Resect first in resectable colorectal liver metastases: Recalibrating the default.

Perioperative chemotherapy is frequently used for resectable colorectal liver metastases (CRLM), despite persistent uncertainty regarding the extent of its survival benefit. This perspective revisits the evidence supporting this practice and asks whether upfront liver-directed treatment should be more strongly considered in selected patients. A central paradox underpins this debate: although adjuvant chemotherapy improves OS in stage III colon cancer, randomized trials in resectable CRLM have consistently failed to demonstrate an OS advantage for perioperative or adjuvant systemic therapy. Instead, chemotherapy primarily appears to delay recurrence while exposing patients to potential harms. These harms include treatment-related hepatic injury, increased perioperative morbidity, and, in some cases, progression during induction therapy that may preclude curative resection. Several explanations may account for this discrepancy, including clonal selection of resistant disease, the influence of the hepatic metastatic microenvironment, and the availability of salvage local therapy at recurrence. Nevertheless, systemic therapy remains relevant in selected patients with technically or biologically complex disease, such as those requiring staged liver surgery, downsizing for resectability, or treatment sequencing in synchronous primary and liver disease. Additionally, thermal ablation is emerging as a valid early liver-directed option for carefully selected small-volume metastases. Looking forward, circulating tumor DNA and other molecular tools may better identify the subgroup most likely to benefit from perioperative treatment. Treatment sequencing in resectable CRLM should therefore be guided by anatomy, tumour biology, and emerging molecular markers of residual risk, with systemic therapy used selectively rather than as a universal default.