Candida species colonisation as an independent or synergistic risk factor for oral cancer among betel quid, tobacco, and/or alcohol users: a protocol for a systematic review and meta-analysis

Oral cancer remains a major public health problem in regions with a high prevalence of betel quid chewing, tobacco use, and alcohol consumption. Emerging evidence suggests that Candida species may contribute to oral carcinogenesis. However, their independent and combined effects with established behavioural risk factors have not been systematically synthesised. This review aims to evaluate whether Candida species act as an independent risk factor or have a synergistic effect with betel quid, tobacco, and/or alcohol exposure in the development of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) among exposed adults. Published and unpublished studies will be searched in PubMed, Embase, Scopus, the Cochrane Library, Google Scholar, and the Open Science Framework without any geographical, language, or time restriction. Studies will be eligible if they include adults aged 18 years or above with histopathologically confirmed OPMDs or OSCC and documented exposure to betel quid, tobacco in smoked or smokeless forms, and/or alcohol. Included studies must report results as risk ratios (RR) or odds ratios (OR) or provide sufficient raw data to calculate these measures. Oral Candida colonisation must be confirmed using recognised laboratory methods. Studies involving immunocompromised individuals will be excluded. Two reviewers will independently screen studies, assess methodological quality, extract data, and perform meta-analysis using a random-effects model where appropriate. Heterogeneity, publication bias, and sensitivity analyses will be assessed. The certainty of evidence will be evaluated using the GRADE approach. This review will clarify whether Candida colonisation independently or synergistically increases risk in the presence of betel quid, tobacco, and alcohol use.