Title: Weight loss as a predictor for cancer in primary care.
Funder: Department of Health and Social Care

Abstract: BackgroundCHAR(13) + CHAR(10) CHAR(13) + CHAR(10) NICE recommends urgent referral for the investigation of cancer in patients with unexplained weight loss in primary care, but provide no guidance on the extent or timing of weight loss. In NHS primary care (unlike primary care in the United States) weight loss is not routinely measured on primary care attendance but it is recorded on computer databases as a presenting symptom.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Overall Aim CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) The overall aim is to provide the evidence necessary to allow GPs to more effectively implement the NICE cancer guidance on the management of unexplained weight loss.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Research questionsCHAR(13) + CHAR(10)CHAR(13) + CHAR(10)Review of the existing evidence on weight loss as a predictor for cancer in primary care exposes key evidence gaps where questions remain unanswered: 1) How should GPs interpret the term weight loss in the NICE guidance?CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) 2) What is the diagnostic predictive value of weight loss volunteered or elicited as a symptom in primary care?CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) 3) What is the diagnostic predictive value of measured weight loss in primary care?CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) 4) Is weight loss predictive only of late stage cancer?CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) If it is measured rather than reported weight loss that has diagnostic value in primary care, it is also unclear how this would be best implemented in everyday NHS practice.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) MethodsCHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Study 1. A systematic review and meta-analysis of studies reporting the predictive value of weight loss for cancer in primary care following Cochrane Diagnostic Test Accuracy Review methodology. CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Study 2a: A cohort analysis of UK Clinical Practice Research Datalink (CPRD) data to: 1) Identify the predictive value of reported weight loss for cancer in primary care; 2) Describe how often the symptom of reported weight loss is recorded, and when weight is measured, in NHS primary care. The cohort analysis will compare the incidence of cancer over time in those with and without weight loss, using Cox regression to explore and adjust for covariates as appropriate. Preliminary work in CPRD estimates that weight loss as a symptom is recorded for about 30,000 patients >40 years, providing adequate statistical power and precision in relation to cancer overall and common cancers individually.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Study 2b: A cohort analysis of US Group Health Research Institute (GHRI) data to: 1) Explore patterns of measured weight change over time and to define and stratify weight loss; 2) Identify the predictive value for cancer diagnosis of these defined strata of measured weight loss. The method of cohort analysis will be the same as for the UK data. Preliminary work confirms that measured weight is recorded at virtually all attendances; the power and precision of the analysis will therefore depend on preliminary work to define and stratify weight loss (but should be adequate as the database covers a population of 600,000+ and is linked to the SEERS cancer registry). CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Study 3: A feasibility study of routine weight measurement in 5 NHS primary care practices. Options for approaching the patient to encourage self-weighing, the optimal type and location of weighing scales, and the method for recording identity and consent (to allow weight to be added to the patient record) will all be assessed. The main outcome will be the uptake of self-weighing at routine attendance. Interview and focus group methodology will be used to gather patient, professional, and industry perspectives on the intervention.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10) Potential benefits to patients and the NHSCHAR(13) + CHAR(10) CHAR(13) + CHAR(10) By substantially strengthening the evidence base underpinning the current NICE guidelines, and thereby providing clearer and more pragmatic advice to GPs on the investigation and referral of patients with unexpected weight loss, it is hoped that the diagnostic delay which characterises cancer diagnosis in UK primary care will be reduced.

Lay abstract: The underlying problem - delays in cancer diagnosis.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Delays in cancer diagnosis are linked with poor cancer survival in the UK. Large investments have been made developing clinical guidance for GPs as the vast majority of patients will first go to their GPs with symptoms of cancer. Research suggests that this guidance has had some impact in reducing delay related to high-risk symptoms (such as coughing up blood) and it is therefore worth putting effort into developing and clarifying guidance about other potentially important symptoms such as weight loss.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Existing evidence and the evidence-gap.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Existing research on some individual cancers suggest that weight loss is a low-risk, but not no-risk symptom, estimating that between 1 in 200 and 1 in 30 patients with unexplained weight loss go on to develop cancer. However, it is not clear how weight loss should be interpreted by general practitioners - how much weight loss is important and over what time-period? Should they routinely measure and monitor patients weight or wait for the symptom to be volunteered? And is its diagnostic value independent of other symptoms? It is also unclear whether weight loss is a useful symptom for diagnosing cancer at an early and potentially curable stage. Without clarification, GPs may adopt too high a risk threshold for referral (choosing to watch and wait inappropriately and potentially missing cancer cases) or too low a threshold (overburdening resources in secondary care and exposing patients to unnecessary investigation).CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)The proposed research.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)I am proposing three linked studies: CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Study 1 is a systematic literature review to identify, assess the quality of, and synthesise all the previous research on the diagnostic value of weight loss as an indication of cancer. I will use a technique called meta-analysis to combine the results of studies that are similar enough to combine thus producing better estimates of the diagnostic value of weight loss.CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Study 2 is the core study and involves new new analysis of two cohorts to examine the extent to which weight loss indicates cancer in patients presenting to primary care. Weight loss is recorded as a symptom in the UK national Clinical Practice Research Datalink (CPRD) database (which covers 15 million patients and is linked to cancer data). It will be analysed using a cohort approach - patients with and without weight loss will be followed-up on the database to examine the number that turn out to have cancer within 18 months of reporting weight loss. However, weight is not routinely measured at primary care attendance in the UK and so to discover the diagnostic value of measured weight loss (rather weight loss as a symptom reported by patients) it is necessary to use data from another country. I will therefore conduct the same analysis on a primary care database from the US (Group Health).CHAR(13) + CHAR(10) CHAR(13) + CHAR(10)Study 3 is a feasibility study to allow me to take forward this research after my fellowship if, as I suspect, it reveals that weight loss is important but existing data is inadequate to answer all of the questions. I will work with primary care software developers and a scale manufacturer to create a system that can automatically put patients' weights into the medical record and test how feasible and acceptable this is to staff and patients in 5 general practices. In principle, this is acceptable to patients in cultures similar to our own, e.g. the US, but issues of system, workload and priority will dominate whether it will work in the UK. Patient and public involvement. Patients of the Macmillan Cancer Voices forum completed an online questionnaire to inform this fellowship application. A Public and Patient Involvement (PPI) group consisting of 8 patients recruited through GP practices and the Macmillan website will meet twice a year throughout the fellowship to assist in tasks such as writing lay summaries, designing the weight measurement intervention, designing questionnaires for the feasibility study, wording and piloting questions for focus groups, and developing educational materials for dissemination. Dissemination. In addition to conventional outputs such as national and international conference presentations and high profile peer reviewed publications, findings will be prepared for dissemination through Oxford University's established media channels including social media. Clinician and patient education on weight loss will be developed with the PPI group and colleagues from the leading cancer charities (Macmillan, Cancer Research UK), and summary results for policymakers will be made available to download from the University's website. Towards the end of the fellowship a one-day workshop will take place for all intended beneficiaries.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS