treatment Abbreviations: HCC hepatocellular carcinoma, OLT orthotopic liver transplantation, RCT randomized controlled trial, TACE transarterial chemoembolization Received 21 April 2006, revised 1 June 2006 and accepted for publication 26 June 2006
Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and the third most common cause of cancer-related death (1,2). Transarterial chemoembolization (TACE), first proposed by Yamada et al. in 1977 (3), con-
2644
sists in the selective embolization of the artery feeding a tumor preceded by the injection of chemotherapeutic agents. The combination of highly concentrated chemotherapy and some degree of ischemia in the tumor was postulated to be synergistic in causing tumor necrosis (4). TACE has been used with three aims: (i) as a neoadjuvant therapy for resectable HCC, (ii) as a palliative treatment for unresectable HCC and (iii) as a neoadjuvant therapy prior to orthotopic liver transplantation (OLT) in patients with small and larger HCC. A recent review of randomized clinical trials (RCTs) of neoadjuvant therapy for resectable HCC clearly demonstrated that TACE failed to provide any benefit after curative surgery (5). TACE is most commonly used as a palliative treatment for unresectable HCC, often because of the lack of alternative strategies. Over the last 20 years, most RCTs have reported conflicting results about the role of TACE for unresectable HCC. Most of these trials were seriously flawed comparing patients with various selection criteria, the use of various chemoembolization regimens or omitting control groups. Since 2002, new RCTs and metaanalyses have been published clearly indicating a benefit of TACE in patients with unresectable HCC (6–9). Therefore, these two indications will not be discussed further. OLT offers the theoretical advantage of removing both the tumor and the underlying irreversible cirrhosis, and is currently an established therapy for small HCC in patients with cirrhosis (10,11). However, results of OLT alone for advanced HCC have been disappointing with 5-year survival rates ranging between 18% and 25% (12,13). The rationale for using TACE as a neoadjuvant therapy prior to OLT is 2-fold. To control tumor growth while the patient awaits an organ and to cause significant tumor necrosis, which may reduce tumor dissemination during surgery. In addition, some have argued that TACE may achieve tumor downstaging in patients with advanced HCC, allowing to safely expand the current criteria for OLT in patients with HCC. TACE is also used by some to gain time and learn more about the natural history of a particular tumor prior to OLT. Finally, most of the teams perform TACE in an attempt to minimize the dropout rate from the waiting list to cope with the increasing waiting time for OLT. However, the benefit of TACE remains uncertain because of conflicting results and the lack of RCT in OLT patients (14–22).
TACE for HCC Prior to Transplantation
The aim of the present review was to assess TACE as a neoadjuvant therapy prior to OLT according to an evidencebased medicine approach (23,24). We focused on efficacy, morbidity and survival benefit of TACE and assessed whether TACE could be considered as a bridge to OLT for HCC.
Materials and Methods An electronic search on Medline was undertaken to identify comparative randomized trials, meta-analyses and reviews about the subject. The terms ‘hepatocellular carcinoma’, ‘chemoembolization’ and ‘liver transplantation’ were used in various combinations. The search terms were identified in the title, abstract or medical subject heading. With few exceptions, only original articles published in English between January 1990 and December 2005 were selected for further analysis. Manual cross-referencing was also used to find further relevant articles. All articles were classified according to their level of evidence. The classification proposed by the Oxford Centre for Evidence-based Medicine was used to rank each publication and to give the grade of recommendations (A, B, C, D) based on the available literature for each question (Table 1) (23,24). Whenever possible, the best-ranked studies were used for the data analysis (levels 1 and 2). When no RCTs were available for a question, low-ranked studies were reviewed (levels 3–5). Meta-analyses were accepted and classified in accordance to the studies included. Definition of arterial embolization procedures We evaluated procedures aimed at achieving arterial occlusion, such as arterial embolization or chemoembolization. Other procedures, such as arterial chemotherapy, not aiming at vessel occlusion were excluded from this review. The goals of TACE are to deliver a highly concentrated dose of chemotherapy to tumor cells, to prolong the contact time between the chemotherapeutic agents and the cancer cells and to minimize systemic toxicity. Drugs, such as doxorubicin, epirubicin or cisplatin, can be mixed with
lipiodol as a vehicle, which is selectively retained within cancer tissues for several weeks (4,25–28).
Results Should TACE be used as a bridge to OLT in patient with HCC? The wide acceptance and use of TACE as a bridge to OLT contrasts with the paucity of convincing data. Indeed, there is no RCT available for comparing patients who underwent OLT for HCC with or without neoadjuvant TACE. Only four retrospective comparative studies (level 3b) were identified (14,15,21,22). Other noncomparative studies have reported small retrospective or prospective series of patients who underwent TACE prior to OLT for HCC (16–20,29–31) (Table 2). Does preoperative TACE improve patient survival after OLT? Oldhafer et al. (15) carried out a case-control study (level 3b) comparing 21 liver transplant patients with HCC who underwent pretransplant TACE with 21 matched pair historical controls. Sixty percent of the patients had a stage I or II tumor according to the modified International Union Against Cancer (UICC) (32) in both groups. Marked tumor necrosis (>50%) was found in 66% of the patients in the TACE group. However, there was no difference in overall survival between the groups with or without pretransplant TACE at 1 year (60.8% vs. 61.5%, NS) and at 3 years (48.4% vs. 53.9%, NS). Survival in the TACE group was penalized by three cases of pneumonia thought related to TACE, a complication not observed in other reports. In a retrospective analysis (level 3b), Majno et al. (14) compared 54 liver transplant patients with HCC who underwent preoperative TACE with 57 patients who underwent an OLT for HCC in the same period but without preoperative TACE. Both groups received postoperative systemic chemotherapy with doxorubicin and 5-fluorouracil, when their general condition allowed it. There was no difference between the groups in terms of tumor size or number.
Table 1: Levels of evidence and grade of recommendation proposed by the Oxford Centre for Evidence-based Medicine (23,24) Level of evidence
Grading criteria
Grade of recommendation
1a 1b 1c 2a 2b 2c 3a 3b 4 5
Systematic review of RCTs including meta-analysis Individual RCT with narrow confidence interval All-or-none studies Systematic review of cohort studies Individual cohort study and low-quality RCT Outcome research study Systematic review of case-control studies Individual case-control study Case-series, poor quality cohort and case-control studies Expert opinion
A A B B B C C C C D
RCT = randomized controlled trial.
American Journal of Transplantation 2006; 6: 2644–2650
2645
2646 TACE
4
3b
American Journal of Transplantation 2006; 6: 2644–2650 28% of patients in both groups received other pretransplantation treatment
–
–
–
–
IV 5FU + Leucovorin (four patients) IV Doxorubicin
100
100
28
18
54
20
63
80
24
21
57 21
54
IV 5FU + Doxorubicin
–
11
21
9
No. of patients
–
–
IV Mitoxantrone
Postoperative
TACE = transarterial chemoembolization; RT = radiotherapy; n.a. = not applicable.
No TACE
TACE
No TACE
–
TACE
Decaens et al., Liver 3b Transplant (21) 2005
–
TACE
Maddala et al., Liver 4 Transplant (19) 2004 Perez Saborido 3b et al., Am J Transplant (22) 2005
–
TACE
–
IV Doxorubicin
Hayashi et al., Am J 4 Transplant (20) 2004
TACE
4
–
TACE
TACE
4
–
–
–
–
–
Peroperative
4
Graziadei et al., Liver Transplant (18) 2003
Harnois et al., Liver Transpl Surg (16) 1999 Roayaie et al., Ann Surg (17) 2002
No TACE TACE + IV chemo (6 patients) No TACE
TACE
4
Spreafico et al., Radiology (30) 1994 Venook et al., Liver Transpl Surg (31) 1995 Majno et al., Ann Surg (14) 1997
Oldhafer et al., J 3b Hepatol (15) 1998
TACE
4
TACE + RT
Level Preoperative
Cherqui et al., Cancer (29) 1994
Authors
Regimens
Table 2: Reported series of TACE prior to liver transplantation for HCC
n.a.
I-II 66/100
I-II 66/100
I-III 20/28
I-III 13/18
n.a.
n.a.
15
16
50
–
–
–
–
100
Downstaging 20 n = 15 I-II 35
I-II
0
10
14 10
28
0
14
33
23
13
36
16
11
0
30
2.4
–
–
77
83
–
–
93
98
91
91
61
77 61
87
–
100
–
–
–
–
–
–
–
78
98
72
84
–
69 –
65
–
100
–
–
–
58
60
–
–
58
–
54
– 48
–
90
–
64
59
59
38
60
61
61
41
94
44
–
–
62 –
55
–
–
–
Survival (%) Recurrence (% of 1 2 3 5 patients) year years years years
Decrease 40 AFP >50% 32.5
68
–
– 66
96
46
n.a.
n.a.
52
Milano crite- 0 ria n = 48
Advanced HCC > 5 cm
I–II 15/24
I–II 13/21
Systematic n.a. TACE except child C
72
36
–
Tumor Dropout regression (% of >50% (% of patients) patients)
Multifocal n.a. disease central location Milano crite- n.a. ria
IVA 7/9
Staging
Lesurtel et al.
TACE for HCC Prior to Transplantation
Downstaging (tumor reduction >50%) occurred in 52% of the patients treated with TACE. Overall, there was no difference in survival between the groups with versus without TACE (55% vs. 62% at 5 years, p = 0.77). However, patients with large tumors (>3 cm) that were downstaged by TACE had a significantly better disease-free survival in comparison with patients in whom the regimen failed to achieve significant downstaging (71% vs. 28% at 5 years, p = 0.01). On the other hand, there was no significant difference in term of disease-free survival between downstaged patients and patients who did not undergo TACE (71% vs. 49% at 5 years, p = 0.09). More recently, two European teams carried out comparative studies still in a retrospective way (level 3b). Perez Saborido et al. (22) compared 18 liver transplant patients with HCC who underwent preoperative TACE with 28 patients who underwent an OLT for HCC in the same period but without preoperative TACE. Seventy percent of the patients had a stage I–III tumor in both groups. All patients with TACE underwent only one pretransplant procedure. Patients who underwent TACE had a lower recurrence rate (16%) than patients without TACE (36%), but the difference did not reach statistical significance (p = 0.16). There was no difference in 1-, 3-, 5-year actuarial survival rates between the groups with versus without TACE (83%, 60% and 60% vs. 77%, 58% and 38%, respectively, p = 0.56). The French multicentric case-control study by Decaens et al. (21), compared 100 patients who received TACE before OLT with 100 control patients without TACE. Patients and controls were matched for the pre-OLT tumor characteristics, the period of transplantation, the time spent on the waiting list and the preand posttransplantation treatments. With a mean waiting period of 4.2 months in both groups, and one TACE procedure in the TACE group, overall 5-year survival was 59% in both groups (p = 0.7). The patients in the TACE group in which more than 80% of the tumor was necrotic at the time of transplantation and their matched controls had 5year survival rate of 63% and 54%, respectively (p = 0.9). It is noteworthy that 28% of the patients in both groups received pretransplantation treatments other than TACE for HCC. Two prospective and two retrospective studies (level 4) selected patients who met the Milano criteria (one single lesion
