Transarterial embolisation, with or without chemotherapy, for liver metastases

Review question
Can transarterial embolisation, with (TACE) or without chemotherapy (TAE) destroy cancer metastases in the liver? Metastases are new cancer sites that spread to other parts of the body from the original site of the cancer.

We looked for randomised clinical trials (studies in which participants are allocated to groups by a play of chance) that assessed the benefits and harms of TAE or TACE, compared with no intervention or placebo, for people with liver metastases from cancer of any location. We were interested in the risk of death, survival time, recurrence rates, progression of the disease, health-related quality of life, and adverse events (unwanted effects caused by the intervention).

Background
One of the most common sites of metastasis is the liver. Primary cancers of the liver, and metastases from colorectal cancer are the most common cancers affecting the liver. More than half of the people who have liver metastases die of complications.

Liver metastases can be destroyed by several methods. One method is based on the concept that the blood supply to liver (hepatic) tumours comes mainly from the hepatic artery. Transarterial chemoembolisation (TACE) of the hepatic artery involves the injection of a chemotherapeutic drug, followed by agents (small particles) that block the blood vessels. This interaction leads to death (necrosis) of the liver tumour, while leaving normal liver tissue virtually unaffected. The hepatic artery can also be blocked without chemotherapy, in which case it is called bland transarterial embolisation (TAE).

Search results and study characteristics
We last searched for evidence on 20 December 2019. We included one randomised trial from earlier searches. This trial randomly assigned people with colorectal liver metastases that could not be surgically removed, to one of three intervention groups: TAE (22 participants), TACE (19 participants), and a control group (20 participants) that received no active therapeutic intervention.

Cancer Research Campaign, a non-profit organisation, provided a grant for the study; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres.

Key results
Trial participants were followed for a minimum of seven months.

Mortality at 44 months from trial entry was 86% in the TAE group, 79% in the TACE group, and 95% in the control group. Median survival after trial entry was 7.0 months in the TAE group, 10.7 months in the TACE group, and 7.9 months in the control group. Median survival from diagnosis was 8.7 months in the TAE group, 13.0 months in the TACE group, and 9.6 months in the control group. Local recurrence was reported in 10 participants, without further details of their treatment group.

None of the participants in the control group reported side effects; 82% of the TAE group experienced short-term pain, nausea, vomiting, and high temperature, which got better with symptomatic treatment, and there was one report of bruising at the puncture site. TACE recipients reported short-term nausea, with or without vomiting, after most of the treatment sessions, and short-lived pain or discomfort; there was one wound infection, and one case of deep vein thrombosis.

All the results were inconclusive between groups. The evidence from one small randomised clinical trial showed neither beneficial nor harmful effects of TAE or TACE compared to no intervention, in people with liver metastases, measured by mortality. We did not find data on the other outcomes of interest.

Quality of evidence
We judged the evidence to be of very low certainty. The identified trial was small, at high risk of bias, and with inconclusive results.

Authors' conclusions: 

Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Short-term, minor adverse events were recorded in the intervention groups only.

Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.

Read the full abstract...
Background: 

The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma or other extrahepatic primary cancers. Liver metastases are significantly more common than primary liver cancer, and long-term survival rate after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of people; therefore, other treatments have to be considered. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents, and can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. This can also be performed without chemotherapy, which is called bland transarterial embolisation (TAE).

Objectives: 

To assess the beneficial and harmful effects of TAE or TACE compared with no intervention or placebo in people with liver metastases.

Search strategy: 

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and four more databases (December 2019). We also searched two trials registers and the US Food and Drug Administration database (September 2019).

Selection criteria: 

Randomised clinical trials assessing beneficial and harmful effects of TAE or TACE compared with no intervention or placebo for liver metastases.

Data collection and analysis: 

We followed standard Cochrane methodological procedures. We extracted information on participant characteristics, interventions, study outcomes, study design, and trial methods. Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence with GRADE. We resolved disagreements by discussion.

Main results: 

We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5-fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very-low-certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very-low-certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short-term symptoms of 'post-embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very-low-certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short-term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life.

Cancer Research Campaign, a non-profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres.

We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first-line chemotherapy (NCT03783559).

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