Impact of Comorbidity Burden on Clinical Outcomes in Older Adults With Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Older adults represent most patients with metastatic colorectal cancer (mCRC), yet their management is often complicated by multimorbidity. Comorbid conditions may influence treatment selection, tolerance, and survival, but the prognostic role of comorbidity burden in mCRC remains unclear. We conducted a systematic review and meta-analysis to assess the association between comorbidity, measured by the Charlson Comorbidity Index (CCI), and clinical outcomes in older patients with mCRC. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, we systematically searched PubMed, Embase, and Web of Science (2000 to April 2025) for studies of adults aged ≥65 years with mCRC that assessed clinical outcomes according to baseline comorbidity, as measured by the CCI. Eligible endpoints included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). Data were extracted in duplicate, and study quality was appraised using the Newcastle-Ottawa Scale. Random-effects models were applied to pool hazard ratios (HRs). Fourteen studies involving 16,736 patients met the inclusion criteria. Thirteen studies reported OS, two reported PFS, and two reported AEs. Higher comorbidity burden was significantly associated with worse OS (pooled HR = 1.19, 95% CI: 1.02-1.39; I² = 84.1%). No significant difference was observed for PFS (pooled HR = 1.00, 95% CI: 0.89-1.14; I² = 4.9%). For AEs, estimates were imprecise, with wide confidence intervals suggesting uncertainty about the association between high CCI and increased risk (pooled HR = 1.73, 95% CI: 0.79-3.79; I² = 86.4%). Multimorbidity, as measured by the CCI, is modestly associated with poorer overall survival in older mCRC patients (HR ≈ 1.19), but does not appear to influence progression-free survival or treatment-related toxicity consistently. Given the substantial heterogeneity across studies and the limited data on progression-free survival and adverse events, these findings should be interpreted with caution. Nevertheless, they suggest that comorbidity should guide, but not preclude, standard therapy, underscoring the importance of individualized, non-ageist treatment strategies.