Treatment of very early- or early-stage primary liver cancer (hepatocellular carcinoma)

Background

Hepatocellular carcinoma (primary liver cancer) arises from the liver cells and is distinct from cancer arising from other parts of the body and spreading to the liver. The Barcelona Clinic Liver Cancer (BCLC) group staging classifies cancer based on patient's life expectancy. It is broadly based on the size of the cancer, number of cancers in the liver, how well the liver functions, and whether one's activities are affected by the cancer. People with very early- or early-stage hepatocellular carcinoma have single cancer or multiple small cancers confined to the liver, have good liver function, and no restriction of activities. There is significant uncertainty in the management of early-stage hepatocellular carcinoma. Therefore, we searched literature databases for randomised clinical trials (RCTs) on the topic until September 2016. We excluded trials in which participants had previously undergone liver transplantation. Apart from using standard Cochrane methods, which allow comparison of only two treatments at a time, we planned to use advanced methods described in full in the review.

Study characteristics of included trials

Four trials (593 participants; 574 participants included for one or more analyses) compared surgery (removal of part of the liver containing cancer) versus radiofrequency ablation (cancer destruction using heat generated by electric current) in people with early hepatocellular carcinoma, eligible to undergo surgery; and 14 trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early hepatocellular carcinoma, not eligible to undergo surgery.

Key results

Surgery versus radiofrequency ablation

The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral cause. The trials did not report the participants' portal hypertension status or whether they received adjuvant antiviral treatment or adjuvant immunotherapy. Three trials reported average follow-up (range 29 months to 42 months). One trial was funded by a party with vested interests; three trials were funded by parties without any vested..

In people eligible for surgery, there was no evidence of a difference in death between radiofrequency ablation and surgery; although there were fewer deaths due to cancer in the surgery group. There were more serious complications in the the surgery group than in the radiofrequency ablation group. None of the trials reported health-related quality of life.

Non-surgical interventions

The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral cause. Most trials did not report the portal hypertension status of the participants, and none reported whether the participants received adjuvant antiviral treatment or adjuvant immunotherapy. Eleven trials reported average follow-up (range 6 months to 37 months). Trial participants, who were not eligible for surgery, were treated with radiofrequency ablation, laser ablation (cancer destruction using laser), microwave ablation (cancer destruction using microwaves), percutaneous acetic acid injection (cancer destruction using vinegar), percutaneous alcohol injection (cancer destruction using alcohol), a combination of radiofrequency ablation with systemic chemotherapy, a combination of radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation (blocking the artery supplying the cancer with beads containing chemotherapy drugs) with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with radiofrequency ablation. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials.

In people not eligible for surgery, the percentage of people who died during the follow-up period was higher in the percutaneous acetic acid injection and percutaneous alcohol injection groups than in the radiofrequency ablation group. There was no evidence of any difference in the percentage of people who died between any of the remaining comparisons. The percentage of people who died because of cancer was also higher in the percutaneous alcohol injection group than in the radiofrequency ablation group. There was no evidence of any difference in the percentage of people who died because of cancer between any of the remaining comparisons. None of the trials reported health-related quality of life at any time point.

Quality of evidence

The overall quality of evidence was low or very low because of the way trials were conducted. Therefore, the conclusions made could overestimate the benefits or underestimate the harms of a given treatment. Further high-quality RCTs are needed.

Authors' conclusions: 

The evidence was of low or very low quality. There was no evidence of a difference in all-cause mortality at maximal follow-up between surgery and radiofrequency ablation in people eligible for surgery. All-cause mortality at maximal follow-up was higher with percutaneous acetic acid injection and percutaneous alcohol injection than with radiofrequency ablation in people not eligible for surgery. There was no evidence of a difference in all-cause mortality at maximal follow-up for the other comparisons. High-quality RCTs designed to assess clinically important differences in all-cause mortality and health-related quality of life, and having an adequate follow-up period (approximately five years) are needed.

Read the full abstract...
Background: 

Hepatocellular carcinoma (primary liver cancer) is classified in many ways. The Barcelona Clinic Liver Cancer (BCLC) group staging classifies the cancer based on patient's life expectancy. People with very early- or early-stage hepatocellular carcinoma have single tumour or three tumours of maximum diameter of 3 cm or less, Child-Pugh status A to B, and performance status 0 (fully functional). Management of hepatocellular carcinoma is uncertain.

Objectives: 

To assess the comparative benefits and harms of different interventions used in the treatment of early or very early hepatocellular carcinoma through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead assessed the benefits and harms of different interventions versus each other or versus sham or no intervention using standard Cochrane methodology.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and trials registers to September 2016 to identify randomised clinical trials (RCTs) on hepatocellular carcinoma.

Selection criteria: 

We included only RCTs, irrespective of language, blinding, or publication status, in participants with very early- or early-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, portal hypertension, aetiology of hepatocellular carcinoma, size and number of the tumours, and future remnant liver volume. We excluded trials including participants who were previously liver transplanted. We considered interventions compared with each other, sham, or no intervention.

Data collection and analysis: 

We calculated the odds ratio, mean difference, rate ratio, or hazard ratio with 95% confidence intervals using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed the risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and the quality of the evidence using GRADE.

Main results: 

Eighteen trials met the inclusion criteria for this review. Four trials (593 participants; 574 participants included for one or more analyses) compared surgery versus radiofrequency ablation in people with early hepatocellular carcinoma, eligible to undergo surgery. Fourteen trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early hepatocellular carcinoma, not eligible to undergo surgery. Overall, the quality of evidence was low or very low for all outcomes for both comparisons.

Surgery versus radiofrequency ablation

The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. The trials did not report the participants' portal hypertension status or whether they received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 29 months to 42 months (3 trials).

There was no evidence of a difference in all-cause mortality at maximal follow-up for surgery versus radiofrequency ablation (hazard ratio 0.80, 95% confidence interval (CI) 0.60 to 1.08; 574 participants; 4 trials; I2 = 68). Cancer-related mortality was lower in the surgery group (20/115 (17.4%)) than in the radiofrequency ablation group (43/115 (37.4%)) (odds ratio 0.35, 95% CI 0.19 to 0.65; 230 participants; 1 trial). Serious adverse events (number of participants) was higher in the surgery group (14/60 (23.3%)) than in the radiofrequency ablation group (1/60 (1.7%)) (odds ratio 17.96, 95% CI 2.28 to 141.60; 120 participants; 1 trial). The number of serious adverse events was higher in the surgery group (adjusted rate 11.3 events per 100 participants) than in the radiofrequency ablation group (3/186 (1.6 events per 100 participants)) (rate ratio 7.02, 95% CI 2.29 to 21.46; 391 participants; 2 trials; I2 = 0%). None of the trials reported health-related quality of life. One trial was funded by a party with vested interests; three trials were funded by parties without any vested.

Non-surgical interventions

The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. Most trials did not report the portal hypertension status of the participants, and none of the trials reported whether the participants received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 6 months to 37 months (11 trials). Trial participants, who were not eligible for surgery, were treated with radiofrequency ablation, laser ablation, microwave ablation, percutaneous acetic acid injection, percutaneous alcohol injection, a combination of radiofrequency ablation with systemic chemotherapy, a combination of radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with radiofrequency ablation.

The mortality at maximal follow-up was higher in the percutaneous acetic acid injection (hazard ratio 1.77, 95% CI 1.12 to 2.79; 125 participants; 1 trial) and percutaneous alcohol injection (hazard ratio 1.49, 95% CI 1.18 to 1.88; 882 participants; 5 trials; I2 = 57%) groups compared with the radiofrequency ablation group. There was no evidence of a difference in all-cause mortality at maximal follow-up for any of the other comparisons. The proportion of people with cancer-related mortality at maximal follow-up was higher in the percutaneous alcohol injection group (adjusted proportion 16.8%) compared with the radiofrequency ablation group (20/232 (8.6%)) (odds ratio 2.18, 95% CI 1.22 to 3.89; 458 participants; 3 trials; I2 = 0%). There was no evidence of a difference in any of the comparisons that reported serious adverse events (number of participants or number of events). None of the trials reported health-related quality of life. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials.

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