Metabolic traits and the risk of head and neck cancer: a systematic review and meta-analysis

Introduction The overall incidence of head and neck cancer (HNC) continues to rise, despite a decline in smoking rates, particularly within developed countries. Obesity and related metabolic traits have been attributed to a growth in cancer rate, so further exploration of these risk factors is warranted in HNC. A comprehensive systematic review and meta-analysis was conducted in order to obtain the most precise observational estimates between metabolic trait exposures and risk of HNC. Methods A search strategy was developed with an information and content specialists. Multiple databases including Cochrane Library, OVID SP versions of Medline, EMBASE, pre-prints and the grey literature were searched. The primary outcome for included studies was incident HNC and exposures included obesity defined by body mass index (BMI), type 2 diabetes, dyslipidaemia, and hypertension, using pre-specified definitions. A combined risk effect across studies was calculated using both fixed and random-effects meta-analysis. Heterogeneity was assessed between studies using the Cochrans Q and I2 statistical tests. The ROBINS-E preliminary tool was used to assess the bias in each included result. Results The search generated 7,316 abstracts, of these 197 full text articles were assessed for eligibility and 36 were included for full qualitative and quantitative synthesis. In the analysis of 5 studies investigating the association between obesity and incidence of HNC, there was an overall RR of 1.06 (95%CI (0.76, 1.49), P heterogeneity <0.024, I2= 73.2%) using a random-effects model. 6 studies reported on the association between type 2 diabetes and incidence of HNC, with an overall RR of 1.13 (95%CI (0.95, 1.34), P heterogeneity= <0.0001, I2= 80.0%) using a random-effects model. An increased risk of hypertension was consistent across HNC subsites, with the strongest association found in the larynx (RR= 1.17, 95%CI (1.10, 1.25), P heterogeneity= 0.186, I2= 37.7%). For dyslipidaemia, only 2 studies were available for meta-analysis in the laryngeal subsite, with some evidence of an increased risk association of both low high-density lipoprotein (RR= 1.12, 95%CI (1.07, 1.18), P heterogeneity= 0.103, I2= 62.5%) and high triglyceride levels (RR= 1.10, 95%CI (1.05, 1.15), P heterogeneity= 0.319, I2= 0.0%)) using random-effects models. Over 80% of studies were judged to be at Very High or High risk of bias using the ROBINS-E tool. Conclusion Despite individual studies suggesting an association between BMI and HNC, limited effect was demonstrated in this meta-analysis. There was evidence of an association between hypertension and dyslipidaemia on incident HNC, however caution is required due to the high levels of heterogeneity recorded in these studies. Observational associations are susceptible to confounding, bias and reverse causality so these results must be interpreted with caution. Future work should include meta-analysing studies separately by geographic region, as this appears to be a clear source of heterogeneity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement A.G. is a National Institute for Health and Care Research (NIHR) doctoral research fellow (NIHR302605). C.R. is currently supported by a Wellcome Trust GW4-Clinical Academic Training PhD Fellowship. F.S. was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). E.E.V is supported by Diabetes UK (17/0005587). E.E.V is also supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG\_2019\_2009). R.C.R. is a de Pass VC research fellow at the University of Bristol (no grant number). J.P.T.H supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol (no grant number), the NIHR Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust (no grant number) and is a National Institute for Health Research (NIHR) Senior Investigator (no grant number). M.G. was supported by a Wellcome Trust GW4-Clinical Academic Training PhD Fellowship. This research was funded in part, by the Wellcome Trust [Grant number 220530/Z/20/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome, NIHR, the NHS or Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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