title: Cryotherapy for liver metastases.
abstract: BACKGROUND
  Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. In cryoablation, liquid nitrogen or argon gas is delivered to the liver tumour, guided by ultrasound using a specially designed probe. Ice crystal formation during the rapid freezing process causes destruction of cellular structure and kills the tumour cells.
  
  
  OBJECTIVE
  To study the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases.
  
  
  METHODS
  We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012.
  
  
  METHODS
  We included all randomised clinical trials assessing the beneficial and harmful effects of cryotherapy and its comparators, irrespective of the location of the primary tumour.
  
  
  METHODS
  We extracted relevant information on participant characteristics, interventions, study outcomes, and data on the outcomes for our review, as well as information on the design and methodology of the trials. Bias risk assessment of and data extraction from the trials fulfilling the inclusion criteria were done by one author and checked by a second author.
  
  
  RESULTS
  One randomised clinical trial fulfilled the inclusion criteria of the review. The trial was judged as a trial with high risk of bias due to the unclear report on the generation of the allocation sequence and allocation concealment, blinding, incomplete outcome data and the selective outcome reporting domain. The trial included 123 consecutive patients with solitary or multiple unilobar or bilobar liver metastases who were randomised into two groups, 63 received cryotherapy and 60 received conventional surgery. There were 36 females and 87 males. The primary sites for the metastases were colorectal (66.6%), stomach (7.3%), breast (6.5%), melanoma (4.9%), ovarian adenocarcinoma (4.1%), uterus (3.3%), kidney (3.3%), intestinal (1.6%), pancreatic (1.6%), and unknown (0.8%). The tumours were resectable and non-resectable.The patients were followed for up to 10 years (minimum five months). Mortality at the last follow-up was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group (RR 0.88; 95% CI 0.77 to 1.02); that is, no statistically significant difference was observed. In the cryotherapy group, 60%, 44%, and 19% of the participants survived 3, 5, and 10 years respectively, while in the conventional surgery group the percentages were 51%, 36%, and 8%. The hazard ratio calculated using the Parmar method was 0.71 (95% confidence interval (CI) 0.47 to 1.09). Recurrence in the liver was observed in 86% (54/63) of the patients in the cryotherapy group and 95% (57/60) of the patients in the conventional surgery group (relative risk (RR) 0.9; 95% CI 0.8 to 1.01); that is, no statistically significant difference was observed. 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 control group. However, it was not reported by the authors whether the differences were significant. No intervention-related mortality and no bile leakage were observed.
  
  
  CONCLUSIONS
  On the basis of one randomised clinical trial with high risk of bias, there is insufficient evidence to conclude if in patients with liver metastases from various primary sites cryotherapy brings any significant benefit in terms of survival or recurrence compared with conventional surgery. In addition, there is no evidence for the effectiveness of cryotherapy when compared with no intervention. At present, cryotherapy cannot be recommended outside randomised clinical trials.
authors.affiliation: 2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland. gosiabala@mp.pl.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Bala
authors.forename: Robert P
authors.initials: RP
authors.lastname: Riemsma
authors.forename: Robert
authors.initials: R
authors.lastname: Wolff
authors.forename: Jos
authors.initials: J
authors.lastname: Kleijnen
mesh_terms: D000328:Adult; D017679:Cryotherapy / Q000379:methods*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008297:Male; D016032:Randomized Controlled Trials as Topic