Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

BACKGROUND

Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation.

OBJECTIVES

Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms.

DESIGN

A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study.

SETTING

Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands.

PARTICIPANTS

Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation.

INTERVENTIONS

Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol.

MAIN OUTCOME MEASURES

Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study.

RESULTS

In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial.

CONCLUSIONS

Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN52040363.

FUNDING

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in

In about 50% of people with bowel cancer, cancer spreads to the liver (colorectal liver metastases) within 5 years of detection and treatment. Liver resection (i.e. surgical removal of a portion of the liver) is the standard treatment in people below 70 years of age who are otherwise well, provided that the liver cancer is confined to a limited part of the liver. Such patients are considered ‘low-risk’ patients. Older patients and those with major medical problems or extensive cancers are considered ‘high-risk’ patients, as they are at a higher risk of developing complications following liver resection. Thermal ablation destroys the liver cancers using a needle that heats the cancer deposits until they are destroyed. There is significant uncertainty as to whether or not ablation can offer equivalent survival compared with surgery for ‘high-risk’ patients. We planned and conducted a randomised controlled trial comparing ablation with surgery to resolve this uncertainty. In this trial, some patients received ablation and others received surgery. The treatment was allocated at random with neither patients nor the study organisers choosing the treatment. The trial had an internal pilot (i.e. a smaller version of the full trial to resolve any ‘teething problems’ and ensure that a sufficient number of participants can be included in the full trial). Only nine patients were recruited in the 1-year internal pilot, compared with the anticipated recruitment of 45 patients. Therefore, the trial closed early as a result of poor recruitment, and the uncertainty about the best treatment for high-risk patients with colorectal liver metastases continues. The main reasons for the poor recruitment included fewer than anticipated eligible participants, clinicians’ unconscious bias towards surgery, and patients’ preference for one treatment or the other. In the future, comparisons involving two very different treatments may benefit from a feasibility study or a longer period of pilot study to resolve any difficulties.

Déclaration de conflit d'intérêts

Julia Brown is a member of Health Technology Assessment (HTA) Mental, Psychological and Occupational Health Methods Group, HTA Clinical Trials Committee, HTA Prioritisation Committee Methods Group and HTA Funding Committee Policy Group. Stephen Morris was formerly a member of the National Institute for Health Research (NIHR) Health Services and Delivery Research (HSDR) Research Funding Board, the NIHR HSDR Commissioned Board, the NIHR HSDR Evidence Synthesis Sub Board, the NIHR Unmet Need Sub Board, the NIHR HTA Clinical Evaluation and Trials Board, the NIHR HTA Commissioning Board, the NIHR Public Health Research (PHR) Research Funding Board and the NIHR Programme Grants for Applied Research (PGfAR) expert subpanel. Maureen Twiddy is a member of the Research for Patient Benefit North East and Yorkshire Advisory Panel. Brian Davidson is chairperson of the London NIHR Research for Patient Benefit panel. Daniel Hochhauser reports Medical Research Council CASE studentship with Merck Serono (Darmstadt, Germany). Kurinchi Gurusamy reports grants from NIHR, Cancer Research UK Multidisciplinary Award, UK Oncology Nursing Society, University College London and Wellcome Trust/Department of Health and Social Care – Health Innovation Challenge Fund 4 – Smart Surgery, during the conduct of the study.