Interventional procedure consultation document

Cryotherapy for the treatment of liver metastases

Cancer cells can spread from where they start (the ‘primary tumour’) to other parts of the body to form one or more ‘secondary tumours’, which are also known as ‘metastases’. Liver metastases occur when cancer spreads from other parts of the body to the liver.

Cryotherapy is a process that uses cold temperatures to destroy cancer cells; it is applied directly to the tumour through a special needle.

The National Institute for Health and Clinical Excellence (NICE) is examining cryotherapy for the treatment of liver metastases and will publish guidance on its safety and efficacy to the NHS in England, Wales, Scotland and Northern Ireland. NICE’s Interventional Procedures Advisory Committee has considered the available evidence and the views of Specialist Advisers, who are consultants with knowledge of the procedure. The Advisory Committee has made provisional recommendations about cryotherapy for the treatment of liver metastases.

This document summarises the procedure and sets out the provisional recommendations made by the Advisory Committee. It has been prepared for public consultation. The Advisory Committee particularly welcomes:

• comments on the provisional recommendations
• the identification of factual inaccuracies
• additional relevant evidence, with bibliographic references where possible.

Note that this document is not NICE’s formal guidance on this procedure. The recommendations are provisional and may change after consultation.

The process that NICE will follow after the consultation period ends is as follows.

• The Advisory Committee will meet again to consider the original evidence and its provisional recommendations in the light of the comments received during consultation.
• The Advisory Committee will then prepare draft guidance which will be the basis for NICE’s guidance on the use of the procedure in the NHS in England, Wales, Scotland and Northern Ireland.

For further details, see the Interventional Procedures Programme manual, which is available from the NICE website (www.nice.org.uk/ipprogrammemanual).

NICE is committed to promoting through its guidance race and disability equality and equality between men and women, and to eliminating all forms of discrimination. One of the ways we do this is by trying to involve as wide a range of people and interest groups as possible in the development of our guidance on interventional procedures. In particular, we aim to encourage people and organisations from groups in the population who might not normally comment on our guidance to do so. We also ask consultees to highlight any ways in which draft guidance fails to promote equality or tackle discrimination and give suggestions for how it might be improved. NICE reserves the right to summarise and edit comments received during consultations, or not to publish them at all, where in the reasonable opinion of NICE, the comments are voluminous, publication would be unlawful or publication would otherwise be inappropriate.

Closing date for comments: 27 July

Target date for publication of guidance: November 2010

1   Provisional recommendations

1.1  Current evidence on the safety of cryotherapy for the treatment of liver metastases appears adequate in the context of treating patients whose condition has such a poor prognosis, but the evidence on efficacy is inadequate in quality. Therefore cryotherapy for the treatment of liver metastases should only be used with special arrangements for clinical governance, consent and audit or research.

1.2  Clinicians wishing to undertake cryotherapy for the treatment of liver metastases should take the following actions.

• Inform the clinical governance leads in their Trusts.
• Ensure that patients and their carers understand that other ablative treatments are available and provide them with clear written information. In addition, the use of NICE’s information for patients (‘Understanding NICE guidance’) is recommended (available from www.nice.org.uk/IPGXXXpublicinfo). [[details to be completed at publication]]

1.3  Audit and review clinical outcomes of all patients having cryotherapy for liver metastases (see section 3.1).

2   The procedure

2.1  Indications and current treatments

2.1.1  Liver metastases are most commonly caused by the spread of colorectal cancer, but they may also result from other malignancies, such as lung and gastric cancer.

2.1.2  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 can be used for an individual patient, either concomitantly, or sequentially.

2.2   Outline of the procedure

2.2.1  Thermal ablation procedures including cryotherapy can be used as the primary treatment for liver metastases if the patient is not sufficiently fit for surgery, or to treat post-resection recurrence. They may also be used as an adjunct to hepatic resection to ablate small-volume disease in the liver remnant.

2.2.2  Cryotherapy aims to destroy liver metastases while sparing most of the normal liver tissue. Tumour cells are destroyed both by the direct freezing action of subzero temperatures and through vascular thrombosis and tissue anoxia.

2.2.3  Cryotherapy can be delivered as part of an open resection procedure (requiring general anaesthesia and intraoperative ultrasound), or percutaneously (requiring local anaesthesia, sedation and image guidance with ultrasound, computed tomography [CT] or magnetic resonance imaging).

2.2.4  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.

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

2.2.6  Various devices can be used for this procedure.

 

Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview, available at www.nice.org.uk/IP400overview

2.3   Efficacy

2.3.1  A non-randomised controlled study of 223 patients reported no significant difference in perioperative mortality between the cryotherapy group (2% [1/55]) and the surgical resection group (5% [8/168]) (p = 0.30) at median 23-month follow-up. However overall perioperative morbidity was significantly lower in the cryotherapy group (11% [6/55] than in the resection group (26% [44/168]) (p = 0.01).

2.3.2  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% (9/63) and 5% (3/60) of patients respectively at 10-year follow-up (significance not stated).

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

2.3.4  A case series of 326 patients reported that median overall survival was 29 months after cryotherapy for colorectal liver metastases, with tumour recurrence reported in 42% (136/326) of patients at a median time to recurrence 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% (41/280), partial response  in 41% (115/280), stable disease in 24% (68/280), and progressive disease in 20% (56/280) (follow-up not stated).

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

2.4   Safety

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

2.4.2  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 course of cryotherapy via an open approach.

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

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

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

3   Other comments

3.1  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 was limited in quantity.

4   Further information

4.1  This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and is developing an audit tool (which is for use at local discretion), which will be available when the guidance is published.

4.2  For related NICE guidance see www.nice.org.uk

Bruce Campbell

Chairman, Interventional Procedures Advisory Committee
July 2010

_{Personal data will not be posted on the NICE website. In accordance with the Data Protection Act names will be anonymised, other than in circumstances where explicit permission has been given.}

 _{It is the responsibility of consultees to accurately cite academic work in order that they can be validated.}