title: Percutaneous ethanol injection or percutaneous acetic acid injection for early hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is the fifth most common global cancer. When HCC is diagnosed early, interventions such as percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), or radiofrequency (thermal) ablation (RF(T)A) may have curative potential and represent less invasive alternatives to surgery.
  
  
  OBJECTIVE
  To evaluate the beneficial and harmful effects of PEI or PAI in adults with early HCC defined according to the Milan criteria, that is, one cancer nodule up to 5 cm in diameter or up to three cancer nodules up to 3 cm in diameter compared with no intervention, sham intervention, each other, other percutaneous interventions, or surgery.
  
  
  METHODS
  We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (July 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (1946 to July 2014), EMBASE (1976 to July 2014), and Science Citation Index Expanded (1900 to July 2014). We handsearched meeting abstracts of six oncological and hepatological societies and references of articles to July 2014. We contacted researchers in the field.
  
  
  METHODS
  We considered randomised clinical trials comparing PEI or PAI versus no intervention, sham intervention, each other, other percutaneous interventions, or surgery for the treatment of early HCC regardless of blinding, publication status, or language. We excluded studies comparing RFA or combination of different interventions as such interventions have been or will be addressed in other Cochrane Hepato-Biliary Group systematic reviews.
  
  
  METHODS
  Two review authors independently selected trials for inclusion, and extracted and analysed data. We calculated the hazard ratios (HR) for median overall survival and recurrence-free survival using the Cox regression model with Parmar's method. We reported type and number of adverse events descriptively. We assessed risk of bias by The Cochrane Collaboration domains to reduce systematic errors and risk of play of chance by trial sequential analysis to reduce random errors. We assessed the methodological quality with GRADE.
  
  
  RESULTS
  We identified three randomised trials with 261 participants for inclusion. The risk of bias was low in one and high in two trials.Two of the randomised trials compared PEI versus PAI; we included 185 participants in the analysis. The overall survival (HR 1.47; 95% confidence interval (CI) 0.68 to 3.19) and recurrence-free survival (HR 1.42; 95% CI 0.68 to 2.94) were not statistically significantly different between the intervention groups of the two trials. Trial sequential analysis for the comparison PEI versus PAI including two trials revealed that the number of participants that were included in the trials were insufficient in order to judge a relative risk reduction of 20%. Data on the duration of hospital stay were available from one trial for the comparison PEI versus PAI showing a significantly shorter hospital stay for the participants treated with PEI (mean 1.7 days; range 2 to 3 days) versus PAI (mean 2.2 days; range 2 to 5 days). Quality of life was not reported. There were only mild adverse events in participants treated with either PEI or PAI such as transient fever, flushing, and local pain.One randomised trial compared PEI versus surgery; we included 76 participants in the analyses. There was no significant difference in the overall survival (HR 1.57; 95% CI 0.53 to 4.61) and recurrence-free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group while three postoperative deaths occurred in the surgery group.In addition to the three randomised trials, we identified one quasi-randomised study comparing PEI versus PAI. Due to methodological flaws of the study, we extracted only the data on adverse events and presented them in a narrative way.We found no randomised trials that compared PEI or PAI versus no intervention, best supportive care, sham intervention, or other percutaneous local ablative therapies excluding RFTA. We found also no randomised clinical trials that compared PAI versus other interventional treatments or surgery. We identified two ongoing randomised clinical trials. One of these two trials compares PEI versus surgery and the other PEI versus transarterial chemoembolization. To date, it is unclear whether the trials will be eligible for inclusion in this meta-analysis as the data are not yet available. This review will not be updated until new randomised clinical trials are published and can be used for analysis.
  
  
  CONCLUSIONS
  PEI versus PAI did not differ significantly regarding benefits and harms in people with early HCC, but the two included trials had only a limited number of participants and one trial was judged a high risk of bias. Thus, the current evidence precludes us from making any firm conclusions.There was also insufficient evidence to determine whether PEI versus surgery (segmental liver resection) was more effective, because conclusions were based on a single randomised trial. While some data from this single trial suggested that PEI was safer, the high risk of bias and the lack of any confirmatory evidence make a reliable assessment impossible.We found no trials assessing PEI or PAI versus no intervention, best supportive care, or sham intervention.There is a need for more randomised clinical trials assessing interventions for people with early stage HCC. Such trials should be conducted with low risks of systematic errors and random errors.
authors.affiliation: Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig Hospitals and Clinics, AöR, Leipzig, Germany, 04103.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weis
authors.forename: Annegret
authors.initials: A
authors.lastname: Franke
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Fleig
authors.forename: Konrad
authors.initials: K
authors.lastname: Schoppmeyer
mesh_terms: D019342:Acetic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D000279:Administration, Cutaneous; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017115:Catheter Ablation / Q000379:methods; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D016032:Randomized Controlled Trials as Topic; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D000431:Ethanol; D019342:Acetic Acid