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Keywords:

  • Chemoembolization;
  • evidence-based medicine;
  • hepatocellular carcinoma;
  • liver transplantation;
  • neoadjuvant treatment

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

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.


Abbreviations: 
HCC

hepatocellular carcinoma

OLT

orthotopic liver transplantation

RCT

randomized controlled trial

TACE

transarterial chemoembolization

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

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), consists 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 meta-analyses 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).

The aim of the present review was to assess TACE as a neoadjuvant therapy prior to OLT according to an evidence-based 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

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.

Table 1.  Levels of evidence and grade of recommendation proposed by the Oxford Centre for Evidence-based Medicine (23,24)
Level of evidenceGrading criteriaGrade of recommendation
  1. RCT = randomized controlled trial.

1aSystematic review of RCTs including meta-analysisA
1bIndividual RCT with narrow confidence intervalA
1cAll-or-none studiesB
2aSystematic review of cohort studiesB
2bIndividual cohort study and low-quality RCTB
2cOutcome research studyC
3aSystematic review of case-control studiesC
3bIndividual case-control studyC
4Case-series, poor quality cohort and case-control studiesC
5Expert opinionD

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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

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).

Table 2.  Reported series of TACE prior to liver transplantation for HCC
AuthorsLevelRegimensNo. of patientsStagingDropout (% of patients)Tumor regression >50% (% of patients)Recurrence (% of patients)Survival (%)
PreoperativePeroperativePostoperative1 year2 years3 years5 years
  1. TACE = transarterial chemoembolization; RT = radiotherapy; n.a. = not applicable.

Cherqui et al., Cancer (29) 19944TACE + RTIV Mitoxantrone9IVA 7/9n.a.3364
Spreafico et al., Radiology (30) 19944TACE  21Multifocal disease central locationn.a.3614100100  
Venook et al., Liver Transpl Surg (31) 19954TACE11Milano criterian.a.72090
Majno et al., Ann Surg (14) 19973bTACE IV 5FU + Doxorubicin54Systematic TACE except child Cn.a.52288765 55
No TACE57 147769 62
Oldhafer et al., J Hepatol (15) 19983bTACE + IV chemo (6 patients)21I–II 13/21n.a.66106148
No TACE21106154
Harnois et al., Liver Transpl Surg (16) 19994TACE IV 5FU + Leucovorin (four patients)24I–II 15/24n.a.6809184  
Roayaie et al., Ann Surg (17) 20024TACEIV DoxorubicinIV Doxorubicin80Advanced HCC > 5 cm46Decrease AFP >50% 32.54091725844
Graziadei et al., Liver Transplant (18) 20034TACE  63Milano criteria n = 480962.49898 94
Downstaging n = 1520100309378 41
Hayashi et al., Am J Transplant (20) 20044TACE20I-II35061
Maddala et al., Liver Transplant (19) 20044TACE  54I-II15 11  61
Perez Saborido et al., Am J Transplant (22) 20053bTACE18I-III 13/18n.a.16836060
No TACE28I-III 20/2836775838
Decaens et al., Liver Transplant (21) 20053bTACE28% of patients in both groups received other pretransplantation treatment100I-II 66/100n.a.5013   59
No TACE100I-II 66/100162359

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. 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 pre- and 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 5-year 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 <5 cm or three lesions <3 cm) corresponding to stages I and II (UICC) (18–20,31). In this setting, overall survival reached 90% at 3 or 5 years in the prospective (18,31) but only 60% at 5 years in the retrospective studies (19, 20). However, the very good results of the two prospective studies have not been compared with the same selected patients who would not have received preoperative TACE. Unfortunately, only the three most recent studies (18–20) reported the survival on an intent-to-treat basis. Therefore, these figures cannot be compared with the older data, which did not report the survival data on an intent-to-treat basis.

We conclude that there is insufficient evidence that TACE prior to liver transplantation for HCC does improve long-term survival (recommendation grade C). However, studies with higher level of evidence, reporting survival on an intent-to-treat basis, are urgently needed to clarify this question.

Could TACE convert an advanced HCC unsuitable for OLT into a less advanced HCC suitable for OLT?

TACE reduces tumor size in about half of the patients. An increasingly popular strategy consists in applying TACE before OLT in order to reduce tumor size as a possibility of expanding selection criteria in patients with advanced HCC.

Only one prospective study (level 4) has addressed this question. Graziadei et al. (18) compared the effect of preoperative TACE on the outcome of transplanted patients for early-stage HCC and advanced HCC. Patients with early-stage HCC met the Milano criteria (UICC stages I and II) while patients with advanced HCC were outside the selection criteria (UICC stages III and IV) but had at least 50% tumor reduction following TACE (downstaging). None of the patients with early-stage HCC had to be removed from the waiting list because of tumor progression, while there was a dropout rate of 20% in patients with advanced HCC. Recurrence rates of HCC after OLT was only 2.4% in the early-stage group and 30% in the downstaging group. Therefore, despite successful downstaging before OLT, patients with primarily advanced HCC had a significantly less favorable outcome in the intent-to-treat analysis as well as in the posttransplantation survival compared with patients with early-stage HCC (31% vs. 94% at 5 years, p < 0.001 and 41% vs. 94% at 5 years, p < 0.001). The authors concluded that pretransplant TACE failed to show benefits in patient survival in advanced HCC.

The prospective series by Roayaie et al. (17) (level 4) reported the long-term outcome of OLT in patient with HCC exceeding 5 cm treated in a multimodality adjuvant protocol. Patients received pretransplant TACE, a single systemic intraoperative dose of doxorubicin and six cycles of systemic doxorubicin postoperatively. The dropout rate was 46% after a mean waiting time of 207 days and a mean number of TACE treatments of 2.1. Only 32.5% of the transplanted patients responded to TACE based on a decrease in α-fetoprotein by more than 50% after TACE. Recurrent HCC was diagnosed in 40% of the transplanted patients. A tumor size larger than 7 cm and the presence of vascular invasion correlated significantly with a high recurrence rate. Overall and recurrence-free survival rates (survival on intent to treat not reported) in transplanted patients at 5 years were 44% and 48%, respectively, and there was no difference in recurrence-free survival between those who did or did not respond to TACE.

Majno et al. (14) (level 3b) found that patients with tumors larger than 3 cm in whom downstaging occurred had an improved 5-year recurrence-free survival rate compared with those who could not be downstaged. These discrepancies between Roayaie's and Majno's findings may be explained by the different definitions of response to TACE as well as different tumor characteristics, and the retrospective data collection in Majno's study.

After a median of one TACE procedure, Decaens et al. (21) (level 3b) found that tumor necrosis reached more than 80% of the lesions on histological analysis in 30% of the patients in the TACE group and 9% of the patients in the non-TACE group (p < 0.05). In these subgroups of patients, overall 5-year survival was slightly higher in TACE group (63%) than in controls (54%) but the difference was not significant (p = 0.9).

We conclude that there is currently no sufficient evidence that pretransplant TACE may delineate a possibility of expanding current selection criteria for OLT in patients with HCC (recommendation grade C). However, more studies are urgently needed in this area.

Does TACE impact on waiting list dropout?

Many teams are reluctant to observe patients with HCC on the waiting list without the use of neoadjuvant therapies such as TACE in order to prevent tumor metastases, progression and vascular invasion. However, as this therapy has never been assessed in a RCT, its impact on dropout rates cannot be directly ascertained.

Llovet et al. (33) reported a 23% dropout rate due to tumor progression in the first 6 months of waiting for OLT without any neoadjuvant therapy. Unfortunately, dropout rates in the context of intention-to-treat analysis were available only in four of the noncomparative studies (level 4) (17–20) (Table 2). Roayaie et al. (17) reported a 46% dropout rate, but only advanced HCC (<5 cm) were included in this study. Graziadei et al. (18) found no dropout from the waiting list in patients meeting Milano criteria. Of note, the mean waiting time was only 178 days. Furthermore, the monitoring protocol of repeat staging and the criteria for dropout were not specified. Hayashi et al. (20) and Maddala et al. (19) reported 35% and 15% of dropout rates, respectively, in patients with stage I or II HCC. This difference was probably explained by a mean waiting time of 340 days in the first study compared with 200 days in the second one.

We conclude that there is insufficient evidence that TACE prior to OLT for HCC decreases dropout rates on the waiting list (recommendation grade C).

Does TACE increases postoperative complications in liver transplant recipients?

Since local arteritis may develop as a result of TACE, recipients may be exposed to a higher prevalence of complications such as hepatic arterial thrombosis, which is a catastrophic graft-threatening complication of OLT. In the retrospective comparative study by Majno et al. (14) (level 3b), the rate of complications did not significantly differ between the transplanted patients with or without pretransplant TACE (43% vs. 31%, NS). No arterial complication occurred in the patients treated with TACE, while 5% of the transplanted patients without preoperative TACE developed an arterial complication, but the difference was not significant. Oldhafer et al. (15) reported three cases of unexplained severe pneumonia, leading to death early after OLT in patients receiving preoperative TACE. However, postoperative infectious complications specifically related to TACE have not been reported by other groups (14,16–18,21,22).

In the comparative study (level 3b) by Perez Saborido et al. (22) no significant difference was observed in incidence of complications between patients with pretransplant TACE (61%) and patients without TACE (74%) (p = 0.41). There was no vascular complication in either group.

A retrospective comparative study by Richard et al. (34) (level 3b) compared the prevalence of hepatic arterial complications between 47 patients who underwent TACE before OLT for HCC and a total population of 1154 liver transplant recipients who did not undergo TACE. Arterial complications, including pseudo-aneurysm, stenosis, anastomotic disruption and thrombosis were comparable in patients with versus without pretransplant TACE (13% vs. 6%, respectively). Arterial thrombosis rates were also comparable between the two groups (8% vs. 5%, p = 0.32).

We conclude that TACE does not expose liver transplant recipient to additional risk at surgery (recommendation grade C).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References

This is the first review assessing TACE as a neoadjuvant therapy prior to OLT according to the evidence-based medicine approach. The question whether TACE as a neoadjuvant treatment prior to OLT for HCC improves outcome is difficult to address from an evidence-based perspective as there are no RCTs available comparing patients undergoing OLT for HCC with versus without preoperative TACE. This lack of RCTs may be explained by the fact that most of the medical teams nowadays consider it unacceptable not to offer some form of tumor treatment to patients with HCC on the waiting list.

It has been shown that OLT offers good results in patients with early-stage HCC with an 83% recurrence-free survival rate at 4 years, as reported by Mazzaferro et al. (11). However, in the context of organ shortage, the constant increase in waiting time reduced the long-term outcome of HCC patients after OLT because of tumor progression (33). Therefore, TACE was used as a neoadjuvant treatment prior to OLT in order to impede tumor progression on the waiting list. Four studies including patients with early-staged HCC (Milano criteria) offered TACE prior to OLT (18–20,31). The reported 3- and 5-year survival rates ranged between 60% and 90%. Unfortunately, these results were not compared with those obtained without preoperative TACE in a comparable group of patients, e.g. matched for the waiting time and the degree of liver failure, as all studies used a nonselected group of patients with HCC staging, who did not received preoperative TACE (14,15,21,22). These studies failed to show any survival benefit of pretransplant TACE on survival. Furthermore, none of the studies focusing on advanced HCC could identify a benefit for pretransplant TACE (14,17,18). Even downstaged patients appear to have a higher dropout rates, higher recurrence rates and unfavorable outcome compared with early-stage patients.

Finally, none of the study could prove beneficial impact of pretransplant TACE on waiting list dropout rates. Recent data suggest that listed patients have a relative low predicted risk of list dropout in the first 6 months (7–11%) using the MELD-based system that was implemented on February 2002 in the United States (35). Considering that the majority of patients with HCC were transplanted within 3 months during the first 12 months under the MELD system (36), the necessity of pretransplant TACE becomes more and more debatable.

In summary, the current review failed to show any benefit of TACE as a neoadjuvant treatment prior to OLT.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. References
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