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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

Background

Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and its incidence rate has consistently increased over the past 15 years in Canada. Although transarterial embolization therapies are palliative options commonly used for the treatment of HCC, their efficacy is still controversial. The objective of this guideline is to review the efficacy and safety of transarterial embolization therapies for the treatment of HCC and to develop evidence-based recommendations.

Method

A review of the scientific literature published up to October 2013 was performed. A total of 38 studies were included.

Recommendations

Considering the evidence available to date, the CEPO recommends the following: (i) transarterial chemoembolization therapy (TACE) be considered a standard of practice for the palliative treatment of HCC in eligible patients; (ii) drug-eluting beads (DEB)-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities; (iii) the decision to treat with TACE or DEB-TACE be discussed in tumour boards; (iv) bland embolization (TAE) not be considered for the treatment of HCC; (v) radioembolization (TARE) not be considered outside of a clinical trial setting; and (vi) sorafenib combined with TACE not be considered outside of a clinical trial setting.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

Worldwide, hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer and the third cause of cancer mortality.[1] Although the incidence rate of HCC in Canada is lower compared with other regions, an increase of 3.7% per year in men and of 2.4% per year in women has been observed from 1998 to 2007.[2] HCC usually develops on a background of cirrhosis, which is most often caused by hepatitis B or C, non-alcoholic steatohepatitis or alcohol abuse. The choice of treatment is based on multiple factors and takes into account not only the tumour stage but also the patient's residual hepatic function and general condition. In early disease stage, the potentially curative treatments of HCC are surgical resection, liver transplantation and local tissue ablation therapies. When these options are not indicated, a palliative treatment is offered. Transarterial embolization therapies are commonly used to act locally in the intermediate disease stage and sorafenib is the indicated systemic treatment in the advanced stage.[3]

Transarterial embolization therapies involve the transcatheter delivery, through the hepatic artery, of solid particles into an artery feeding the target tumour to block its blood supply. These therapies include bland embolization (TAE), chemoembolization (TACE), chemoembolization using drug-eluting beads (DEB-TACE) and radioembolization (TARE). A combination treatment with TACE and sorafenib has also been investigated recently with the intention of delaying time to progression.[4]

The CEPO (Comité de l'évolution des pratiques en oncologie) is a group of specialists in oncology reporting to the Institut national d'excellence en santé et en services sociaux. Its role is to provide physicians and other health professionals working in oncology with evidence-based guidelines and clinical support tools to optimize and standardize the clinical practice in the province of Quebec (Canada). As of today, the efficacy of the early transarterial embolization therapies (TAE and TACE) is still controversial and the latest ones are still being investigated. Thus, the CEPO reviewed the efficacy and safety of transarterial embolization therapies for the treatment of HCC and made clinical recommendations based on the best available evidence.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

This article is an updated adaptation of an original clinical guideline available at http://www.msss.gouv.qc.ca/cancer. Initially, a review of the scientific literature published up to February 2013 was performed in PubMed with the following keywords: chemoembolization (MeSH), transarterial chemoembolization, transcatheter chemoembolization, oily chemoembolization, embolization, transarterial embolization, transcatheter embolization, drug-eluting beads, radioembolization, transarterial radioembolization, transcatheter radioembolization, microsphere embolization, therasphere, sir sphere, selective internal radiation, sorafenib, liver neoplasms (MeSH), liver cancer and HCC. Prospective studies and meta-analyses were considered. Only meta-analyses published from 2003 to February 2013 were included. Comparative retrospective studies were also considered, providing patients' baseline characteristics were relatively balanced between groups. Only studies comparing TACE, TAE or TARE to absence of treatment, one to another, DEB-TACE to TACE and a combination of TACE and sorafenib to TACE were included. Studies using transarterial embolization therapies for the treatment of hepatic metastasis or as a bridge to transplantation were not considered. Studies using fine powder of cisplatin in suspension (not available in Canada) were excluded. Economic studies were also excluded. Abstracts of randomized controlled trials (RCTs) presented at relevant international conferences held in 2011 and 2012 were also reviewed. The literature review was subsequently updated to cover the time period from February 2013 to October 2013. Only published articles or abstracts reporting efficacy results from RCTs were included for that period.

The level of evidence of selected studies and the strength of recommendations were evaluated using the American Society of Clinical Oncology and the European Society for Medical Oncology grading system.[5] The original guideline was developed by a CEPO sub-committee, reviewed by independent experts, and finally adopted by the CEPO by consensus.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

The review of the literature included 38 articles. Transarterial embolization therapies being indicated in palliative intent, overall survival was regarded as the most important efficacy endpoint.

TACE

Seven prospective trials, including six RCTs, and five retrospective trials evaluated the efficacy of TACE (Table 1).[6-20] Two studies investigated the effect of TACE on quality of life.[7, 21] All prospective trials were of a small size. Results on overall survival were not consistent across prospective studies: three studies demonstrated increased overall survival with TACE,[8, 9, 12] whereas the other four showed no effect.[6, 7, 10, 11] All retrospective studies found that TACE was associated with a survival benefit.[13-17] Three meta-analyses including RCTs investigating TACE and TAE,[18, 20] or TACE, TAE and transarterial chemotherapy (TAC),[19] compared the treatments with absence of treatment or suboptimal treatment (Table 2). In the two earlier meta-analyses, published in 2003 and 2007, TACE and TAE significantly reduced the mortality risk.[18, 19] In the most recent meta-analysis, published in 2011 by Oliveri et al.[20], TACE and TAE were associated with a 20% mortality risk reduction, but this estimate did not reach statistical significance.

Table 1. Summary of studies evaluating TACE
Study (median follow-up)PopulationTreatmentnTumour response (A versus B)Overall survival (A versus B)
  1. a

    Tumour response based on WHO criteria.

  2. b

    Partial tumour response defined as >50% reduction in tumour size.

  3. c

    Partial tumour response defined as >25% reduction in the longest tumour diameter.

  4. d

    Tumour response as reduction in both tumour size and in AFP levels; partial tumour response defined as > 50% reduction of initial value.

  5. BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CLIP, Cancer of the Liver Italian Program; CR, complete response; HR, hazard ratio; n, number of patients; NA, not available; NS, statistically non-significant; OR, objective response; PD, progressive disease; RR, relative risk; SD, stable disease; TAC, transarterial chemotherapy; TACE, transarterial chemoembolization; TAE, embolization; WHO, World Health Organization.

Randomized controlled trial (Level of evidence II)

 Doffoel et al. 2008[7]

(A/B: 12.4/11 months)

Child–Pugh grade:

A: 70%, B: 30%

Okuda stage:

I: 72%, II: 28%

  • A) 
    TACE + tamoxifen
  • B) 
    Tamoxifen

Total: 123

  • A: 62
  • B: 61
NA

Median: 13.8 versus 11 months

Cumulative rate:

  • 1 year: 51% versus 46%
  • 2 years: 25% versus 22%

P = 0.68

 Llovet et al. 2002[8]

(A/B/C: 21.2/21.7/14.5 months)

Child–Pugh grade:

A: 71%, B: 29%

Okuda stage:

I: 65%, II: 35%

BCLC stage:

B: 80%, C: 20%

  • A) 
    TACE
  • B) 
    TAE
  • C) 
    No treatment

Total: 112

  • A: 40
  • B: 37
  • C: 35

ORa ≥ 6 months, n = 102

  • A versus C: 35% versus 0%; P = 0.004

A versus C

Mean: 28.7 versus 17.9 months

Cumulative rate:

  • 1 year: 82% versus 63%
  • 2 years: 63% versus 27%
  • 3 years: 29% versus 17%

P = 0.009

Risk of death:

HR: 0.47 (95% CI: 0.25–0.91); P = 0.025

 Lo et al. 2002[9]

(NA)

Okuda stage:

I: 47%, II: 53%

  • A) 
    TACE
  • B) 
    No treatment

Total: 79

  • A: 40
  • B: 39

At 3 monthsb (n = 46)

  • OR: 39% versus 6%; P = 0.014
  • CR: 0% versus 0%

Cumulative rate:

  • 1 year: 57% versus 32%
  • 2 years: 31% versus 11%
  • 3 years: 26% versus 3%

P = 0.002

Risk of death:

RR: 0.50 (95% CI: 0.31–0.81); P = 0.005

 Pelletier et al. 1998[10]

(698 days)

Child–Pugh grade:

A: 77%, B: 23%

Okuda stage:

I: 68%, II: 32%

  • A) 
    TACE + tamoxifen
  • B) 
    Tamoxifen

Total: 73

  • A: 37
  • B: 36

Within ≤250 daysb (n = 45)

  • OR: 24% versus 5.5%; P = 0.046
  • CR: 0% versus 0%

Cumulative rate:

  • 1 year: 51% versus 55%
  • 2 years: 24% versus 26%

P = 0.77

Risk of death:

RR: 0.92 (95% CI: 0.55–1.56)

 GETCH 1995[6]

(NA)

Child–Pugh grade:

A: 100%

Okuda stage:

I: 90%, II: 10%

  • A) 
    TACE
  • B) 
    No treatment

Total: 96

  • A: 50
  • B: 46

At 2 monthsc(n = 81)

  • OR: 53% versus 13%
  • SD: 37% versus 37%
  • PD: 9% versus 50%

P = 0.001

Cumulative rate:

  • 8 months: 70% versus 50%
  • 1 year: 62% versus 43.5%
  • 2 years: 37.8% versus 26%

Risk of death (B versus A):

RR: 1.4 (95% CI: 0.9–2.2); P = 0.13

 Pelletier et al. 1990[11]

(>1 year)

Okuda stage:

I: 26.2%, II: 52.4%, III: 21.4%

  • A) 
    TACE
  • B) 
    No treatment

Total: 42

  • A: 21
  • B: 21

A and Bd (P = NA)

  • OR: 33% versus 0%
  • CR: 19% versus 0%

Cumulative rate:

  • 6 months: 33% versus 52%
  • 1 year: 24% versus 31%

P = NS

Non-randomized prospective study (Level of evidence III)

 Yuen et al. 2003[12]

(NA)

Child–Pugh grade:

A: 79%, B: 21%

Okuda stage:

I: 67%, II: 33%

  • A) 
    TACE
  • B) 
    No treatment

Total: 96

  • A: 80
  • B: 16

A onlya (n = 75)

  • OR: 28%
  • CR: 2.7%
  • SD: 44%
  • PD: 28%

Median: 31.2 versus 14.1 months; P = 0.0126

Cumulative rate:

  • 6 months: 98.3% versus 62.5%; P = 0.002
  • 1 year: 86.3% versus 62.5%; P = 0.023
  • 2 years: 78.8% versus 50%; P = 0.017
  • 3 years: 57.5% versus 50%; P = NS
  • 4 years: 51.3% versus 43.8%; P = NS
Retrospective study (Level of evidence IV)

 Huang et al. 2006[15]

(NA)

Child–Pugh grade:

A: 75%, B: 25%

CLIP stage:

2: 39%, 3–5: 61%

Tumours > 10 cm

  • A) 
    TACE
  • B) 
    No treatment

Total: 57

  • A: 31
  • B: 26
NA

Median: 9.1 versus 2.1 months

Cumulative rate:

  • 1 year: 41.9% versus 7.7%
  • 2 years: 22.6% versus 7.7%
  • 3 years: 12.9% versus 0%
  • 4 years: 9.7% versus 0%
  • 5 years: 6.5% versus 0%

P < 0.0001

 Bronowicki et al. 1996[13]

(NA)

Child–Pugh grade:

A: 100%

Okuda stage:

I: 100%

  • A) 
    Resection
  • B) 
    Transplantation
  • C) 
    TACE
  • D) 
    No treatment

Total: 122

  • A: 30
  • B: 17
  • C: 42
  • D: 33
NA

Cumulative rate (C versus D):

  • 3 years: 54% versus 11%
  • 5 years: 47% versus 0%

A, B and C versus D: P < 0.0001

 Stefanini et al. 1995[16]

Matched historical control

(NA)

Child–Pugh grade:

A: 42.1%, B: 46.3%, C: 11.6%

Okuda stage:

I: 39%, II: 52.6%, III: 8.4%

  • A) 
    TACE
  • B) 
    TAC
  • C) 
    No treatment

Total: 164

  • A: 69
  • B: 31
  • C: 64
NA

Cumulative rate (A versus C):

  • 6 months: 86% versus 27%
  • 1 year: 73% versus 16%
  • 2 years: 44% versus 8%
  • 3 years: 36% versus 3%
  • 4 years: 20% versus 0%

P < 0.001

 Bronowicki et al. 1994[14]

Matched case–control

(NA)

Child–Pugh grade:

A: 56.8%, B: 29.5%, C: 14.2%

Okuda stage:

I: 36.8%, II: 48%, III: 13.4%

  • A) 
    TACE
  • B) 
    No treatment

Total: 254

  • A: 127
  • B: 127
NA

Cumulative rate:

  • 1 year: 64% versus 18%
  • 2 years: 38% versus 6%
  • 3 years: 27% versus 5%
  • 4 years: 27% versus NA

P < 0.0001

 Vetter et al. 1991[17]

Matched case–control

(NA)

Child–Pugh grade:

A: 48.3%, B: 41.7%, C: 10%

Okuda stage:

I: 26.6%, II: 46.6%, III: 26.6%

  • A) 
    TACE
  • B) 
    No treatment

Total: 60

  • A: 30
  • B: 30
NA

Cumulative rate:

  • 1 year: 59% versus 0%
  • 2 years: 30% versus NA

P < 0.001

Table 2. Summary of meta-analyses on TACE and TAE (level of evidence I)
Meta-analysisTreatmentNumber of studies (n)HeterogeneityEstimated risk of death (95% CI)
  1. CI, confidence interval; HR, hazard ratio; I2, heterogeneity test (<25%: low, 25–50%: moderate, > 50%: high); n, number of patients; NA, not available; OR, odds ratio; TAC, transarterial chemotherapy; TACE, transarterial chemoembolization; TAE, embolization; χ2, heterogeneity test (P < 0.1: high).

Oliveri et al. 2011[20]TACE or TAE versus suboptimal or no treatment8 (648)I2 = 31%HR: 0.81 (0.64–1.02); P = 0.067
TACE versus suboptimal or no treatment5 (489)I2 = 46%HR: 0.79 (0.58–1.06); P = 0.11
TAE versus suboptimal or no treatment3 (194)I2 = 0%HR: 0.94 (0.62–1.42); P = 0.76
TACE or TAE versus no treatment5 (410)I2 = 52%HR: 0.75 (0.53–1.07); P = 0.12
Marelli et al. 2007[19]TACE, TAE or TAC versus suboptimal or no treatment9 (632)χ2: P = 0.69OR: 0.705 (0.499–0.994); P = 0.0026
TACE or TAE or TAC versus no treatment6 (460)NAOR: 0.674 (0.445–1.021)
TACE versus suboptimal or no treatment5 (366)NAOR: 0.619 (0.377–1.016)
TAE versus suboptimal or no treatment3 (215)NAOR: 0.746 (0.430–1.296)
TACE versus TAE3 (447)χ2: P = 0.052OR: 1.384 (0.94–2.04); P = 0.1
Llovet and Bruix 2003[18]TACE or TAE versus suboptimal or no treatment6 (503)χ2: P = 0.14At 2 years, OR: 0.53 (0.32–0.89); P = 0.017
TACE or TAE versus suboptimal or no treatment7 (545)χ2: P = 0.14At 1 year, OR: 0.64 (0.41–1.01); P = 0.051
TACE or TAE versus no treatment4 (367)NAOR: 0.46 (0.23–0.89); P = 0.022
TACE versus suboptimal or no treatment4 (323)NAOR: 0.42 (0.20–0.88); P = 0.021
TAE versus suboptimal or no treatment3 (215)NAOR: 0.59 (0.29–1.20); P = 0.14

Overall, symptoms related to post-embolization syndrome (fever, nausea and abdominal pain) were observed in up to 80% of patients and were generally mild, transient and manageable. The most common complications included liver failure, cholecystitis, gastro-intestinal bleeding, ascites and encephalopathy. Treatment-related death rates varied between 0% and 6%. Quality of life after TACE was not changed,[7] or deteriorated less rapidly compared with absence of treatment.[21]

TAE

Two RCTs compared the efficacy of TAE with absence of treatment (level of evidence II).[8, 22] Llovet et al.[8] chose a sequential triangular design, and the TAE versus control comparison was stopped prematurely. TAE did not significantly increase survival, but a statistical trend was found [hazard ratio (HR): 0.57 (95% confidence interval (CI): 0.31–1.04); P = 0.07]. Bruix et al.[22] showed no change in overall survival with TAE (P = 0.72). The three meta-analyses specifically evaluating the effect of TAE compared with absence of treatment did not show any difference in terms of overall survival between the two groups (Table 2).[18-20]

Two RCTs (levels of evidence I and II) and one retrospective study (level of evidence IV) compared TAE with TACE and showed no difference in overall survival.[23-25] Although Chang et al.[23] reported more emesis with TACE than TAE, the toxicity profile was similar between the two treatments in the study from Kawai et al.[24]

TAE performed with Bead Block® has also been compared with DEB-TACE in two small RCTs, one of them presented as an abstract (level of evidence II and not evaluable).[26, 27] In the study from Malagari et al.[26], although the primary endpoint, median time to progression, was significantly shorter for the Bead Block® group (36.2 versus 42.4 weeks; P = 0.008), there was no difference in overall survival between the groups at 12 months (86% versus 85.3%). In the abstract from Brown et al.[26, 27], the median overall survival was similar in both groups (14 versus 16 months; P = 0.7).[27] Toxicity was similar with both treatments.

DEB-TACE

Three RCTs and four retrospective studies compared DEB-TACE with conventional TACE (Table 3).[28-34] Only one RCT provided overall survival data;[29] the primary efficacy endpoints were tumour response or pharmacokinetic patterns in the other two studies.[28, 30] No difference was observed in terms of overall survival and tumour response between the treatments. A meta-analysis published by Gao et al.[35] in 2013 also showed no difference between DEB-TACE and conventional TACE for different tumour response parameters. However, a subgroup analysis of Lammer et al.[28] showed a better tumour response in favour of DEB-TACE in patients presenting less favourable prognostic factors [Child–Pugh B, Eastern Cooperative Oncology Group (ECOG) performance status 1, prior radical treatment (recurrence) or bilobar disease; 52.4% versus 34.7%; P = 0.038]. The peak and cumulative blood levels of doxorubicin after treatment were significantly lower with DEB-TACE than with conventional TACE.[30] In the three retrospective studies providing survival data, overall survival was found to be longer with DEB-TACE than with conventional TACE.[31, 32, 34] However, objective tumour response data were less consistent: two studies showed a better tumour response rate with DEB-TACE[31, 32] and one study showed no difference between the treatments.[34]

Table 3. Summary of studies comparing DEB-TACE with conventional TACE
Study (median follow up)PopulationTreatmentnTumour response (A versus B)Overall survival (A versus B)
  1. a

    Tumour response based on RECIST criteria.

  2. b

    Tumour response based on EASL criteria.

  3. c

    One-sided P-value.

  4. BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; CR, complete response; cTACE, conventional TACE; DC, disease control; DEB, drug-eluting bead; n, number of patients; NA, not available; NS, statistically non-significant; OR, objective response; PD, progressive disease; SD, stable disease; TACE, transarterial chemoembolization; RECIST, Response Evaluation Criteria in Solid Tumours; EASL, European Association for the Study of the Liver.

Randomized controlled trial (Level of evidence II)

 Sacco et al. 2011[29]

(28.2 months)

Child–Pugh grade:

A: 81%, B: 19%

BCLC stage:

A: 66%, B: 34%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 67

  • A: 33
  • B: 34

At 1 montha

  • OR: 100% versus 100%
  • CR: 51.5% versus 70.6%

P = 0.1

Cumulative rate:

  • 2 years: 86.8% versus 83.6%; P = 0.96

 van Malenstein et al. 2011[30]

(NA)

Child–Pugh grade:

A: 93%, B: 7%

BCLC stage:

A: 10%, B: 63%, C: 27%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 30

  • A: 16
  • B: 14

At 6 weeksa

  • SD: 77% versus 92%
  • PD: 23% versus 8%

P = 0.54

NA

 Lammer et al. 2010[28]

PRECISION V

(NA)

Child–Pugh grade:

A: 83%, B: 17%

Okuda stage:

I: 91%, II: 9%

BCLC stage:

A: 26%, B: 74%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 212

  • A: 102
  • B: 110

At 6 monthsb

  • OR: 51.6% versus 43.5%; P = 0.11c
  • CR: 26.9% versus 22.2%
  • SD: 11.8% versus 8.3%
  • PD: 32.3% versus 40.7%
  • DC: 63.4% versus 51.9%; P = 0.11c
NA
Retrospective study (Level of evidence IV)

 Song et al. 2012[32]

(18 months)

Child–Pugh grade:

A: 92%, B: 8%

BCLC stage:

A: 44%, B: 56%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 129

  • A: 60
  • B: 69

At 3 months

  • OR: 81.6% versus 49.4%
  • CR: 55% versus 23.1%
  • SD: 15% versus 30.4%
  • PD: 3.4% versus 20.2%

P < 0.001

Mean: 32.2 versus 24.7 months

Cumulative rate:

  • 6 months: 93% versus 80%
  • 12 months: 88% versus 67%
  • 18 months: 88% versus 61% P = 0.005

 Song et al. 2011[33]

Matched case-control

(NA)

Child–Pugh grade:

A: 85%, B: 15%

BCLC stage:

A: 32.5%, B: 40%, C: 27.5%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 40

  • A: 20
  • B: 20

At 1 montha

  • OR: 85% versus 30%; P = 0.001
  • CR: 35% versus 20%
  • PD: 0% versus 0%
NA

 Wiggermann et al. 2011[34]

(NA)

Child–Pugh grade:

A: 100%

BCLC stage:

A: 12%, B: 76%, C: 12%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 44

  • A: 22
  • B: 22

After average of 8 monthsb

  • OR: 22.7% versus 22.7%; P = NS
  • CR: 13.6% versus 0%
  • SD: 68.2% versus 45.5%
  • PD: 9.1% versus 31.8%
  • DC: 90.9% versus 62.8%; P = 0.066

Mean: 651 versus 414 days; P = 0.01

Cumulative rate:

  • 1 year: 70% versus 55%

 Dhanasekaran et al. 2010[31]

(NA)

Child–Pugh grade:

A: 46.4%, B: 31%, C: 22.6%

Okuda stage:

I: 33.3%, II: 49%, III: 13.8%

CLIP stage:

0–3: 74.1%, 4–6: 25.9%

  • A) 
    DEB-TACE
  • B) 
    cTACE

Total: 71

  • A: 45
  • B: 26
NA

Median: 403 versus 114 days; P = 0.016

Cumulative rate:

  • 6 months: 71% versus 50%
  • 1 year: 58% versus 31%
  • 2 years: 48% versus 12%

The two treatments caused toxicity at similar rates in terms of post-embolization syndrome[29, 30, 32, 33, 36] and an increase in bilirubin[29, 30, 33, 36] and albumin[29] levels, but DEB-TACE was associated with a reduced elevation of aspartate aminotransferase (AST)[28, 30, 32, 36] and alanine aminotransferase (ALT)[28-30, 36] levels, and a lower rate of constitutional symptoms,[28, 30] alopecia[30] and myelosuppression.[30] However, the overall incidence of grade 3 and 4 toxicities was similar with the two treatments.[36]

TARE

Four retrospective studies compared the efficacy of TARE with TACE (Table 4).[37-40] Yttrium 90-coupled TheraSpheres®[37, 39, 40] or SIR Spheres®[38] were used. All studies included patients with relatively advanced disease: 12% to 28% with Barcelona Clinic Liver Cancer (BCLC) stage C,[39, 40] 6% with Okuda stage III[38] and about 40% presenting with vascular invasion.[37, 38] Carr et al.[37] showed that patients treated with TARE had a significantly longer overall survival than those treated with TACE, but when stratification analyses were done to compare more similar patients, the effect was not significant anymore. In the other three studies, overall survival was similar with the two treatments.[38-40] Tumour response data were not consistent between studies. Carr et al.[37] showed a better response rate with TARE, and the other two studies showed no difference between the groups.[38, 39] In addition, Salem et al.[40] showed a significantly longer time to progression with TARE than with TACE. A meta-analysis of retrospective studies from Xie et al.[41] demonstrated a survival benefit of TARE over TACE [HR: 0.73 (95% CI: 0.60–0.88); P = 0.0009]. However, another analysis including five studies specifically using yttrium 90-coupled beads showed no difference between TARE and TACE in the 1-year overall survival rate [relative risk (RR): 1.04 (95% CI: 0.94–1.16); P = 0.45].

Table 4. Summary of retrospective studies comparing TARE with TACE (level of evidence IV)
Study (median follow-up)PopulationTreatmentnTumour response (A versus B)Overall survival (A versus B)
  1. a

    Tumour response based on WHO criteria.

  2. b

    Tumour response based on EASL criteria.

  3. BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CR, complete response; DC, disease control; HR, hazard ratio; n, number of patients; NA, not available; OR, objective response; ORR, overall response rate; PD, progressive disease; SD, stable disease; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TTP, time to progression; TTR, time to response; WHO, World Health Organization; EASL, European Association for the Study of the Liver.

Moreno-Luna et al. 2012[39]

Matched case-control (≥52 months)

Child–Pugh grade:

A: 84%, B: 16%

BCLC stage (A versus B):

  • A: 20% versus 42%
  • B: 57% versus 24%
  • C: 23% versus 35%
  • A) 
    TARE
  • B) 
    TACE

Total: 116

  • A: 61
  • B: 55
  • OR: 51% versus 51%; P = 1.00
  • CR: 12% versus 4%; P = 0.17
  • SD: 39% versus 34%
  • PD: 9% versus 15%
  • DC: 89% versus 85%; P = 0.56

Median: 15 versus 14.4 months; P = 0.47

Cumulative rate:

  • 2 years: 30% versus 24%
  • 3 years: 21% versus 16%
  • 5 years: 9% versus 5%

Salem et al. 2011[40]

(A/B: 22.7/32.6 months)

Child–Pugh grade:

A: 54.6%, B: 43.7%, C: 1.6%

BCLC stage:

A: 36.7%, B: 51.4%, C: 10.2%, D: 1.6%

  • A) 
    TARE
  • B) 
    TACE

Total: 245

  • A: 123
  • B: 122
  • ORRa: 49% versus 36%; P = 0.104
  • Median TTR: 6.6 versus 10.3 months; P = 0.050
  • ORRb: 72% versus 69%; P = 0.748
  • Median TTR: 1.2 versus 2.2 months; P = 0.016

Median TTP: 13.3 versus 8.4 months; P = 0.046

Median: 20.5 versus 17.4 months; P = 0.232

Risk of death:

HR: 1.06 (95% CI: 0.70–1.62); P = 0.780

Carr et al. 2010[37]

(NA)

NA
  • A) 
    TARE
  • B) 
    TACE

Total: 790

  • A: 99
  • B: 691

At 6 monthsa

  • OR: 41% versus 60%
  • CR: 3% versus 5%
  • SD: 35% versus 29%
  • PD : 23% versus 11%
  • DC: 76% versus 89%

P = NA

Median: 11.5 versus 8.5 months; P < 0.0146

Kooby et al. 2010[38]

(6 months)

Child–Pugh grade:

A: 49%, B: 51%

Okuda stage:

I: 39.4%, II: 56.3%, III: 5.6%

  • A) 
    TARE
  • B) 
    TACE

Total: 71

  • A: 27
  • B: 44

At 3 months

  • OR: 11% versus 6%
  • CR: 0% versus 2%
  • SD: 41% versus 36%
  • PD: 33% versus 36%
  • DC: 52% versus 42%

P = 0.73

Median: 6 versus 6 months; P = 0.74

Cumulative rate:

  • 1 year: 16% versus 20%

Risk of death:

HR: 1.09 (95% CI: 0.61–1.92); P = 0.79

Kooby et al.[38] observed fewer complications with TARE than with TACE. Overall, TARE caused more fatigue, and TACE caused more haematological toxicities and greater elevations of AST and ALT levels. Other data, less consistent across studies, showed that TARE was associated with less fever[39] and abdominal pain.[40]

Combination of (DEB)-TACE and sorafenib

Two published RCTs,[42, 43] one RCT presented as an abstract[44] and two retrospective studies[45, 46] compared the combination (DEB)-TACE and sorafenib to (DEB)-TACE and placebo (Table 5). The primary endpoint of all three RCTs was time to progression and it differed between studies.[42-44] Sansonno et al.[43] showed that sorafenib delayed time to progression, Kudo et al.[42] also observed a delayed time to progression with sorafenib but this was not confirmed by central review, and in Lencioni et al.[44], time to progression was not significantly delayed with sorafenib. The addition of sorafenib to (DEB)-TACE did not increase overall survival compared with placebo.[42, 44] However, the two retrospective studies comparing the combination of TACE and sorafenib to TACE alone showed a longer overall survival in the sorafenib group.[45, 46]

Table 5. Summary of studies evaluating combination TACE or DEB-TACE and sorafenib
Study (median follow-up)PopulationTreatmentnTumour response (A versus B)Overall survival (A versus B)
  1. a

    Tumour response based on RECIST criteria.

  2. BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CR, complete response; DC, disease control; DEB, drug-eluting bead; HCV + , hepatitis C virus seropositivity; HR, hazard ratio; n, number of patients; NA, not available; NS, statistically non-significant; OR, objective response; PD, progressive disease; PFS, progression-free survival; SD, stable disease; TACE, transarterial chemoembolization; TTP, time to progression; RECIST, Response Evaluation Criteria in Solid Tumours.

Randomized controlled trial

 Sansonno et al. 2012[43]

Double blinded

Level of evidence II

(NA)

Inclusion criteria:

CR with TACE, HCV+, Child–Pugh grade A, BCLC stage B

  • A) 
    TACE + sorafenib
  • B) 
    TACE + placebo

Total: 80

  • A: 40
  • B: 40

Median TTP:

9.2 versus 4.9 months; P < 0.001

Risk of progression:

HR: 2.5 (95% CI: 1.66–7.56)

NA

 Kudo et al. 2011[42]

Double blinded

Level of evidence I

(NA)

Inclusion criteria:

TACE response ≥25%,

tumor ≤3 cm, Child–Pugh grade A

  • A) 
    TACE + sorafenib
  • B) 
    TACE + placebo

Total: 458

  • A: 229
  • B: 229

Central review

Median TTP: 5.4 versus 3.7 months

Risk of progression:

HR: 0.87 (95% CI: 0.70–1.09); P = 0.252

Cumulative PFS rate:

  • 3 months: 65% versus 58.7%
  • 6 months: 45.7% versus 33.5%

Median: 29.7 months versus not reached

Cumulative rate:

  • 1 year: 94.6% versus 94.1%
  • 2 years: 72.1% versus 73.8%

Risk of death:

HR: 1.06 (95% CI: 0.69–1.64); P = 0.790

Retrospective study (Level of evidence IV)

 Qu et al. 2012[45]

Matched case-control

(NA)

Child–Pugh grade:

A: 76%, B: 24%

BCLC stage:

B: 37%, C: 63%

  • A) 
    TACE + sorafenib
  • B) 
    TACE alone

Total: 90

  • A: 45
  • B: 45
NAMedian: 27 versus 17 months; P = 0.001

 Tan et al. 2010[46]

(A/B: 14/6 months)

Inclusion criteria: multiple recurrence after transplantation

Child-Pugh grade:

A: 55%, B: 45%

  • A) 
    TACE + sorafenib
  • B) 
    TACE alone

Total: 20

  • A: 10
  • B: 10

After 4 to 6 weeksa

  • OR: 0% versus 10%
  • CR: 0% versus 0%
  • SD: 70% versus 30%
  • PD: 30% versus 60%
  • DC: 70% versus 40%

P = NS

Median (post-recurrences):

14 versus 6 months; P = 0.005

Risk of death – overall:

HR: 0.305 (95% CI: 0.104–0.890); P = 0.03

Risk of death – post-recurrence:

HR: 0.195 (95% CI: 0.057–0.669); P = 0.009

Communication abstract (Level of evidence not evaluable)

 Lencioni et al. 2012[44]

(NA)

Child–Pugh grade: A

BCLC stage: B

  • A) 
    DEB-TACE + sorafenib
  • B) 
    DEB-TACE + placebo

Total: 307

  • A: 154
  • B: 153

Risk of progression:

HR: 0.797 (95% CI: 0.588–1.080); P = 0.072

Median: not reached

Risk of death:

HR: 0.898 (95% CI: 0.606–1.330); P = 0.295

Sorafenib was generally not well tolerated and doses frequently had to be reduced or the treatment stopped because of unacceptable toxicities. Common toxicities were hand/foot skin reactions, haematological toxicities, hypertension, diarrhoea, alopecia, elevation of serum lipase levels, rash and desquamation.[42, 43, 45]

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

Transarterial embolization therapies are local palliative treatments aiming to prolong survival in intermediate stage HCC patients. Although some of these therapies have been used for many years as standard, their efficacy is still being questioned.

TACE

Results from prospective studies comparing TACE with absence of treatment were not consistent across studies,[6-12] whereas all retrospective studies reported a survival benefit with TACE.[13-15, 17] However, the level of evidence of the latter studies is lower. From a methodological point of view, all published RCTs were of low power, and some aspects affected the study quality or the external validity of most of them. Indeed, a number of flaws were observed: patients with advanced disease stage were recruited (>20% of Okuda III stage[11] and at least 66% were symptomatic[7]); gelfoam powder, recognized today as being unsafe, was used for TACE;[11] groups were not balanced;[6] about 15% of patients in the TACE group received no or unsatisfactory treatments;[7, 10] and 7% of patients in the control group received TACE.[7] Previous studies from Llovet et al.[8] and Lo et al.[9] had no major methodological flaws.

Heterogeneity of RCTs' results could not obviously be associated with any patient's characteristic. However, it was noticed that all three positive prospective studies[8, 9, 12] were amongst the four published after the year 2000.[7-9, 12] TACE procedure has improved over the years, notably by the introduction of the use of microcatheters at the end of the 1990s; these changes could have improved the efficacy of the technique and explain the pattern of results related to time.

Considering these heterogeneous results, meta-analyses were of particular importance to conclude on the efficacy of TACE. The Oliveri et al.[20] meta-analysis has advantages over the two earlier ones:[18, 19] it included all studies published on the subject to date, and it used survival data of all time points (hazard ratio), as opposed to survival data at a fixed time point (odds ratio). Oliveri et al.[20] showed that TACE was not significantly associated with a survival benefit, but the P-value was close to the significance threshold. The authors of three replies to this meta-analysis criticized the studies selection.[47-49] Forner et al.[47] argued that it was too permissive and explained why studies from Akamatsu et al.[50], Pelletier et al.[11] and Doffoel et al.[7] should not have been included. In contrast, Ray et al.[48] found the studies selection too restrictive because only RCTs were considered, ignoring a large body of evidence. Finally, Rose et al.[49] argued that the TACE procedure and patient selection criteria have changed over the years, a point also acknowledged in the two other replies, and that studies selection should have been based on this criterion. Thus, they recalculated the estimates of mortality risk by including only the three most recent studies,[7-9] and found that TACE increased overall survival [HR: 0.79 (95% CI: 0.63–1.00)].

Overall data on TACE indicate that it is a relatively safe procedure. It is acknowledged that the incidence of complications and deaths can greatly be reduced by a proper patient selection.[51, 52] Accordingly, the incidence of death is generally lower than 6% and complication rates can be limited to about 10%.[51]

In summary, when considering the methodological quality of studies and the improvement of the TACE procedure, the two positive RCTs stand out as the ones that should be given more weight.[8, 9] As for the Oliveri et al.[20] meta-analysis, taken as it is, the CEPO considers that it would be difficult not to recommend TACE strictly on the basis of statistical considerations, as the upper limit of the 95% CI barely exceeded the 1.00 significance threshold value. This is besides the fact that, with today's knowledge, some authors consider that a few negative studies could have been arguably left out,[47-49] thus, the results would probably have been positive.[49] Although they are of lower level of evidence, the non-randomized prospective study and the retrospective ones add to the body of evidence showing the positive effect of TACE on survival.[12-14, 16, 17] For all these considerations, the CEPO recognizes that TACE probably provides a survival benefit.

TAE

The evidence on the efficacy of TAE holds to two small RCTs,[8, 22] one of which was not properly completed.[8] Both studies showed that TAE does not significantly increase overall survival compared with no treatment. The three TAE-specific meta-analyses also showed no survival advantage with the treatment.[18-20] In contrast, other studies comparing TAE to TACE showed similar survival results between the two treatments,[23-25] suggesting that, just as TACE, TAE also has an effect on survival. However, the methodological quality of these studies was poor and the evidence of an actual effect only indirect. Similar results were reported with Bead Block® TAE compared with DEB-TACE, although in one study, the follow-up time was too short to evaluate survival[26] and in the second, too little details are available to fully appreciate the results.[27] Thus, the available data are not sufficient to definitively conclude on the efficacy of TAE. Moreover, the CEPO feels that it would be unethical to deny the potential effects of the local chemotherapy that is part of the TACE procedure. With these considerations in mind, TACE should be preferred to TAE. However, in patients with contraindications to chemotherapy, notably because of cardiac or renal co-morbidities, TAE could be considered. But again, this is not based on solid evidence.

DEB-TACE

To date, only one RCT comparing the efficacy of DEB-TACE with conventional TACE has published overall survival data. This study, from Sacco et al.,[29] recruited a small number of patients (n = 67), but was otherwise of good quality. The PRECISION V study, the largest one (n = 212), published data on tumour response and safety so far.[28, 36] This study is not without flaws however; besides the apparent imbalance between groups in terms of Okuda stage distribution, about 10% of the patients dropped out before the first treatment or the first imaging follow up,[28] and no embolizing agent was used at any time for nearly 28% of patients of the TACE group.[36] The other RCT, that of van Malenstein et al.,[30] compared the pharmacokinetics of DEB-TACE with that of conventional TACE. In this small study (n = 30), patients of the DEB-TACE group were older, and 43% of the patients had received previous treatment.

Sacco et al.[29] showed no difference between the two treatments in terms of overall survival and all three RCTs reported no difference in tumour response.[28-30] The absence of a difference in tumour response was corroborated by the Gao et al.[35] meta-analysis. However, in patients with more advanced disease, tumour response was better for DEB-TACE than with conventional TACE.[28] It is however worth mentioning that, with transarterial embolization therapies, tumour response does not necessarily translate into increased survival.[6, 10, 11, 22] The pharmacokinetic data indicate that patients treated with DEB-TACE are significantly less systemically exposed to doxorubicin than those treated with TACE.[30]

Just like it was observed with TACE, data from retrospective studies comparing DEB-TACE with conventional TACE are not consistent with those of RCTs; indeed, longer overall survival was observed with DEB-TACE.[31, 32, 34] However, considering that the follow-up of the Song et al.[32] study was very short, and that the disease stage of patients in the Dhanasekaran et al.[31] study was overall more advanced, their results must be interpreted prudently.

Overall, DEB-TACE appears to be safer than conventional TACE because the AST and ALT transient elevation is lower, and the incidence of constitutional symptoms, alopecia and myelosuppression are lower.[28-30, 32, 33, 36] However, alopecia and myelosuppression are not very common toxicities, and AST and ALT increased levels are not deleterious in themselves, so the clinical significance of this apparent better tolerability is arguable. Moreover, the overall incidence of grade 3 and 4 toxicities was very similar with both treatments.[36]

In summary, the best level of evidence indicates that DEB-TACE and conventional TACE are equivalent treatments in terms of overall survival. However, the apparent better toxicity profile of DEB-TACE does not seem clinically significant.

TARE

The four studies comparing TARE with TACE were retrospective and of low methodological quality.[37-40] Groups in all studies were unbalanced. No difference in overall survival was found between the treatments, except in the study by Carr et al.[37] In this latter study, however, when similar patients were compared with stratification strategies, the survival effect disappeared. The meta-analysis by Xie et al.[41] confirmed these findings. Data on tumour response were not consistently different between groups.[37-39] Data on toxicity showed that TARE is well tolerated.[38-40] Salem et al.[53] published in 2013 a non-randomized prospective study (n = 56) evaluating quality of life and showed that TARE may be associated with a modestly better quality of life than TACE, at least when certain subscales of the survey are considered separately. However, the study had important limitations: the data collection was limited to 4 weeks post-treatment and the groups were unbalanced regarding tumour stages (TARE patients generally had a more advanced disease). Thus, TARE is still in the investigation phase and RCTs will be necessary to determine its place in the treatment of HCC.

Because of its microembolic effect,[54] TARE could, in theory, be the only local option to treat patients with portal vein thrombosis, especially in the absence of collateral irrigation. The only comparative data on the subject come from Kooby et al.,[38] in which 50% and 30% of the patients in the TARE and TACE groups presented a vascular invasion. For the whole population, no significant difference was observed between the groups in terms of treatment-related death (7% versus 9%) and hepatic failure (7% versus 14%). Moreover, in a recently published meta-analysis, Xue et al.[55] claimed that TACE can be relatively safe for the treatment of HCC in the presence of a portal vein thrombosis. Thus, this notion of TARE being safer than TACE for these patients needs to be more formally demonstrated. In fact, the accumulating data on the Asian experience with TACE for this indication challenges the idea of considering portal vein thrombosis as an absolute contraindication for TACE, at least from a safety point of view (see section on patient selection below).[56-63] The efficacy of TACE in this setting is still not clear though; this body of literature is of a low evidence level and bears several methodological concerns, making the data difficult to interpret. Consequently, the meta-analysis of these data cannot be much more informative, besides the important heterogeneity revealed with the analyses.[55] Efficacy needs to be confirmed in RCTs.

Combination of (DEB)-TACE and sorafenib

Results on time to progression were not consistent between studies.[42-44] Interestingly, the magnitude of the response needed in these studies to go on with the administration of sorafenib was more or less restrictive (complete response,[43] ≥25% response[42] or no restriction[44]) and seemed to correlate with the ability of sorafenib to delay time to progression.

The ultimate goal of delaying progression of the disease is to increase survival. In this regard, RCTs showed that sorafenib had no effect,[42, 44] whereas two small retrospective studies found that it increased survival.[45, 46] As for safety, sorafenib was not well tolerated and caused severe toxicities in a large proportion of patients.

In summary, the best available evidence shows that the addition of sorafenib to TACE adds considerable toxicity without providing survival benefits.

Patients selection for TACE (including DEB-TACE) and treatment programme

TACE is a palliative treatment that should be offered to patients ineligible for a potentially curative therapy. The decision to treat with TACE must take into account the residual liver function, the disease stage and the general condition of the patient. It is generally accepted that eligible patients to TACE are of intermediate disease stage (BCLC B, ECOG performance status 0, large multinodular tumours, Okuda stage I–II and Child–Pugh grade A-B).[64] However, in daily practice, with the actual poor knowledge on the predictability of a survival benefit, safety and feasibility are of particular importance to make a decision. The decision must be discussed in a tumour board including preferably gastroenterologists (hepatologists), surgeons, medical oncologists, radiologists, interventional radiologists and pathologists.[3] The CEPO considers the following criteria as absolute contraindications to TACE: advanced cirrhosis (Child–Pugh ≥8, jaundice, encephalopathy, refractory ascites and hepatorenal syndrome); bilobar tumour replacing a large proportion of the liver; reversed portal flow; contraindication to a transarterial procedure (e.g. non embolizable intra-hepatic arteriovenous shunt, absence of vascularization at imaging); and extra-hepatic metastases. The relative contraindications to TACE are: tumour size ≥10 cm (consider hepatic residual function); portal vein thrombosis; co-morbidity involving the dysfunction of an organ (e.g. cardiovascular disease and active pulmonary disease); renal failure; biliary obstruction; and aerobilia. In the presence of a portal vein thrombosis, the CEPO considers that TACE can be safe only in highly selected patients, when the presence of factors reducing the risk of liver failure are present [e.g. thrombosis in the right or left branch, good hepatic reserve (Child Pugh < 8), evidence of portal collateral vascularization and feasibility of superselective embolization (segmental or further)].

Re-treatment with TACE can result in an increased tumour response.[52, 65] However, too aggressive a repetition programme can lead to complications, including hepatic decompensation.[52] The Society of Interventional Radiology,[51] as well as Lencioni et al.,[66] suggested that TACE should not be systematically repeated, but only in the presence of a residual viable tumour or intra-hepatic progression. When a complete response is achieved, the tumour should be followed by imaging every 2 to 3 months. If the tumor is not responding after two consecutive TACE sessions, the treatment should be stopped.[66] The Assessment of Re-Treatment with TACE (ART) prognostic system is a newly available tool that can be considered for a re-treatment decision after the first TACE.[67] Although the modified RECIST response system appears to be the one correlating best with overall survival,[68, 69] the EASL response system has to be used when using the ART prognostic system.[67] With these considerations in mind, the CEPO suggests a TACE treatment programme algorithm in Fig. 1.

figure

Figure 1. Suggested (TACE) programme algorithm. Algorithm inspired from Raoul et al.[52] See details in the ‘Patients selection for TACE [including drug-eluting beads (DEB)-TACE] and treatment programme’ section.[1] Assessment of Re-Treatment with TACE (ART) overall survival prognostic system.[67] This system is based on the EASL response criteria.[70] CT, computer-assisted tomography; EASL, European Association for the Study of the Liver; mRECIST, modified Response Evaluation Criteria in Solid Tumours;[71] MRI, magnetic resonance imaging; TACE, transarterial chemoembolization

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Conclusion and recommendations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

The CEPO acknowledges the therapeutic value of TACE for the palliative treatment of HCC for selected patients. DEB-TACE provides a survival benefit similar to that of TACE and is considered an equivalent alternative. In patients with less favourable criteria, DEB-TACE seems to cause a better tumour response than conventional TACE. Moreover, the incidence of some toxicities is lower with DEB-TACE, although that of grade 3 and 4 toxicities is overall similar. TACE or DEB-TACE should be preferred to TAE. TARE is still in the experimental phase and should not be used outside of clinical trials. Finally, the administration of sorafenib together with TACE does not add a survival advantage and should not be used outside of clinical trials.

Considering the evidence available to date, the CEPO recommends the following:

  1. TACE be considered a standard of practice for the palliative treatment of HCC in eligible patients (Grade C recommendation);
  2. DEB-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities (Grade B recommendation);
  3. the decision to treat with TACE or DEB-TACE be discussed in tumour boards, preferably including gastroenterologists (hepatologists), surgeons, medical oncologists, radiologists, interventional radiologists and pathologists (Grade D recommendation);
  4. TAE not be considered for the treatment of HCC (Grade C recommendation), except in patients with contraindications to the chemotherapy used in the TACE procedure (e.g. in patients with cardiac or renal co-morbidities, grade D recommendation);
  5. TARE not be considered outside of a clinical trial setting (Grade B recommendation); and
  6. sorafenib combined with TACE not be considered outside of a clinical trial setting (Grade B recommendation).

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

The CEPO would like to thank Francine Aubin MD, Hôpital Notre-Dame (CHUM); Tatiana Cabrera Aleksandrova MD, Royal-Victoria Hospital (MUHC); Jean Couture MD, Hôtel-Dieu de Lévis (CHAU); André Lamarre MD, Centre hospitalier de l'Université Laval (CHU de Québec); Frédéric Lemay MD, Hôtel-Dieu (CHUS); Luc Minville MD, Centre hospitalier régional de Rimouski (CSSS de Rimouski-Neigette) and Jean-Luc Raoul MD, Institut Paoli-Calmettes, Marseille (France), for their contribution as external reviewers of the original clinical practice guideline.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References

Doctor Prosanto Chaudhury is a local co-investigator at McGill University Health Centre for the Nordion STOP-HCC study. He does not receive any financial compensation.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion and recommendations
  8. Acknowledgements
  9. Financial support
  10. Conflict of interest
  11. References
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