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Meta-Analysis
. 2024 Jun 4;6(6):CD013731.
doi: 10.1002/14651858.CD013731.pub2.

Gene therapy for people with hepatocellular carcinoma

Cho Naing  1 , Han Ni  2 , Htar Htar Aung  3 , Norah Htet Htet  3 , Dimitrinka Nikolova  4
Affiliations
Meta-Analysis

Gene therapy for people with hepatocellular carcinoma

Cho Naing et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation.

Search methods: 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 We searched five online clinical trial registries to identify unpublished or ongoing trials.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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

CN: none.

HN is a Cochrane Editor, but had no role in the editorial process for this review.

HHA: none.

NHH: none.

DN is the Managing Editor of the Cochrane hepato‐Biliary Group, but had no role in the editorial process for this review.

Figures

1
1
Study flow diagram (Page 2021a; Page 2021b). Date of last search 20 January 2023
2
2
Adenovirus‐thymidine kinase with ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone. All‐cause mortality two years after randomisation (Li 2007). The diversity‐adjusted required information size (DARIS) was calculated based on all‐cause mortality at two years of 77% in the control group, risk ratio reduction in the ADV‐TK/GCV group of 15%, alpha of 2.5%, and beta of 10% (90% power). The required information size was 763 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for benefit, but not for harm (red inward sloping lines), and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The accrued sample size (45 trial participants) was only a fraction of the DARIS of 763 participants. The 95% trial sequential analysis adjusted CI was 0.03 to 5.94.
3
3
Double‐dose of adenovirus‐thymidine kinase with ganciclovir (ADV‐TK/GCV) plus liver transplantation compared with liver transplantation alone All‐cause mortality five years after randomisation (Zhu 2018). The diversity‐adjusted required information size (DARIS) was calculated based on all‐cause mortality of 58% in the control group, risk ratio reduction in the double‐dose ADV‐TK/GCV group of 15%, alpha of 2.5%, and beta of 10% (90% power). The required information size was 1632 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for benefit, but not for harm (red inward sloping lines) and did not enter the trial sequential monitoring area for futility (inner‐wedge with red outward sloping lines). The accrued sample size (86 trial participants) was only a fraction of the DARIS of 1632 participants. The 95% trial sequential analysis adjusted CI was 0.04 to 3.84.
1.1
1.1. Analysis
Comparison 1: Pexastimogene devacirepvec (Pexa‐Vec) plus best supportive care versus best supportive care alone, Outcome 1: Overall survival at censored observation (measured at end of treatment, i.e. 20 months)
1.2
1.2. Analysis
Comparison 1: Pexastimogene devacirepvec (Pexa‐Vec) plus best supportive care versus best supportive care alone, Outcome 2: Serious adverse events (Intention‐to‐treat) (measured at end of treatment, i.e. 20 months)
1.3
1.3. Analysis
Comparison 1: Pexastimogene devacirepvec (Pexa‐Vec) plus best supportive care versus best supportive care alone, Outcome 3: Disease progression (measured at end of treatment, i.e. 20 months)
1.4
1.4. Analysis
Comparison 1: Pexastimogene devacirepvec (Pexa‐Vec) plus best supportive care versus best supportive care alone, Outcome 4: Any adverse events considered non‐serious (number of participants) (during 20 months of treatment)
2.1
2.1. Analysis
Comparison 2: Adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 1: All‐cause mortality (measured at 1‐year follow‐up)
2.2
2.2. Analysis
Comparison 2: Adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 2: All‐cause mortality (measured at 2‐year follow‐up)
2.3
2.3. Analysis
Comparison 2: Adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 3: Any adverse events considered non‐serious (number of participants)
3.1
3.1. Analysis
Comparison 3: Double‐dose adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 1: All‐cause mortality (measured at 1‐year follow‐up)
3.2
3.2. Analysis
Comparison 3: Double‐dose adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 2: All‐cause mortality (measured at 3‐year follow‐up)
3.3
3.3. Analysis
Comparison 3: Double‐dose adenovirus‐thymidine kinase and ganciclovir (ADV‐TK/GCV) plus liver transplantation versus liver transplantation alone, Outcome 3: All‐cause mortality (measured at 5‐year follow‐up) (primary time point)
4.1
4.1. Analysis
Comparison 4: Recombinant human adenovirus‐p53 with hydroxycamptothecin (rAd‐p53/HCT) versus hydroxycamptothecin alone, Outcome 1: Overall survival (measured at 6 months)
4.2
4.2. Analysis
Comparison 4: Recombinant human adenovirus‐p53 with hydroxycamptothecin (rAd‐p53/HCT) versus hydroxycamptothecin alone, Outcome 2: Overall survival (measured at 12 months)
4.3
4.3. Analysis
Comparison 4: Recombinant human adenovirus‐p53 with hydroxycamptothecin (rAd‐p53/HCT) versus hydroxycamptothecin alone, Outcome 3: Disease progression (measured at 6 months)
5.1
5.1. Analysis
Comparison 5: Recombinant human adenovirus‐p53/5‐fluorouracil (rAd‐p53/5‐Fu) plus transarterial chemoembolisation versus transarterial chemoembolisation alone, Outcome 1: Disease progression at median 12.8 months
6.1
6.1. Analysis
Comparison 6: E1B‐deleted (dl1520) adenovirus versus percutaneous ethanol injection (PEI), Outcome 1: Disease progression at 2 weeks
6.2
6.2. Analysis
Comparison 6: E1B‐deleted (dl1520) adenovirus versus percutaneous ethanol injection (PEI), Outcome 2: Any adverse events considered non‐serious (number of events)
6.3
6.3. Analysis
Comparison 6: E1B‐deleted (dl1520) adenovirus versus percutaneous ethanol injection (PEI), Outcome 3: Proportion of people without improvement in liver function tests at 2 weeks
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