Clinicopathological Features Associated With the High Risk of Recurrence of Stage II Colorectal Cancer: Variability Among Guidelines and Studies, and Potential Implications for Market Access

OBJECTIVES: High-risk recurrence status in patients with stage II colorectal cancer (CRC) is assessed based on various characteristics and is a key determinant of adjuvant therapy. This study aimed to analyse high-risk features (HRFs) defined in the guidelines applicable to stage II CRC and their use in research studies.

METHODS: A literature search was conducted to identify key European and US guidelines for CRC and compare them regarding HRFs in stage II disease. A similar analysis was conducted for clinical and observational studies in CRC patients with circulating DNA (ctDNA), a potential new marker of high-risk disease.

RESULTS: The European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines were analysed and demonstrated notable differences in their approach to HRFs in stage II CRC. The US guidelines included tumour budding and surgical margin, which were not mentioned in the European recommendations. Conversely, ESMO considered a high preoperative carcinoembryonic antigen (CEA) level an additional HRF, not included in the US documents. ESMO uniquely categorises HRFs into major and minor groups, which is not present in the US guidelines. Similar inconsistencies were found across 4 research studies including patients with stage II CRC and ctDNA. Key differences concerned consideration of mismatch-repair/microsatellite instability status, investigation of lymph nodes and several other HRFs.

CONCLUSIONS: Lack of a unified, international classification for high-risk stage II CRC may cause significant challenges for technology assessment and global market access strategies. The classification inconsistent with local guidelines or clinical practice could hamper the generalizability of studies and their indirect comparisons. Until valid and unambiguous markers are adopted to drive the classification, a mitigation strategy could include combinations of adaptive designs, large sample sizes with broad patient data collection, and advanced statistical methods, to allow various subgroup analyses and patients’ characteristics adjustments.