Review question
Is cryotherapy (cooling) beneficial or harmful for local destruction of cancer (tumours) spread to the liver?
Background
When cancer spreads in the body (metastasis), one of the most common sites is the liver. Besides cancers of the liver (primary liver cancer), liver metastases from colorectal cancer are the most common cancer affecting the liver. More than half of people who have cancer spread to the liver die from complications. Cryotherapy is one of methods, used to destroy metastases in the liver. This method requires placing a special probe near the cancer site. The probe is used to deliver extreme cold to the site, which is produced by liquid nitrogen or argon gas. Placement of the probe can be guided using ultrasound or computed tomography (a special x-ray). The rapid freezing process kills the cancer cells, and the size of the cancer is reduced. However, it is not clear if this treatment prolongs life or increases quality of life of affected people.
We reviewed the evidence about the effect of cryotherapy in destroying cancer metastases in the liver. We searched for studies assessing the effect of cryotherapy in comparison with no treatment or any other treatment in people with liver metastases from cancer of any location. We aimed to assess the effect of cryotherapy on the risk of death, quality of life, and adverse events (side effects caused by the treatment).
Study characteristics
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).
Funding
The trial did not provide information on funding.
Key results
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.
Reliability of the evidence
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.
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.
The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma. Liver metastases are significantly more common than primary liver cancer and long-term survival rates reported for patients after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients. Cryotherapy is performed with the use of an image-guided cryoprobe which delivers liquid nitrogen or argon gas to the tumour tissue. The subsequent process of freezing is associated with formation of ice crystals, which directly damage exposed tissue, including cancer cells.
To assess the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and six other databases up to June 2018.
Randomised clinical trials assessing beneficial and harmful effects of cryotherapy and its comparators for liver metastases, irrespective of the location of the primary tumour.
We used standard methodological procedures expected by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, and data on the outcomes important for our review, as well as information on the design and methodology of the trials. Two review authors independently assessed risk of bias in each study. One review author performed data extraction and a second review author checked entries.
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.