Percutaneous ethanol injection or percutaneous acetic acid injection for early hepatocellular carcinoma: Cochrane systematic review
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.Objectives
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.Search 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.Selection criteria
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.Data collection and analysis
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.Main 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.Authors' 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.
Weis Sebastian, Franke Annegret, Berg Thomas, Mössner Joachim, Fleig Wolfgang E., Schoppmeyer Konrad
Percutaneous ethanol injection for the treatment of early liver cancer
Liver cancer (hepatocellular carcinoma) is the fifth most common cancer worldwide. In the majority of people, liver cancer is diagnosed at advanced stages of the disease and is mostly accompanied by liver cirrhosis. In high-income countries, about 30% of people present with the more favourable early liver cancer. For these people, percutaneous ablation techniques (destruction of the cancer cells by heat, cold, or chemical substances such as ethanol), surgical resection (removal of part of the liver), and liver transplantation (which is limited by organ donor shortage) are currently considered potentially curative treatments. We aimed to investigate the role of percutaneous injection of ethanol (PEI) and acetic acid (PAI) as compared with other treatments or no intervention for early liver cancer. This review excluded the effects of radiofrequency thermal ablation as this has been already addressed in a previous Cochrane Hepato-Biliary Group systematic review.
The review authors searched the medical literature in order to clarify the role of PEI and PAI for the treatment of liver cancer and to compare their benefits and harms with no treatment, with placebo (a pretend treatment), or with other treatments (such as laser, cryoablation, or microwave ablation; hepatic resection; and liver transplantation). We collected and analysed data from randomised clinical trials (where people were allocated at random to one of two or more treatments groups) of people with liver cancer who were able to receive PEI or PAI. Evidence is current to July 2014.
Key results and quality of evidence
The review authors only identified three randomised trials with 261 participants. The risk of bias was low in one and high in two trials. We found two trials that compared PEI versus PAI and one trial that compared PEI versus surgery. We found no trials that compared PEI or PAI versus sham (pretend) intervention, best supportive care, cryotherapy, laser-induced thermotherapy, or high-frequency ultrasound. We found no randomised trials that compared PAI versus surgery.
The review authors found low-quality evidence suggesting that PEI yielded the same result as PAI regarding overall survival (the length of time that the person remains alive) and recurrence-free survival (time that the person remains free of cancer). We calculated the number of participants that would be required to judge a relative risk reduction (relative risk is a comparison of the risk of an event happening for one treatment group compared with another treatment group) for survival of 20%. We found that for the comparisons PEI versus PAI, the number of participants was too low to reach valid conclusions. In both groups, participants reported the occurrence of mild side effects such as transient fever, flushing, and local pain. Based on one randomised trial with high risk of bias, there was very low quality evidence that surgical resection does not seem to be superior to PEI in people with early liver cancer. Of note, no severe side effects occurred in people treated with PEI while there were three postoperative deaths in people treated surgically. Again, too few participants were randomised to claim or reject important differences.
There is a need for more randomised clinical trials assessing interventions for people with early-stage liver cancer. Such trials should be conducted with low risks of bias (systematic errors, that is overestimation of benefits and underestimation of harms) and of play of chance (random errors, that is errors due to too few participants and too few outcomes).
Implications for practice
On the basis of the limited evidence from the randomised clinical trials that we identified and included in this analysis, percutaneous ethanol injection (PEI) did not seem to differ from percutaneous acetic acid injection (PAI) regarding benefits and harms in people with one to three small (3 cm or less) HCC nodules. However, this evidence from two randomised trials was insufficient to guide the choice between PEI and PAI. This is also the case for the evidence for the comparison of PEI versus surgery for which we included only one trial.
Implications for research
Due to the risk of systematic errors (bias) and risk of random errors ('play of chance') as well as the limited number of participants studied, randomised clinical trials to assess the benefits and harms of local ablative interventions for people with small HCC should be conducted.
Furthermore, in intermediately progressed HCC (i.e., single nodule larger than 4 cm, more than four small nodules), no standard treatment has been sufficiently assessed. In particular, the role of combination therapies (e.g., transarterial chemoembolisation plus percutaneous local ablative therapy) in these tumours should be investigated in randomised trials. In addition, transarterial chemoembolisation itself is often applied in clinical practice, but we still lack large randomised trials or a conclusive meta-analysis that confirmed its effectiveness. Future trials should also address other clinically relevant aspects, such as number of treatment sessions, adverse events, and quality of life. The agreement on one optimal prognostically relevant staging system is important in order to make studies comparable. Another therapeutic interface that has not been well studied is the therapy to bridge the waiting time for people with HCC on the liver transplantation list. Randomised trials in this field are most awaited. Randomised trials ought to be designed according to the SPIRIT guidelines (Standard Protocol Items: Recommendations for Interventional Trials; www.spirit-statement.org) and reported according to the CONSORT guidelines (CONsolidated Standards of Reporting Trials; www.consort-statement.org).Get full text at The Cochrane Library
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