Feasibility of a cluster randomised trial of a nutritional intervention to improve outcomes after cancer surgery in low-income countries

THE PROBLEM: For many types of cancer, high quality surgery is the only cure. This is particularly true in low-income countries where treatments such as chemotherapy or radiotherapy may not be available. It is important that surgery goes well. When complications occur, longer term outcomes are worse, and some patients will die. It is increasingly recognised that boosting the health of patients before surgery can greatly improve the chances of success. Of course, a balance must be struck between the urgency to operate and remove the cancer and a desire to take time and improve a patient's health. Cancer often causes extreme weight loss and, in many countries, this occurs on top of pre-existing malnutrition.

THE QUESTION: Would it be of benefit to intensively treat patients with nutritional supplements prior to surgery? Studies from high income countries suggest it could be, and the benefit may be even greater in low-income countries.

THE TEAM: We are a well-established team working to improve surgical care worldwide. Surgeons from low- and middle-income countries are supported in Research Hubs and set their own research agenda. Nutrition in cancer surgery has been identified as an area of high priority. Our team has the broad set of skills required to make this work.

OUR CURRENT WORK: We are gathering data on patients undergoing cancer surgery worldwide. It is the largest study of its kind and is taking place in 100 countries. This information will allow us to work out the relationship between malnutrition and the results of surgery in a way that hasn't been possible before. But what we really want to do is come up with a solution. This grant application is for funding to bridge the gap between our current observational study and a trial to treat patients prior to surgery. We have broad experience and are currently launching the FALCON trial, looking at steps to reduce wound infection after surgery in low-income countries.

FUTURE PROPOSED TRIAL: We want to perform a large study in low- and middle-income countries giving a nutritional supplement (sometimes called ready-to-use therapeutic food) to patients undergoing cancer surgery. We will then measure whether it results in fewer complications and better outcomes after surgery. Before we can do that, we need to do three things.

NEED FOR THIS PUMP PRIMING GRANT: First, we need to find a good way of screening patients for malnutrition in low-income countries. This is to identify those who may benefit most from a treatment. One would have thought that this would be easy and well-established, but it is not. Simple but accurate screening methods for malnutrition, which can be used by a nurse or a doctor for patients undergoing surgery, need to be developed or adapted. Second, we need to find an appropriate product. This needs to fulfil specific nutritional requirements but must be inexpensive, sustainable and ideally locally sourced. We will work with companies, experts, patients, and clinicians to find what is best. Third, we then need to make sure that a trial can actually be run. We will ask pragmatic questions such as, will there be a sufficient number of patients in our partner hospitals who can take part? Will they be able to take the nutritional supplement? Is the hospital in contact with patients after discharge to ensure we know what happens to them etc.? Determining the practicalities and planning for any problems identified is essential in ensuring the success of a study such as this.

THE BENEFIT: We propose to perform this preliminary work in a small area of our network (Ghana, Zambia, Pakistan and the Philippines), but the research promises great benefits beyond this. Focusing on fitness prior to surgery and issues such as malnutrition will be essential in improving the outcomes of cancer surgery worldwide.

In WP1, we will develop a pragmatic but robust screening tool for malnutrition. This will identify patients to be recruited to the final trial and be used to stratify severity. Systematic reviews will be registered with PROSPERO and performed/reported using PRISMA guidelines. We have good experience and a related Cochrane review already published. We have brought in qualitative/mixed methods expertise and all work will be performed using the SRQR guidelines. All focus group work will be examined using framework analysis and identified themes used to create or adapt a pre-existing tool for use in LMICs. Validation of the tool will take place along with WP3.

WP2 is concerned with the identification of the most appropriate nutritional intervention. Our "expert advisory group on nutrition" will guide this work. Existing contacts in industry/logistics will ensure the intervention is appropriate, locally-sourced, and sustainable. We are particularly multidisciplinary with patients, nutritionists, surgeons, anaesthetists, oncologists, epidemiologists, methodologists and public health doctors. Our target product profile includes low volume, high energy (600 kcals), 40g protein, essential amino acids and micronutrients.

WP3 will determine the feasibility of a cluster RCT. We have extensive experience in cluster trials (BCTU, ECTU, Norrie) and a step-wedged design may be deemed most appropriate. Using the CONSORT 2010 extensions (feasibility trials) we will capture patient/cluster numbers. We will determine the process of patient identification, recruitment, and administration of intervention. We will prospectively trial randomisation, blinding, outcome assessment and data collection instruments and establish longer-term follow-up, e.g. disease-free/overall survival. This will determine final study design, analysis plan and sample size. Our health economics team are essential given the importance of cost effectiveness in developing a long-term sustainable solution.

IMPACT OBJECTIVE 1: To consolidate our low- and middle-income country (LMIC) trials network and expand our Hub and Spoke model.
IMPACT OBJECTIVE 2: To deliver the first high quality global trial of a nutritional intervention in malnourished patients undergoing cancer surgery in low-resource settings.
IMPACT OBJECTIVE 3: To develop trials that will test and prove cost-effective interventions relevant to surgical care in LMICs that can influence policy making.
IMPACT OBJECTIVE 4: To prioritise work that has economic and societal benefit in collaborator countries and meets the UN Sustainable Development Goals.
IMPACT OBJECTIVE 5: To deliver research skills training to local investigators, allowing them build and retain capacity in clinical surgery and pragmatic research.

IMPACT OF THIS PUMP PRIMING GRANT (objectives 1, 3, 5): The programme of work from this pump priming grant will allow us to submit a high-quality application to an MRC grant call within the next two years. As importantly, it will help consolidate our network and expand our Surgical Trial Hubs and Spokes. Our research-priority setting process is working well and ensures full engagement of LMIC partners. In addition, we have introduced new members into the team with specific expertise in nutrition and qualitative research.

IMPACT OF THE FUTURE TRIAL (objective 1, 2, 3, 4, 5): Our future trial plans to test a simple, cost effective nutritional intervention to improve outcomes after cancer surgery. We are focussed on areas our team consider of the highest priority to patients in partner countries. Cost-effectiveness is paramount, and health economic assessment is built into all our trials to reinforce this. Our strategy aligns with the UN Sustainable Development Goals and we envisage the results having global impact when published in a journal such as the Lancet.

IMPACT OF THE NETWORK (objective 1, 4, 5): This collaborative represents a world-first and aims to deliver pragmatic randomised controlled trials in surgical interventions across a range of LMICs. This network will deliver research that is practice changing and will disseminate evidence-based clinical care to patients both within the research network but also to the many thousands of hospitals across all LMICs. We aim for the network to develop to deliver increasingly large and sophisticated trials in the future. By harmonising administration and setting up pathways now, we expect this to become increasingly efficient.

IMPACT OF TEAM DEVELOPMENT (objective 5): We envisage that this programme of work will create a generation of surgeon-researchers with the ability to test cost-effective interventions across international networks. Developing hospitals that can perform surgery has benefits across healthcare systems and society as a whole. Supporting individuals in rewarding roles helps stabilise the workforce and create a global community of surgeon-researchers. We support the development of leadership and management skills amongst collaborating principle investigators, allowing them to develop their own networks, trials programmes and funding.