Abstract: We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision. The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages. We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05). Funding: the trial did not provide information on funding. The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.

Plain-language summary: We last searched for evidence in June 2018. We included only one trial conducted in Ukraine, and participants' primary cancer was colorectal (bowel) cancer in 66% of instances, but there were also people with stomach, breast, skin, and other tumours. All of them had cancer spread to the liver. In this trial, 123 participants were allocated at random to receive either cryotherapy (63 people) or conventional surgery (affected parts of the liver were removed; 60 people). The trial did not provide information on funding. The trial was at high risk of bias. The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. We judged the evidence as low-certainty evidence. We found no evidence of a difference in proportion of participants with recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, it was not reported whether there was any evidence of a difference. The frequency of unwanted effects (adverse events or complications) was mostly similar in both groups, but pain intensity and frequency seemed to differ between the groups. There were no intervention-related mortality or bile leakages. The trial did not provide data on quality of life; cancer mortality, and time to progression of liver metastases. The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.