Abstract: 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. 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).

Plain-language summary: 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. 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. 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.