Elevation of Pretreatment Carcinoembryonic Antigen Level as a Prognostic Factor for Colon Cancer: Incorporating a C Stage in the AJCC TNM Classification

Thirunavukarasu and colleagues1use data from theNational Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to determine whether preoperative serum carcinoembryonic antigen (CEA) status, dichotomized as elevated (C1) or normal (C0), can become a staging component in colon cancer, the C stage, akin to the more common T, N, M, R, and G stages. In their analysis, the authors reveal thatC1stage is independentlyassociatedwithoverall and disease-specific mortality. Of interest, this effect was strongenough thatupstaging couldoccur, ashappened forpatients with node-negative C1 disease who in some cases had worse outcomes than patients with node-positive C0 disease. These findings are potentially important and reinforce the long-standing2bodyofevidence thatelevation inCEA level can be a stage-independent prodrome of advanced disease. This finding is in line with earlier recommendations of the American Society of Clinical Oncology3 and the European Society for Medical Oncology,4 which call for the incorporation of pretreatment measurement of CEA levels into the standard of care. Even so, it remains crucial to view these findings in the context of SEER as its data source and consider its inherent limitations. This data set does not include the actual CEA values and does not use a cutoff value; rather, the database depends on reporting physician interpretation of what is considered elevated. This is understandable from a clinical practice perspective, where interpreting any laboratory value depends on patient characteristics, but it is obviously subject to error. The authors note that work5 that reports the exact numerical value of preoperative CEA levels was of little value for individual outcome prediction. This limitation leads to caution against presumptions that the prognostic value of CEA level thresholds implies that CEA levels can predict outcomes in a linear way. Consequently, whenever any continuous laboratory value is scrutinized as a potential prognostic factor, it remains preferable to have access to raw numerical data. Use of raw data eliminates individual judgment bias and permits defining a consistent threshold that can be objectively tested as a cutoff value. Use of raw data could also have avoided the concessions the authors had to make, such as having to exclude the borderline elevated CEA level category at the cost of likely exaggerating the contrast between the elevated and normal CEA level categories or the inability to numerically correct for influencers of serum CEA level, such as smoking status or liver disease. Nevertheless, the authors havedemonstrated that preoperative CEA level interpreted as elevated can be a poor prognostic factor across stages. However, if the C stage is to be incorporated into the American Joint Committee on Cancer (AJCC) staging system, there will need to be clearly defined thresholds with confounder mitigation. Once proposed, any cutoff valuewill need to be extensively validated in large, diverse populations using prospective data before we can conclude that they are universally applicable.