Title: Liver Resection Surgery Versus Thermal Ablation for Colorectal LiVer MetAstases
Funder: Department of Health and Social Care

Abstract: Design and setting: This is a multicentre, open, pragmatic parallel randomised controlled trial design with internal pilot and will be performed in tertiary liver, pancreatic and gallbladder (HPB) centres. Target population: Eligible patients will be those with resected or potentially resectable colorectal cancer with liver metastases who would currently be considered by a specialist liver MDT review for either liver resection or thermal ablation and who are either elderly (e.g. over 75 years), or have major co-morbidities, or who have poor prognosis but resectable metastatic disease (extensive synchronous disease, two stage resection, small remnant liver volume)). Health technologies being assessed: Thermal ablation (radiofrequency ablation (RFA) or microwave ablation (MWA) according to the local availability of equipment and expertise versus surgical liver resection (performed as per centre protocol). Further chemotherapy will be offered to patients as per current practice. Subgroup analyses to investigate comparisons between the arms with respect to the distinct methods of thermal ablation and surgery will be performed. Measurement of costs and outcomes: The primary outcome of the overall trial will be to assess disease free survival (DFS) at 2 years, defined as time from randomisation until death or recurrence of the index disease. We will assess whether the true difference in DFS between ablation and surgery is less than or equal to 4 months, the non-inferiority margin determined by trading off the short-term benefits and potential decrease in long-term DFS. Secondary outcomes will include overall survival at 2 and 5 years post-randomisation; local and distant recurrence of disease at 2 years post-randomisation; use of subsequent therapies treatment over 2 years, health related quality of life (EQ-5D, EORTC QLQ-C30, EORTC LMC21), complications during treatment, post-treatment complications, length of intensive therapy unit (ITU) and inpatient stay, and costs (NHS and personal social services (PSS) perspective). Outcomes will be assessed, 3 months, 6 months, 12 months, 18 months, and 24 months from randomisation. Five year follow-up for overall survival will be obtained through the use of Office for National Statistics (ONS) data. Sample size: 330 patients are required to demonstrate non-inferiority of thermal ablation with respect to resection in terms of disease free survival (DFS) with 80% power at the 2.5% one-sided level of significance, assuming 14 months DFS in the resection arm and a non-inferiority margin of 4 months and allowing for a 5% drop-out rate. Project timetable: 9 month set-up, internal pilot trial 12 months. Four year recruitment (including pilot), 2 year follow-up, 6 months analysis and write up/dissemination. Total time period 7 years and 3 months. Further analysis of OS at 5 years follow-up. Recruitment rate: Approximately 4 patients per centre per year; 15 UK centres and 5 Dutch centres. Expertise in team: Surgeons, radiologists, oncologists, accredited clinical trials unit, qualitative researcher, health economist, patient representative.

Lay abstract: About 30% of people have bowel cancer spread to the liver (colorectal liver metastases) within 5 years of detection and treatment of bowel cancer. Partial removal of the liver (liver resection) is effective in improving the life expectancy in people with colorectal liver metastases (CLM). However, only about 7% to 20% of people with colorectal liver metastases undergo liver resections because of the age and general fitness (comorbidities) of the patient or because of the extent of cancer spread. Liver resection is a major operation with high complication rates. At present, liver resection is the standard treatment in people below 70 years of age who are otherwise well with cancer confined to the liver and with limited involvement of the liver. However the treatment of elderly people (age above 75 years), those with additional medical problems (such as severe heart or lung disease) and those in whom there is extensive spread to multiple sites within the liver (high risk patients) is less clear. Some surgeons offer liver resection surgery to these high risk patients with the belief that surgery is the only chance of cure in such patients while others do not offer surgery because they do not believe it is justified when risks are great and the chance of cure is small. Ablative treatments (destruction of cancer using methods other than surgery) offer an alternative to surgery in patients with colorectal liver metastases. Thermal ablation destroys the liver cancers using a needle that heats the cancer deposits until they are destroyed. They have been used for many years in the treatment of patients with liver metastases but their benefits remain unclear. The ablation can be carried out by a needle passed into the liver through the skin without any surgery (percutaneous ablation). There is significant controversy as to whether ablation offers equivalent survival compared to surgery. Two methods of thermal ablation are in current practice, radiofrequency ablation (RFA) and microwave ablation (MWA). At present, there is no strong evidence favouring one method of thermal ablation over another. Because of uncertainty as to the best treatment for these high risk patients, this trial will compare the outcome of thermal ablation and liver resection surgery. Patients suitable for either surgery or ablation but considered high risk would be offered one or other on the basis of chance (a randomised trial). The treatment will be performed in centres with experts in liver surgery and ablation therapy. All patients will be followed up carefully to look for any recurrence of the cancer. If further cancer deposits were detected the patients will not be restricted in any way as to the subsequent treatment which can be given. The trial will include patients from all over the UK and in Holland over a period of 4 years. Analysis will be carried out after a minimum follow up period of two years. The trial outcome should allow us to determine which treatment is most effective and provides best value for money in high risk patients with colorectal liver metastases. The best treatment can then be offered to all high risk patients with colorectal liver metastases throughout the NHS. The results may have implications for the management of other patient groups with colorectal metastases.

Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS