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1
In the name of Alla
2
Transarterial chemoembolization in combination
with percutaneous ablation therapy in
unresectable hepatocellular carcinoma a
meta-analysis

• Prepared by
• Dr. Samah Ali Mansoor Mater
• Under supervision by
• Ass. Prof. Dr. Abdul Hakeem
  Atamimi
• 
  May/2010

3
The contributers

• Wei Wang, Jian Shi and Wei-fen xie
• Department of Gasteroenterology, Shanghai
  Changzheng Hospital, Second Military Medical
  University, Shanghai, China

4
INTRODUCTION
5

• Hepatocellular carcinoma (HCC)
• The 6th common cancer in the world
• Small proportion with early stage may benefit
  from radical options
• Surgical resection isnt the 1st treatment of
  choice in the presence of large lesion or poor
  liver function

6

• Transcatheter arterial chemoembolization (TACE)
  and percutaneous ablation (PA) are prescribed to
  prevent and relive suffering and improve qulity
  of life
• Percutaneous ethanol injection (PEI) and
  radiofrequency ablation (RFA) are highly
  effective in the treatment of small lesion

7

• Transcatheter arterial chemoembolization (TACE)
  improve the survival in large and multiple
  lesions
• Some viable tumor cells remain after
  transcatheter arterial chemoembolization (TACE)

8

• Recent evidence suggest that the combination of
  transcatheter arterial chemoembolization (TACE)
  with percutaneous ethanol injection (PEI) or
  radiofrequency ablation (RFA) may have a
  synergistic effect in treating large lesions that
  dont response adequately to either procedure
  alone
• For 5 cm lesions, 90-100 of complete response
  rate at 1 year was reported by applying
  radiofrequency ablation (RFA) after
  transcatheter arterial chemoembolization (TACE)

9

• Kirioshi et al. reported better results in tumor
  response and overall survival with combination of
  transcatheter arterial chemoembolization (TACE)
  and percutaneous ablation (PA) as compared with
  either procedure alone
• However, several studies found no significant
  difference in the overall survival between
  combination and monotherapy

10
Aim of the presented study

• Identify the survival benefits of
• this combination therapy for patients
• with unresectable hepatocellular
• carcinoma (HCC) with those of
• either procedure alone.

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PATIENTS AND METHODS
12
Study objectives

• The primary outcome
• The survival rate
• The secondary outcome
• The initial complete response
  rate, and
• The tumour recurrence rate

13
Search strategy

• Trials assesed the survival benefit or
  tumour recurrence for patients with unresectable
  hepatocellular carcinoma (HCC) were searched
• - On PubMed, Embase and Web of Science
  
• ( all from 1990 to July 2009 )
• - On Cochrane library database ( 2009,
  issue 2 )
• - Manually, in general reviews on
  hepatocellular
• carcinoma (HCC) and references from
  published
• clinical trials

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Including criterea

• A prospective randomized-controlled clinical
  trials
• Above 18 years old patients
• Patients were scheduled to undergo transcatheter
  arterial chemoembolization (TACE) with
  percutaneous ethanol injection (PEI) or
  radiofrequency ablation (RFA)

15

• Non-randomized studies
• Recurrence of the tumour after
• hepatectomy, liver metastases
• Non of the three intervention
• procedures was applied
• No clinical data were collected for
• primary and secondary outcomes

Exclusion criterea
16
Qualitative analysis

• Jadad composite scale
• used to score the included trials (from
  0 to 5
• points ) as assesses descriptions of
• Randomization (
  0-2 point )
• Blinding
  ( 0-2 point )
• dropouts or withdrawals ( 0-1
  point )
• _______________________________________
• High-quality reports at least with 3
  points.
• Low-quality reports with 2 points or
  less.

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• All calculations for the current
  meta-analysis were performed using REVIEW MANAGER
  (version 5.0 for Windows the Cochrane
  Collaboration, Oxford, UK).
• This article follows the QUARUM and the
  Cochrane Collection guidelines (http//
  www.cochrane.de ) for reporting meta-analysis.

18
Statistical methods

• The meta-analysis was carried according to
  the
• Cochrane Reviewers Handbook recommended
• by Cochrane Collaboration.
• Pooled odd ratio (OR) was calculated using
  DerSimonian and Laird method (random- affected
  model).
• The quantitative heterogeneity between trials
  was evaluated by the DLQ statistic.
• A funnel plot was used to test potential
  publication bias.

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RESULTS
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Identification of eligible randomized-controlled
trials from different medicine databases.
21

• - Clinical data from 595 patients from those
  10
• trials were pooled to comparing for the
  current meta-analysis.
• - One trial was with no difference in most
  baseline characteristics.
• - Two trials involved 3 study arms.
• - No overlapping cases were among the 10
  trials.

22
Baseline characteristics of randomized trials
included in the meta-analysis
23
Qualitative analysis of randomized trials

• - 9 trials including 512 patients reported
  the 1-year survival rate.
• - 7 trials reported the 2-years and 3-years
  survival rate separately.
• - 1 trial assessed the qualiy of life and
  used in calculating the secondary outcome.

24
Treatment arms among the 10 selected randomized
controlled studies
25
Methodological characteristics of randomized
trials included in the meta-analysis
26
Child-Pugh score

• Parameter 1 Point
  2 Points 3 Points
• _________________________________________________
• Serum bilirubin lt2
  23 gt3
• (mg/dL)
• Albumin (g/dL)  gt3.5
  2.83.5 lt2.8
• Prothrombin time 13
  46 gt6
• ( ? S)
• Ascites None
  Slight Significant
• Encephalopathy None
  12 34
• _________________________________________________
• Grades
• A, 5 to 6 points
• B, 7 to 9 points
• C, 10 to 15 points

27
Sensitivity analysis of survival
28
Prognosis of patients reported in the randomized
controlled trials included in the meta-analysis
29
DISCUSSION
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• The presented study demonstrated that the
  combination of transcatheter arterial
  chemoembolization (TACE) with percutaneous
  ablation (PA) was superior to transcatheter
  arterial chemoembolization (TACE) or percutaneous
  ablation (PA) alone for the significant benefit
  of survival and decrease of tumour recurrence for
  hepatocellular carcinoma patients.

31

• No enough adverse events data can be pooled for
  systematic analysis among the selected randomized
  controlled trials (RCTs), so no safety profile
  and risk analysis with the different
  interventions was established in this
  meta-analysis presentation.

32
The conclusion

• The combination of transcatheter arterial
• chemoembolization (TACE) with percutaneous
• ablation (PA)
• Improve the overall survival status, especially
  with percutaneous ethanol injection (PEI), more
  significantly than a single monotherapy.
• Decrease the tumour recurrence rate compared with
  that of monotherapy.

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THANKS
34

• - Becker et al. showed no significant
  difference in overall survival.
• - In Okuda stage I hepatocellular carcinoma
  (HCC) patients treated by combination therapy,
  suggesting combination therapy suitable only in
  good liver function.
• - In conflicting reports, Koda et al and
  Yamamato et al, indicates significantly improve
  survival with combination therapy, although
  Child-pugh class C included patient.
• the reason for that conflict may be
  the
• different aetiologies of liver
  disease.

35

• - In Becker et al.s study, 50 liver disease
  was caused by alcohol.
• - In other studies, most patients had chronic
  hepatitis B or C.
• Suggesting that combined transcatheter
  arterial chemoembolization (TACE) with
  percutaneous ethanol injection (PEI) may be less
  effective in patients with alcohol-induced
  cirrhosis than those with an HBV- or an
  HCV-induced pathology.

36

• - In comparing transcatheter arterial
  chemoembolization (TACE) with percutaneous
  ethanol injection (PEI) versus percutaneous
  ethanol injection (PEI) alone, there was improved
  in 1- and 2-year survival but not with 3-year
  survival.
• This may due to that sensitivity
  analysis
• includes only 2 trials with 84
  patients.

37

• - Although Koda et al. showed no
  difference between combination therapy and
  percutaneous ethanol injection (PEI) alone for
  small size lesion, the combination was superior
  for less than 2cm greatest dimension tumours.
• These contrasting results might be
  due to the short period of clinical follow-up.
• Nevertheless, Fracesco et al. showed
  significant survival benefit for transcatheter
  arterial chemoembolization (TACE) with
  percutaneous ethanol injection (PEI) combination
  in up to 5cm nodules compared with percutaneous
  ethanol injection (PEI) alone.

38

• - Transcatheter arterial chemoembolization
  (TACE) is more effective for small lesions than
  large ones. While percutaneous ethanol
  injection (PEI) alone isnt approperiate for
  large lesion as it is difficult for ethanol to
  permeate into tumours.
• Combination should be more
  effective for either small or large lesions.
• This superiority must be
  strengthened by further prospective randomized
  controlled trials (RCTs).

39

• - The sensitivity analysis showed no
  survival benefit from transcatheter arterial
  chemoembolization (TACE) combined with
  radiofrequency ablation (RFA) in small lesions as
  compared with radiofrequency ablation (RFA)
  alone.
• - Few retrospective studies had already
  showed no advantage with this combination in
  local recurrence rate or survival rate.

40

• - The advantage for this combination may
  be
• (a) transcatheter arterial
  chemoembolization (TACE) by block the hepatic
  arterial blood flow contribute to decrease in
  heat-sink effects and increase in the necrotic
  area induced by radiofrequency ablation (RFA).
• (b) effect of anticancer agents on
  cancer cells may be enhanced by the hyperthermia.
• These advantages seem to have no
  any indication according to the current
  meta-analysis. That may due to radiofrequency
  ablation (RFA) has already achieved complete
  necrosis in 90 in small (less than 3cm) nodules.

41

• - A quantitative analysis based on
  the size or number of lesions and liver function
  couldnt be performed because of insufficient
  data.
• - One trial reported that survival
  and recurrence benefit of transcatheter arterial
  chemoembolization (TACE) with percutaneous
  ethanol injection (PEI) was statistically
  significant for (less than 2cm) tumor as
  compared with percutaneous ethanol injection
  (PEI) alone.

42

• - The pooled result showed that combination
  therapy significantly decreased the recurrence
  rate as compared with monotherapy.
• - However, Becker et al. found progressive
  disease in both combination and monotherapy.
• the reason may be the small size of the
  studies and the different treatment arms of
  combination therapy used.
• furthermore, long follow-up randomized
  controlled trials (RCTs) are required to confirm
  either results.

43

• - Different meta-analysis reported the
  superiority of radiofrequency ablation (RFA) to
  percutaneous ethanol injection (PEI) with at
  least more than 2cm diameter tumour.
• - The presented study demonstrate that
  transcatheter arterial chemoembolization (TACE)
  combined with percutaneous ethanol injection
  (PEI) could benefit survival for large lesions.
• - Yang et al. showed transcatheter arterial
  chemoembolization (TACE) combined with
  radiofrequency ablation (RFA) lead to therapeutic
  response.

44

• Well-designed and powered
  douple-blinded randomized controlled trials
  (RCTs) comparing transcatheter arterial
  chemoembolization (TACE) combined with
  radiofrequency ablation (RFA) with transcatheter
  arterial chemoembolization (TACE) are required .