Tumour burden and access to local treatment, rather than the timing of liver metastases detection, determine outcomes in colorectal cancer, a multicentre cohort study has found.

Drawing on data from the Amsterdam Colorectal Liver Met Registry and the phase 3 CAIRO5 trial, the study aimed to determine whether synchronous (detected before or at primary colorectal cancer diagnosis or during surgery), early metachronous (within 12 months of diagnosis or surgery), or late metachronous (more than 12 months after surgery) metastases held independent prognostic significance.

Published in JAMA Network Open, the analysis included 1,250 adult patients (median age 63 years; 65.9% male) treated between 2000 and 2024, with a median follow-up of 44 months. Of these, 817 had synchronous colorectal liver metastases, 208 had early metachronous disease and 225 had late metachronous disease.

Survival outcomes and prognosis for liver metastases

Unadjusted survival analyses showed worse outcomes in patients with synchronous disease. Median overall survival (OS) was 38.3 months for synchronous liver metastases, compared with 64.3 months for late metachronous metastases.

Five-year OS rates were 31.5%, 39.3% and 52.1% for synchronous, early metachronous and late metachronous groups, respectively.

Synchronous metastases were associated with poorer OS compared with early metachronous (hazard ratio [HR] 0.79; 95% CI 0.64–0.97) and late metachronous disease (HR 0.54; 95% CI 0.43–0.68).

However, these differences did not persist after multivariable adjustment for tumour burden, molecular characteristics and treatment strategy.

Adjusted analyses showed no independent association between timing of detection and survival (early vs synchronous: adjusted HR 0.99; 95% CI 0.75–1.31; late vs synchronous: 0.80; 95% CI 0.58–1.08).

Instead, the strongest determinants of survival were the number of liver metastases, patient age and, most notably, receipt of local treatment.

Patients unable to undergo local treatment had a markedly higher risk of death (HR 3.12; 95% CI 2.40–4.05), while systemic therapy without subsequent local treatment was associated with an even greater hazard (HR 6.50; 95% CI 5.25–8.04).

Baseline characteristics varied significantly across timing groups. Patients with synchronous colorectal liver metastases had a higher tumour burden, including more lesions, larger tumours and higher carcinoembryonic antigen levels, compared with the early and late metachronous groups.

Tumour biology vs metastases detection timing

Some methodological challenges and limitations were evident, including immortal time bias when survival was measured from primary tumour diagnosis rather than liver metastasis detection.

Also, when OS was calculated from the primary diagnosis, survival differences between groups seemed more pronounced, highlighting the need to standardise analytical approaches.

Furthermore, the retrospective design and the combination of two diverse cohorts may have introduced selection bias and confounding due to treatment allocation, and improvements in imaging and therapy during the lengthy inclusion period might also have affected outcomes, the authors said.

Nevertheless, the findings suggested that the apparent prognostic disadvantage of synchronous metastases results from underlying tumour biology rather than the timing itself.

The authors also observed that synchronous disease might imply earlier systemic spread or more aggressive disease, although this distinction remains uncertain.

They further emphasised that treatment strategy – especially the ability to achieve local control – was the key factor in survival and concluded that tumour burden, molecular profile and treatment options should be prioritised over the timing of liver metastasis detection when making management decisions.

Reference
Kemna R et al. Time of detection of liver metastases and survival in patients with colorectal cancer. JAMA Netw Open 2026;9(3):e262088.