Selective internal radiation therapy for non-resectable colorectal metastases in the liver - Consultation Document

Interventional procedure consultation document

Selective internal radiation therapy for non-resectable colorectal metastases in the liver

Colorectal liver metastasis occurs when cancer of the bowel has spread to the liver. Selective internal radiation therapy (known as SIRT) uses radiation put into the patient’s liver to kill the cancer cells. Tiny radioactive ‘beads’ are injected into branches of the artery that supplies blood to the liver and become trapped (embolise) in the small blood vessels surrounding the cancer, releasing radiation directly onto it.

The National Institute for Health and Clinical Excellence (NICE) is examining selective internal radiation therapy for non-resectable colorectal metastases in the liver 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 selective internal radiation therapy for non-resectable colorectal metastases in the liver.

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• The Advisory Committee will then prepare draft guidance which will be the basis for NICE’s guidance on the use of the procedure in the NHS in England, Wales, Scotland and Northern Ireland.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).

Through its guidance NICE is committed to promoting race and disability equality, 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 interventional procedures guidance. In particular, we aim to encourage people and organisations from groups who might not normally comment on our guidance to do so.

In order to help us promote equality through our guidance, we should be grateful if you would consider the following question:

Are there any issues that require special attention in light of NICE’s duties to have due regard to the need to eliminate unlawful discrimination and promote equality and foster good relations between people with a characteristic protected by the equalities legislation and others?

Please note that 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: 22 March 2010

Target date for publication of guidance: June 2011

1   Provisional recommendations

1.1  Current evidence on the safety of selective internal radiation therapy (SIRT) for non-resectable colorectal metastases in the liver is adequate.

1.2  The evidence on its efficacy in chemotherapy-naïve patients is inadequate in quantity. Clinicians should offer eligible patients who have not been previously treated by chemotherapy entry into well designed research studies such as the UK FOXFIRE trial (www.octo-oxford.org.uk/alltrials/trials/FOXFIRE). For chemotherapy-naive patients who are not eligible or able, or who prefer not to enter a research trial, the procedure should be used with special arrangements for clinical governance, consent and audit.

1.3  For patients who have previously been treated with chemotherapy, there is evidence that SIRT can achieve control of hepatic metastases but the evidence of its effects on survival and on quality of life is inadequate. Therefore for patients who have been previously treated with chemotherapy this procedure should be used with special arrangements for clinical governance, consent and audit.

1.4  Clinicians undertaking the procedure for patients outside research studies should take the following actions.

• Inform the clinical governance leads in their Trusts.
• Ensure that patients and their carers understand the uncertainty about the procedure’s efficacy 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]]
• Audit and review clinical outcomes of all patients having SIRT for non-resectable colorectal metastases (see section 3.1).

1.5  Patients should be selected for SIRT or entry into trials by a hepatobiliary cancer multidisciplinary team including an interventional radiologist, in liaison with a colorectal cancer multidisciplinary team.

1.6  Selective internal radiation therapy should only be carried out by clinicians with specific training in its use and in techniques to minimise the risk of side effects of the procedure.

1.7  There is an urgent need for further research on SIRT.  A recommendation about research trials for chemotherapy-naïve patients is given in 1.2 above. For patients who have previously been treated with chemotherapy, comparative trials are needed to determine whether SIRT prolongs survival compared with alternative forms of management or no further treatment, and to determine its effect on quality of life. There is also a need to identify which patients are likely to derive clinical benefit from SIRT. Research studies should clearly describe the characteristics of treated patients, and the extent and histological details of their tumours. Outcomes should include survival and quality of life. Downstaging of metastases allowing resection or ablation should be clearly documented.

1.8  NICE may review the procedure on publication of further evidence.

2   The procedure

2.1  Indications and current treatments

2.1.1  Colorectal cancer is common and metastatic spread to the liver occurs frequently. 

2.1.2  Treatment of hepatic metastases depends on their extent and location. Treatment options include surgical resection, thermal ablation, chemotherapy, different types of arterial embolisation and external beam radiotherapy.

2.2  Outline of the procedure

2.2.1  Selective internal radiation therapy is used for the treatment of non‑resectable colorectal cancer liver metastases in patients with limited or no extrahepatic disease. It may be used alone or in combination with chemotherapy. It aims to deliver radiation directly into the metastases, minimising the risk of radiation damage to healthy surrounding tissues.

2.2.2  With the patient under local anaesthesia, radioactive microspheres that are designed to embolise into small vessels around the metastases are injected into branches of the hepatic artery, usually via a percutaneous femoral approach.

2.2.3  A nuclear medicine liver-to-lung shunt study is usually carried out before the procedure to assess the risk of radioactive microspheres causing lung damage. Radiographic imaging and selective coil embolisation of arteries to the stomach and duodenum may also be done. 

2.2.4  Selective internal radiation therapy may be repeated, depending on the response achieved.

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/guidance/IP/228/overview

2.3   Efficacy

2.3.1  In a randomised controlled trial (RCT) of 70 patients with non‑resectable colorectal liver metastases, mean survival after treatment by SIRT plus hepatic artery chemotherapy or hepatic artery chemotherapy alone was 23.5 and 18.4 months respectively (p = 0.18). An RCT of 44 patients treated by SIRT plus systemic chemotherapy or systemic chemotherapy alone reported median overall survival of 10.0 and 7.3 months respectively (p = 0.80).  An RCT of 21 patients treated by SIRT plus systemic chemotherapy or systemic chemotherapy alone reported median survival of 29.4 months and 12.8 months respectively (hazard ratio 0.33, 95% confidence interval 0.12 to 0.91; p = 0.025)

2.3.2  The RCT of 70 patients reported better tumour response following SIRT plus hepatic artery chemotherapy than hepatic artery chemotherapy alone at 3.5 years minimum follow‑up (p = 0.01). The RCT of 44 patients treated by SIRT plus systemic chemotherapy or systemic chemotherapy alone reported median ‘time to liver progression’ of 5.5 months and 2.1 months respectively (hazard ratio 0.38, 95% confidence interval 0.20 to 0.72; p = 0.003).

2.3.3  Downstaging, which enabled surgical resection, was reported in 2 of 50 (4%) patients treated by SIRT in a case series.

2.3.4  The Specialist Advisers listed key efficacy outcomes as tumour response rates, survival and downstaging to allow surgery or chemoresponsiveness.

2.4   Safety

2.4.1  In a case series of 100 patients, 1 patient died from radiation hepatitis 9 weeks after SIRT, and another patient died from acute pancreatitis with peptic ulceration.

2.4.2  The RCT of 44 patients treated by SIRT plus systemic chemotherapy or systemic chemotherapy alone reported grade 3 toxicity in 5% (1/21) and 27% (6/22) of patients respectively (p = 0.10).  The RCT of 70 patients reported that there was no significant difference between the groups (SIRT plus hepatic artery chemotherapy or hepatic artery chemotherapy alone) in the total number of grade 3 or 4 toxicity adverse events.

2.4.3  Radiation-induced cirrhosis was noted in 9% (1/11) of patients after 1 year (later resolved) in the systemic chemotherapy plus SIRT arm of the RCT of 21 patients. Liver abscess requiring drainage was reported in 1 patient (timing not stated).

2.4.4  A case series of 140 patients treated by SIRT reported that radiation-induced liver dysfunction occurred in 2% (3/140) of patients (median follow-up 9 months).

2.4.5  The Specialist Advisers listed adverse events as pain, vomiting, anorexia, fatigue, portal hypertension, and impaired delivery of radioembolic material after antiangiogenic agent use. They considered theoretical adverse events to include pneumonitis, gastrointestinal haemorrhage or ulceration, cholecystitis, biliary strictures, pancreatitis and radiation dermatitis.

2.5   Other comments

2.5.1  The Committee considered that SIRT is a potentially beneficial treatment for patients with non-resectable colorectal metastases in the liver, but that more evidence is required to demonstrate its efficacy, particularly in chemotherapy-naïve patients.    

2.5.2  The Committee noted that large numbers of patients previously treated by chemotherapy have received SIRT in observational studies, but that the number in comparative trials was very small. The Committee considered quality of life after any kind of treatment to be of great importance for these patients. These considerations formed the basis of the recommendations for further research.

2.5.3  The Committee considered that SIRT may be a potential option for patients with limited extra-hepatic disease who have failed chemotherapy.

2.5.4  The Committee noted that there have been a small number of reports of SIRT downstaging colorectal metastases to the extent that treatment by resection or ablation became possible. However, it considered that there was insufficient evidence to comment on the potential use of the procedure with this intent.

2.5.5  The Committee also considered a number of patient commentary questionnaires from patients who described benefits from SIRT.

3   Further information

3.1  This guidance requires that clinicians undertaking the procedure in patients outside a research trial 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.

3.2  This guidance is a review of ‘Selective internal radiation therapy for colorectal metastases in the liver’. NICE interventional procedures guidance 93 (2004).

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

Bruce Campbell

Chairman, Interventional Procedures Advisory Committee

February 2011

_{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.}