Cryotherapy for the treatment of liver metastases

Liver metastases are commonly caused by colorectal cancer or other primary malignancies, such as lung and gastric cancer.

For a minority of patients, surgical resection of liver metastases with curative intent may be possible. For most patients however, treatment is palliative, and options include systemic chemotherapy, external beam radiotherapy, other thermal ablation techniques, and selective internal radiation therapy. Multiple treatment modalities may be used for individual patients.

Thermal ablation procedures including cryotherapy may be used as the primary treatment for liver metastases in patients who are not considered suitable for surgery, or to treat post-resection recurrence. They may also be used as an adjunct to hepatic resection. Cryotherapy can be delivered as part of an open resection procedure (requiring general anaesthesia and intraoperative ultrasound), or percutaneously (under local or general anaesthesia, with ultrasound, CT or MRI guidance).

Cryotherapy probes (single or multiple, depending on the size of the tumour) deliver coolant at subzero temperatures directly to the tumour in freeze-thaw cycles with the aim of destroying tumour cells.

The maximum recommended hepatic tumour size for cryotherapy is 4 cm. Cryotherapy for larger tumours requires multiple probes and is associated with increased morbidity.

Various devices can be used for this procedure.

A randomised controlled trial (RCT) of 123 patients treated by cryotherapy and chemotherapy or by surgical resection and chemotherapy reported disease-free survival in 14% (9 out of 63) and 5% (3 out of 60) of patients respectively at 10-year follow-up (significance not stated).

A non-randomised controlled trial of 415 patients treated by surgical resection and cryotherapy (for remnant lesions) or resection alone reported median survival of 29 and 34 months respectively (p=0.206).

A case series of 326 patients reported median overall survival of 29 months after cryotherapy of colorectal liver metastases, with tumour recurrence in 42% (136 out of 326) of patients at a median of 32 months. In a subset of 280 patients who had CT imaging at baseline and during follow-up, complete response was reported in 15% (41 out of 280), partial response in 41% (115 out of 280), stable disease in 24% (68 out of 280), and progressive disease in 20% (56 out of 280; follow-up not stated).

The Specialist Advisers listed key efficacy outcomes as tumour destruction with small margins of additional tissue destruction, and survival.

A non-randomised controlled study of 223 patients reported no significant difference in perioperative mortality between the cryotherapy group (2% [1 out of 55]) and the surgical resection group (5% [8 out of 168]; p=0.30). However, overall perioperative morbidity was significantly lower in the cryotherapy group (11% [6 out of 55] than in the resection group (26% [44 out of 168]; p=0.01).

A case series of 326 patients reported mortality in 2% (7 out of 326) of patients (follow-up period and details of causes were not reported, but 1 patient died from 'cryoshock' syndrome and 1 from liver failure).

A case report described death of a patient from hepatic failure related to portal vein thrombosis and intra-hepatic MRSA sepsis, 2 months after a second cryotherapy course via an open approach.

Infections directly related to cryotherapy were reported after 8% (12 out of 158) of procedures in the case series of 150 patients (most occurred within 3 weeks of treatment). Fever over 38°C was reported in 33% (108 out of 326) of patients in the case series of 326 patients (timing of events not stated).

Haemorrhage was reported in 4% (2 out of 55) and 1% (2 out of 168) of patients treated with cryotherapy and surgical resection respectively in the non-randomised controlled trial of 223 patients (timing of event not stated).

The Specialist Advisers listed anecdotal adverse events as damage to bile ducts and structures outside the liver. The Specialist Advisers also cited reports of major haemorrhage, the rare but fatal complication of cryoshock syndrome, and a high local recurrence rate; they stated that cryotherapy is therefore no longer widely used.

The Committee noted possible differences in the safety of this procedure when used intraoperatively, compared with the percutaneous approach that uses narrower probes. Evidence on the percutaneous approach is limited in quantity.