Time of Detection of Liver Metastases and Survival in Patients With Colorectal Cancer.

[IMPORTANCE] Colorectal cancer liver metastases (CRLM) are a common manifestation of colorectal cancer, and clinical decision-making for these patients is complex. The timing of CRLM detection, defined as synchronous, early metachronous, or late metachronous, is hypothesized to influence survival outcomes, but the prognostic implications of these classifications remain unclear.

[OBJECTIVE] To determine whether the timing of CRLM detection is associated with overall survival (OS) in patients with up-front locally treatable or initially nonlocally treatable CRLM.

[DESIGN, SETTING, AND PARTICIPANTS] Multicenter cohort study including adult patients from the Amsterdam Colorectal Liver Met Registry and the phase 3 CAIRO5 trial between 2000 and 2024, with analyses conducted from March 2025 to January 2026. Patients were followed up for a median (IQR) of 44 (41-48) months. Survival outcomes were analyzed using multivariable Cox regression models. Inclusion criteria were up-front locally treatable or initially nonlocally treatable CRLM, with key clinical and demographic characteristics recorded.

[EXPOSURE] Timing of CRLM detection categorized as synchronous (detected before or at primary CRC diagnosis or during surgery), early metachronous (within 12 months of diagnosis or surgery), or late metachronous (more than 12 months after surgery), according to European-African Hepato-Pancreato-Biliary Association consensus guidelines.

[MAIN OUTCOMES AND MEASURES] OS from diagnosis of CRLM, stratified by CRLM timing and treatment received. Multivariable analysis accounted for tumor number, size, variant status, carcinoembryonic antigen levels, and treatment strategy.

[RESULTS] A total of 1250 patients were included (median [IQR] age, 63 [56-72] years; 823 [65.9%] men), of whom 817 (65%) had synchronous CRLM, 208 (17%) early metachronous CRLM, and 225 (18%) late metachronous CRLM. Among all patients, 676 (54%) died during follow-up. Synchronous CRLM were associated with worse OS compared with early metachronous CRLM (hazard ratio [HR], 0.79; 95% CI, 0.64-0.97) and late metachronous CRLM (HR, 0.54; 95% CI, 0.43-0.68). After adjustment for tumor and treatment factors, timing of detection of CRLM was not independently associated with OS.

[CONCLUSIONS AND RELEVANCE] In this retrospective multicenter cohort study, timing of CRLM detection was not associated with OS when accounting for tumor characteristics and treatment strategy. These findings suggest that synchronicity may primarily reflect underlying tumor biology rather than directly influencing survival, emphasizing that clinical decisions should focus on synchronicity in combination with tumor burden, variant status, and local treatment.