Prognostic Impact of Cetuximab-Related Hypomagnesemia and Hypokalemia in RAS/RAF Wild-Type Colorectal Cancer: A Multicenter Study

Purpose: The prognostic value of cetuximab-related electrolyte disturbances in metastatic colorectal cancer (CRC) remains unclear. The available reports on the prognostic effect of hypomagnesemia are controversial, while there are no comprehensive analyses regarding hypokalemia. This study aimed to evaluate the impact of hypomagnesemia and hypokalemia on treatment outcomes in patients with RAS/RAF wild-type metastatic CRC receiving first-line cetuximab-based therapy. Patients and Methods: We retrospectively analysed 305 patients treated across seven oncology centers between March 2013 and December 2024. Patients with baseline renal insufficiency or pre-existing electrolyte disturbance were excluded. Serum magnesium and potassium levels were assessed from the initiation of cetuximab until one month after its discontinuation. Results: There was one patient with missing magnesium levels and one patient with missing potassium levels. Three-hundred and four patients were available for the final analyses (n=304). Hypomagnesemia and hypokalemia occurred in 29.9% and 20.7% of the patients, respectively. Neither hypomagnesemia nor hypokalemia was significantly associated with progression-free survival (PFS) (11.9 vs 11.7 months for each; p =0.528 and p =0.327) or overall survival (OS) (25.3 vs 27.9 months; p =0.705 and 22.0 vs 28.8 months; p =0.824, respectively). Hypokalemia was correlated with a higher disease control rate (96.8% vs 87.1%, p = 0.028). In multivariate analyses, only metastatic burden (≥ 2 sites) independently associated with inferior outcomes for both PFS (HR 1.61, 95% CI 1.25– 2.08, p < 0.001) and OS (HR 1.77, 95% CI 1.31– 2.39, p < 0.001). Conclusion: Hypomagnesemia and hypokalemia did not significantly impact survival outcomes despite previous studies indicating otherwise. Moreover, hypokalemia was linked to improved disease control. These results provide incremental evidence regarding the clinical relevance of electrolyte disturbances, particularly hypokalemia, and highlight the need for prospective studies to clarify their prognostic and predictive significance. Keywords: colorectal cancer, cetuximab, hypomagnesemia, hypokalemia