Perioperative treatment for colorectal cancer (CRC) is undergoing a paradigm shift from uniform cytotoxic regimens toward strategies guided by tumor location, microsatellite instability (MSI)/mismatch repair (MMR) status, and recurrence risk. Four clinically relevant subgroups now shape decision-making: microsatellite stable (MSS)/proficient MMR (pMMR) colon cancer, microsatellite instability-high (MSI-H)/deficient MMR (dMMR) colon cancer, MSS/pMMR rectal cancer, and MSI-H/dMMR rectal cancer. In MSS/pMMR colon cancer, adjuvant therapy is being refined through risk-adapted treatment duration and selective use of neoadjuvant chemotherapy. In MSS/pMMR rectal cancer, total neoadjuvant therapy, selective omission of pelvic radiotherapy, and watch-and-wait strategies are redefining treatment sequencing and organ preservation. In MSI-H/dMMR colon cancer, immune checkpoint inhibitor (ICI) therapy has shown marked activity in both adjuvant and neoadjuvant settings. In MSI-H/dMMR rectal cancer, neoadjuvant ICI therapy is being explored as a non-operative organ preservation strategy. In parallel, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assessment is emerging as a tool for postoperative escalation, de-escalation, and surveillance. Across these settings, the maturity of the evidence varies widely, ranging from established phase III standards to guideline-endorsed but still single-arm approaches and investigational strategies that require prospective validation before routine adoption. This review summarizes the current evidence and remaining challenges in biology-, site-, and risk-adapted perioperative management of CRC.

The emergence of novel cytotoxic agents, multikinase inhibitors, and various antibody-based therapies has significantly expanded salvage therapy options for metastatic colorectal cancer (mCRC). Consequently, establishing the optimal treatment sequence for patients has become a formidable clinical challenge. Emerging evidence highlights the value of comprehensive biomarker assessment, particularly longitudinal monitoring of circulating tumor DNA (ctDNA), to capture dynamic molecular changes during treatment. Liquid biopsy-based technologies now enable real-time tracking of molecular alterations, supporting truly personalized therapeutic decision-making. Furthermore, prior treatment exposure and residual toxicities must be carefully considered to balance efficacy, safety, and quality of life. This review provides a comprehensive overview of the current salvage-line landscape for mCRC, discusses the clinical utility of ctDNA as a predictive and prognostic tool, and proposes integrated strategies to optimize therapeutic outcomes in the evolving era of precision medicine.