In the name of Alla

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

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

INTRODUCTION

Hepatocellular carcinoma (HCC) The 6 th common cancer in the world Small proportion with early stage may benefit from radical options Surgical resection isn’t the 1 st treatment of choice in the presence of large lesion or poor liver function

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

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

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 don’t response adequately to either procedure alone For 5 cm lesions, % of complete response rate at 1 year was reported by applying radiofrequency ablation (RFA) after transcatheter arterial chemoembolization (TACE)

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

A im 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.

PATIENTS AND METHODS

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

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

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

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

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. Qualitative analysis

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 ( ) for reporting meta-analysis.

Statistical methods The meta-analysis was carried according to the Cochrane Reviewer’s 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.

RESULTS

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

- 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.

Baseline characteristics of randomized trials included in the meta-analysis

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.

Treatment arms among the 10 selected randomized controlled studies

Methodological characteristics of randomized trials included in the meta-analysis

Child-Pugh score Parameter 1 Point 2 Points 3 Points _________________________________________________ Serum bilirubin 3 (mg/dL) Albumin (g/dL) > – 3.5 <2.8 Prothrombin time 1 – 3 4 – 6 >6 ( ↑ S) Ascites None Slight Significant Encephalopathy None 1 – 2 3 – 4 _________________________________________________ Grades: A, 5 to 6 points B, 7 to 9 points C, 10 to 15 points

Sensitivity analysis of survival

Prognosis of patients reported in the randomized controlled trials included in the meta-analysis

DISCUSSION

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.

 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.

The conclusion The combination of transcatheter arterial chemoembolization (TACE) with percutaneous ablation (PA): 1.Improve the overall survival status, especially with percutaneous ethanol injection (PEI), more significantly than a single monotherapy. 2.Decrease the tumour recurrence rate compared with that of monotherapy.

THANKS

- 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.

- 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.

- 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.

- 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.

- Transcatheter arterial chemoembolization (TACE) is more effective for small lesions than large ones. While percutaneous ethanol injection (PEI) alone isn’t 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).

- 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.

- 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.

- A quantitative analysis based on the size or number of lesions and liver function couldn’t 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.

- 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.

- 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.

** 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.