Background
Hepatocellular carcinoma (primary liver cancer) arises from the liver cells and is distinct from secondary liver cancer, arising from other parts of the body and spreading to the liver. Hepatocellular carcinoma can be classified in many ways. One classification is by Barcelona Clinic Liver Cancer (BCLC) group stage which classifies the cancer based on how long the person is expected to live (life expectancy). This classification is broadly based on the size of the cancer, number of cancers in the liver, how well the liver works, and whether one's activities are affected by the cancer. People with intermediate-stage hepatocellular carcinoma have large, multiple cancers, but they do not have full-blown liver failure. Cancer is confined to the liver, and there is no restriction of daily activities. There is significant uncertainty in the treatment of people with intermediate-stage hepatocellular carcinoma. We sought to resolve this uncertainty by searching for existing studies on the topic. We included all randomised clinical trials (well-designed clinical trials where people are randomly put into one of two or more treatment groups) whose results were reported to September 2016. We included only trials in which participants with intermediate-stage hepatocellular carcinoma had not undergone liver transplantation previously. Apart from using standard Cochrane methods which allow comparison of only two treatments at a time (direct comparison), we planned to use an advanced method which allows comparison of the many different treatments that are individually compared in the trials (network meta-analysis). However, because there was only one comparison, we could only use standard Cochrane methodology.
Study characteristics
Only three trials with 430 participants met our inclusion criteria; however, two of the trials (412 participants) only reported death and no other measures of how well the treatments worked. All three trials included supportive care (treatment to prevent, control, or relieve complications and side effects and improve comfort and quality of life) as a co-intervention. The trials assessed transarterial chemoembolisation (where anti-cancer drugs block the blood supply and treat the cancer through the vessels supplying the cancer), chemotherapy using sorafenib (a drug which blocks cancer growth), or a combination of transarterial chemoembolisation and sorafenib. It appeared that the trials followed participants for about 18 to 30 months from the initiation of treatment.
Two trials were funded by the pharmaceutical industry; one trial did not report the source of funding.
Key results
Over 18 to 30 months, 50% to 75% of participants died. There was no evidence of any difference between the people who received chemotherapy and those who did not receive chemotherapy. None of the trials reported complications, health-related quality of life (a measure of a person's satisfaction with their life and health), cancer recurrence, or length of hospital stay. Overall, there is currently no evidence for benefit of any active treatment in addition to supportive treatment for intermediate-stage hepatocellular carcinoma. There is significant uncertainty on this and further high-quality randomised clinical trials are required.
Quality of evidence
The overall quality of evidence was low or very low and all the trials were at high risk of bias, which means that there is possibility of making the wrong conclusions, overestimating benefits, or underestimating harms of one treatment or the other because of the way that the trials were conducted.
Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).
There is significant uncertainty in the treatment of intermediate-stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi-nodular, Child-Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease.
To assess the comparative benefits and harms of different interventions used in the treatment of intermediate-stage hepatocellular carcinoma (BCLC stage B) through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma.
We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate-stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation.
We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE.
Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I2 = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials.