Large Language Models in Colorectal Cancer Care and Clinical Decision Support: Systematic Review

Background: Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality worldwide. The complexity of guideline-concordant care and unstructured clinical data has driven demand for decision-support tools. Large language models (LLMs) show promise for processing clinical data and patient-provider communication, yet evidence is fragmented, and a CRC-specific synthesis across the full care continuum is lacking. Objective: This systematic review evaluates the current applications, performance determinants, and clinical implications of LLMs across the continuum of CRC care. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), we searched 6 databases (PubMed, Embase, Web of Science, Scopus, CINAHL, Cochrane) through April 1, 2026. Eligible studies were peer-reviewed original investigations of LLMs on CRC tasks with extractable outcomes; reviews, editorials, and abstracts were excluded. Two reviewers assessed quality with QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), PROBAST (prediction model risk of bias assessment tool), and ROBINS-I (Risk of Bias in Nonrandomized Studies - of Interventions). Data on model types, applications, prompts, input/output formats, and outcomes were analyzed descriptively, with narrative synthesis per synthesis without meta-analysis (SWiM) guidelines. Results: Of 8880 records, 37 studies met inclusion criteria (2023-2026), mostly from China and the United States, with GPT series most frequently evaluated. Overall risk of bias was low in 10/37 studies (27.0%), moderate in 14/37 (37.8%), unclear in 7/37 (18.9%), and high or serious in 6/37 (16.2%). Problematic domains included outcome measurement, intervention classification, patient selection, and lack of blinded assessment. LLMs showed utility in automating data extraction from clinical texts, supporting patient education, aiding diagnosis, and assisting clinical decision-making, with emerging visual interpretation and multimodal capacities. Domain-specific and multimodal models showed advantages over general-purpose models in certain tasks. Performance was significantly influenced by prompt design, from zero-shot queries to fine-tuning. Despite efficiency and outcome benefits, challenges persist regarding methodological quality, data privacy, and generalizability. Conclusions: This review provides an integrative framework synthesizing evidence across study designs and LLM categories in CRC care. Unlike prior reviews addressing gastroenterology broadly or limited to one design, it covers the full CRC continuum and, for the first time, comparatively evaluates general-purpose, domain-specific, and multimodal LLMs, clarifying how prompt engineering and heterogeneous metrics shape outcomes. Although findings support LLMs' clinical potential, results must be interpreted cautiously, given low overall evidence quality. Most studies lacked safeguards against bias-blinded assessment, confounder adjustment, or prospective multicenter validation. Substantial heterogeneity across tasks, LLM types, prompts, reference standards, and outcomes means reported advantages cannot be generalized. Future work should prioritize real-world integration via prospective multicenter validation, robust privacy frameworks, and rigorous human oversight. Amid rising global CRC burden and health care disparities, this review informs clinical translation, equitable scaling, and policy on LLM deployment.