Key messages
— We found six small trials, with problems with trial design, low numbers of people taking part, and variability in results. All the people in the trials had inoperable hepatocellular carcinoma (primary liver cancer), none had operable hepatocellular carcinoma.
— We do not know whether any of the tested gene therapies when used alone, or in combination with another treatment, affects risk of death, liver function, or causes unwanted effects.
— We need well-designed, well-reported trials that focus on outcomes such as death, quality of life, and costs, which are important to people with hepatocellular carcinoma and to decision makers.
What is gene therapy?
In gene therapy, abnormal or defective genes are replaced with normal genes.
What is hepatocellular carcinoma?
Hepatocellular carcinoma is a type of primary liver cancer (i.e. a cancer that starts in the liver). People who are obese, misuse alcohol, or have chronic (long-lasting) infections with hepatitis B or hepatitis C viruses, are most at risk of developing hepatocellular carcinoma.
How is hepatocellular carcinoma treated?
The choice of treatment for people with hepatocellular carcinoma depends on how advanced their disease is. Possible treatments include chemotherapy, surgery, or liver transplantation.
What did we want to find out?
We wanted to find out if gene therapy was better than any other treatment for people with operable or inoperable hepatocellular carcinoma.
We also wanted to know if gene therapy improves liver function (how well the liver filters the blood and breaks down poisonous substances) or causes any unwanted effects, including death.
What did we do?
We identified relevant randomised trials, that is, studies in which people are assigned by chance to one of two or more treatment groups, to find out which treatment is best. We summarised the results and rated our confidence in the evidence, based on factors such as trial quality and methods.
What did we find?
We found 6 trials on a total of 364 people with advanced inoperable hepatocellular carcinoma. No trials assessed the effects of gene therapy in people with operable hepatocellular carcinoma.
All 6 trials had problems with design and conduct. The gene therapies investigated were:
— pexastimogene devacirepvec (Pexa-Vec) plus best supportive care;
— a single- or double-dose of adenovirus-thymidine kinase plus ganciclovir (ADV-TK/GCV) plus liver transplantation;
— recombinant adenovirus-p53 (rAd-p53) plus hydroxycamptothecin (an anticancer medicine);
— recombinant adenovirus human p53/5-fluorouracil (rAd-p53/5-Fu) plus transarterial chemoembolisation (injection of an anticancer medicine directly into the blood supply to the tumour); and
— E1B-deleted (dl1520) adenovirus.
The largest trial included 129 people, and the smallest trial included 10 people; 4 trials were conducted in China, 1 in Egypt, and 1 in several countries. The trials lasted from 6 months to 5 years. Trial funding came from industries, local health institutions, foundations, researchers, or the universities at which the people running the trials worked.
The trials compared gene therapy against:
— best supportive care;
— liver transplantation (where a diseased liver is replaced with a healthy one);
— transarterial chemoembolisation; or
— percutaneous ethanol (alcohol) injection directly into the tumour through the skin.
Each trial compared a different combination of treatments, so we could not combine data from all trials to obtain conclusive results. Data on clinically relevant outcomes were also missing.
Main results
We are very uncertain whether:
— Pexa-Vec plus best supportive care affects risk of death from any causes after 20 months compared to best supportive care alone;
— a single dose of ADV-TK/GCV plus liver transplantation affects risk of death from any cause after two years compared to liver transplantation alone.
— rAd-p53/5-Fu plus transarterial chemoembolisation affects disease progression (whether the cancer gets worse) compared to transarterial chemoembolisation alone;
— rAd-p53 plus hydroxycamptothecin affects disease progression compared to hydroxycamptothecin alone;
— dl1520 plus a percutaneous ethanol inection has any effect on disease progression or non-serious unwanted effects, compared to a percutaneous ethanol injection alone.
The evidence suggests that a double-dose of ADV-TK/GCV plus liver transplantation may reduce death from any cause after 5 years compared to liver transplantation alone.
What are the limitations of the evidence?
The people in the trials seemed to be aware of the treatments they received. The trials had problems with their methods and their results were likely to exaggerate or underestimate the benefits of treatment and unwanted effects. Our findings were based on only 1 trial for each gene therapy, with few data. The lack of trials and data prevents us from drawing firm conclusions.
How up to date is this evidence?
The evidence is up to date to 20 January 2023.
The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.
Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing.
To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation.
We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index–Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023.
We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported.
We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up.
We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only.
Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone
There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate."
Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone
There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life.
Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone
There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life.
Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone
There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life.
rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone
The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life.
E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection
The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life.
One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials.
We found five ongoing randomised clinical trials.