Circulating copper-to-zinc ratio and survival in patients with cancer: a systematic review and meta-analysis of prognostic cohort studies

This systematic review and meta-analysis will estimate whether the circulating copper-to-zinc (Cu/Zn) ratio, measured in serum, plasma or whole blood at or near cancer diagnosis, predicts survival in patients with cancer. The ratio is a low-cost laboratory marker that reflects systemic inflammation, nutritional status and oxidative stress. Individual cohorts in several cancers have linked a high ratio to worse outcomes, but no review has pooled prognostic hazard ratios across cancer types. We will search PubMed/MEDLINE, Web of Science and Scopus from inception, plus Google Scholar and citation lists, for cohort studies reporting hazard ratios for overall, cancer-specific or event-free survival by Cu/Zn ratio, or by serum copper or zinc alone. Two reviewers will screen, extract data and assess risk of bias (QUIPS) independently. Log hazard ratios will be pooled with REML random-effects models and the Hartung–Knapp–Sidik–Jonkman adjustment, with prediction intervals, pre-specified subgroup and sensitivity analyses, and GRADE certainty ratings. A key aim is to test whether the ratio predicts survival independently of systemic inflammation (CRP, albumin, Glasgow Prognostic Score). Expected outputs are a pooled prognostic estimate across cancers, site-specific estimates where data allow, and a judgement on whether the ratio adds clinically useful information beyond established inflammatory markers.