Title: A randomised feasibility study evaluating the effect of perioperative intravenous lidocaine on colorectal cancer outcome after surgery
Funder: Department of Health and Social Care

Abstract: BackgroundSurgery is the main curative treatment for colorectal cancer (CRC). Recurrence following surgical resection occurs in up to 50% of patients and is the leading cause of death. Cancer stage affects recurrence. Before surgery, a small number of clinically undetectable circulating cancer cells (CTCs) are often present. Usually, the body can deal with these but the mechanism that occurs during surgery for wound healing changes this. The effect of the surgical stress response on the immune system leads to the release of inflammatory 'soup', promoting the distribution of CTCs into the circulation leading to cancer recurrence and metastasis. Lidocaine is safe, affordable and available worldwide. In preclinical studies lidocaine cause CTC death and alleviate surgery's pro-metastatic inflammatory environments. This evidence provides an exciting possibility that lidocaine could be repurposed as a drug to help prevent cancer metastases and substantiates the urgent need for a randomised control trial. Twelve patient and public involvement (PPI) representatives were involved with the study's development. Three PPI will remain throughout the study. It was prioritised by the James Lind Alliance, a partnership between patients, carers and clinicians, and Bowel Cancer UK, a national charity organisation. Research questions Is it feasible to conduct a study of intravenous lidocaine infusion versus placebo for 24 hours for CRC surgery to look at postoperative cancer outcomes in the NHS setting? Can quantifying circulating free DNA (cfDNA), a by-product of CTCs lysis, provides an early signal of a clinically relevant mechanism of lidocaine and is this a possible outcome measure for the definitive trial?Objectives To assess the feasibility of: recruiting eligible patients for colon or rectal cancers (stages 2 or 3); lidocaine and placebo administration for 24 hours during and after surgery; retaining trial participants for 12 months; data collection instruments, including those for a future economic evaluation, clinical and patient-reported outcomes. A preliminary look at cfDNA as an indicator of cancer cell lysis following lidocaine infusion and assess the feasibility of this work.MethodsThe feasibility study will be a double-blinded, randomised (1:1), controlled study, comparing intravenous lidocaine administration at 1.5mg/kg bolus followed by 1mg/kg infusion for 24 hours versus placebo, in patients undergoing laparoscopic CRC surgery. Patients and clinicians will be asked to complete a feedback questionnaire on the study process. Blood will be collected upon the completion of lidocaine/placebo infusion for cfDNA. This will be processed to quantify cfDNA based on the recommended protocol. Timelines for delivery Recruitment is planned at two sites for 6 months. There are screening, baseline and 6 total visits, including patients facing follow-up on day 3, 6 months and 12 months. Impact and disseminationThis feasibility study is set up to pave the way for a definitive trial. The results will be presented at national and international conferences to stimulate interest and enthusiasm for centres to participate in the definitive trial. This research will also be published in academic journals. The PPI group will guide dissemination to patients and relevant charities.

Lay abstract: BackgroundLarge bowel cancer is a growth (tumour) in the lower part of the gut. If untreated, it can spread to the rest of the body and cause death. Surgery is the main treatment for large bowel cancer. It can lead to a complete cure. However, people still die of cancer spread after surgery. In fact, up to 50% of large bowel cancer comes back within two years of surgery. Even before surgery, a small number of cancer cells from the tumour can move around the body. When the surgeon is removing the tumour, however, further cancer cells can be released. The surgeon cannot help this even by being careful. The body can deal with these cells, but if there are lots of them, they can clump together (known as micrometastases) and this can cause cancer to spread. Around the time of surgery, the body reacts to heal the surgical wound. Sadly, this creates an environment that can encourage cancer cells to grow. Surgery can further reduce the body's defence system. Lidocaine is a local anaesthetic drug. It is safe and widely used, such as at the dentists. Scientists have found in laboratory and animal studies that lidocaine may be able to prevent and kill micrometastases. However, we need a big study to see if lidocaine can do this in bowel cancer patients. Before we do this, though, we need to check that such a study can be done in practice. We do this by running a small study known as a feasibility study. AimThis research aims to see if it is possible to run a big study looking at the effect of lidocaine on large bowel cancer recurrence after surgery. Methods The project will: 1. Perform a feasibility study. This will be similar in design to the future bigger study and will see: if there are any problems in giving lidocaine; if patients and clinicians would be happy to take part in a study using a design where some patients get the drug and others get a non-active substance (known as placebo); how many patients can we get from the different types and stages of bowel cancer; if patients can be followed up successfully; if we can collect all the data on outcomes and resource use that we would need; what measures might work well for the future study;2. Look to see if a blood test can give some idea on how lidocaine might work in patients and if it can be confirmed in the bigger study. The study will involve a small number of patients getting either lidocaine or placebo, and: filling in questionnaires to measure quality of life; having their records looked at to see if cancer comes back; both patients and clinicians to fill in a feedback questionnaire to see how they get on with the study processes; having one extra blood test when they finish the lidocaine/placebo infusion.Patient and public involvement Patient and public involvement (PPI) has been in place since the study was first thought of and will continue throughout it. I sought the opinion of twelve PPI representations, and they think the work is important. Three will be on the project group. This topic has also been highlighted as a priority by the James Lind Alliance, a partnership between patients, carers and clinicians, and Bowel Cancer UK, the national bowel cancer charity. Dissemination of findingsResults will be shared with participants and the public through the involvement of PPI representatives and through charities. Results will also be presented at academic conferences and be published in widely read clinical journals.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS